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What was the outcome of reaction 'Ventricular extrasystoles'? | Plasma concentration of amitriptyline and metabolites after resuscitation from cardiopulmonary arrest following an overdose: A case report.
It may need to pay attention to the sustention of moderate cardiotoxicity and delayed elevation of plasma 10-hydroxynortriptyline level in severe amitriptyline overdose case.
1 INTRODUCTION
In an amitriptyline (AT) overdose case with brief cardiopulmonary arrest, the concentrations of AT and metabolites were measured. Consequently, physiological damage by ischemic‐reperfusion was not suggested to affect disposition of AT and nortriptyline (NT). However, the level of 10‐hydroxynortriptyline (10‐OH‐NT) was belatedly elevated, suggested as a cause of sustention of moderate cardiotoxicity.
AT overdose is frequent among tricyclic antidepressants (TCA)‐related toxicities and more fatal than overdose of other antidepressants, including selective serotonin reuptake inhibitors and noradrenergic and specific serotonin antidepressants.
1
Followings are the pharmacological properties that are reported as toxic effects of TCA: (a) inhibition of norepinephrine reuptake at nerve terminals; (b) direct blockade of α‐adrenergic receptors; (c) membrane stabilizing or quinine‐like effect on the myocardium; and (d) anticholinergic action.
2
Based on these effects, a patient with AT toxicity manifests several clinical complications including sinus tachycardia, prolonged QRS/QTc duration, vasodilation, hypotension, cardiogenic shock, ventricular fibrillation/tachycardia, coma, drowsiness, delirium, respiratory depression, and others.
2
These symptoms are more likely to occur at total blood concentrations of AT and NT >1000 ng/mL or total concentrations of NT and 10‐OH‐NT >300 ng/mL.
3
,
4
,
5
Regarding TCA, plasma concentrations >450 ng/mL tend to show cognitive or behavioral toxicities
6
and >2000 or 3000 ng/mL are fatal,
7
,
8
though therapeutic range is from 50 to 300 ng/mL.
6
Therefore, blood concentrations of AT, NT, and 10‐OH‐NT may provide useful information in assessing the level of toxicity and in predicting subsequent clinical outcomes in patients following an AT overdose. In drug overdose cases, information regarding ingested dose is often sparse and thus a poor predictor of clinical outcome.
2
Therefore, blood concentration data for the drug in question is extremely valuable.
Cardiopulmonary arrest (CPA) sometimes occurs in AT overdose cases. The resuscitation following CPA is often accompanied with ischemic‐reperfusion, during which reactive oxygen species are derived, inflicting injury to living grafts or cells.
9
Injury to hepatocytes or intestinal tissues can result in dysfunctional or unusual protein expression of cytochrome P450 (CYP) 2C19 or CYP2D6, alteration of enterohepatic recirculation, or a dysfunctional elimination process, which can in turn affect the metabolism, distribution, and elimination of AT, NT, and 10‐OH‐NT, resulting in alterations in the overall disposition and pharmacokinetic profile.
10
These alterations in drug disposition may also change the occurrence of both, the onset and duration of clinical features of toxicity in patients. Nonetheless, the effect of CPA on subsequent drug disposition and its clinical effects are rarely investigated and reported, despite numerous reports of AT overdose.
3
,
11
,
12
In this report, we measured the blood levels of AT, NT, and 10‐OH‐NT and evaluated the influence of CPA on the pharmacokinetics of these compounds in a patient who had taken a severe overdose of AT. We also evaluated the decontamination effect of activated charcoal (AC) to evaluate its effects in cases such as this with CPA.
2 CASE DESCRIPTION
A 55‐year‐old man (weight, 70.1 kg) with impaired awareness was found by his roommate in a warm room in his own house and transferred to our hospital. Rescue crews found 280 empty pills of 25 mg AT [corresponding to a total amount of 7 g (99.8 mg/kg)] beside him. A urine‐screening test using a commercial test kit (Triage® DOA, Sysmex Corp., Kobe, Japan) indicated TCA presence. Additionally, concurrent use of chlorpromazine, duloxetine, rabeprazole, trazodone, zolpidem tartrate, nitrazepam, and magnesium oxide was suspected. However, there was no evidence of excessive ingestion of these drugs, and the patient did not present with toxicity relevant to these drugs. Considering these observations and following comprehensive clinical assessments, we suspected that he likely ingested a massive dose of AT. The elapsed time of ingestion of the overdose could not be exactly estimated because the patient's awareness was impaired and there was no information available about anyone who had contacted him during the 12‐hours period before he was found. The roommate told us that she found him in a coma 12 hours after her last contact with him. Unfortunately, we did not have any other means of knowing if he had any pre‐existing disorders, other than depression. His comorbidity and past medical history were not available. On admission, the Glasgow Coma Scale (GCS) score was 3 (E1; V1; M1); systolic/diastolic blood pressure, 101/62 mm Hg; oxygen saturation, 94%; body temperature, 38.7°C; heart rate, 120/min; respiration rate, 20/min; blood pH, 7.022; QTc interval, 610 ms; and QRS interval, 270 ms (Figure 1A). Other relevant clinical data are included in the supporting information (Table S1). Atrial fibrillation (AF) with ventricular aberration or premature ventricular contraction, complete right bundle branch block, escape rhythm, and abnormal T wave were observed on the electrocardiogram (ECG; Figure 1A).
Figure 1 Representative electrocardiograms obtained during hospitalization. (A) On admission; (B) 10 h later; (C) 12 h later; (D) 15 h later; (E) 60 h later; (F) 112 h later
Immediately after admission, a CPA following 10 seconds of clonus occurred, and 20 minutes later, he was resuscitated; however, his awareness remained impaired. The patient was thereafter intubated and treated for shock‐like hemodynamic status with the initiation of an infusion of 0.30 mg/h (approximately 0.07 μg/kg/min) of adrenaline, 0.60 mg/h of (approximately 0.14 μg/kg/min) of noradrenaline, and 15 mg/h (approximately 3.60 μg/kg/min) of dopamine. Totally, 1.1 mg/h (approximately 0.26 μg/kg/min) of adrenaline, 0.70 mg/h (approximately 0.17 μg/kg/min) of noradrenaline, and 30 mg/h (approximately 7.13 μg/kg/min) of dopamine were administered during the subsequent 11 hours period. The blood was alkalized by administering sodium bicarbonate (500 and 120 mL/d on the first and second hospital day, respectively). Additionally, 50 g of AC was repeatedly administered (five times in total) at 3, 14, 19, 27, and 35 hours after admission (Figure 1). Gastrointestinal decontamination other than AC administration was not conducted.
Approximately 15 hours after resuscitation from CPA, the drastically elongated QTc and QRS intervals were shortened to their near‐normal values (441 and 128 ms, respectively, Figure 1D), although their values remained near the upper limits of normal for several more hours. AF with ventricular aberration or premature ventricular contraction, nonspecific intraventricular conduction delay and temporal escape rhythm were also observed at some time point (Figure 1C,D). Clinical laboratory parameters of liver and renal function were elevated during the initial 10 hours; subsequently, the parameter values reduced (Figure S1). However, these values persistently remained at higher than normal levels, although there were no significant toxic effects observed. Approximately 60 hours after admission, the patient's awareness improved [GCS score of 14 (E4; V4; M6)]. The ECG showed the indications of sinus rhythm, although nonspecific intraventricular conduction delay was sometimes observed (Figure 1E). The creatinine clearance was almost normalized (approximately 80 mL/min) at 72 hours after admission. Nutritional provision was started with a small amount of enteral nutrition sometime after the end of catecholamine administration. During the 7th and 9th days of hospitalization, delirium was observed; however, the patient did not show any signed of orientation. ECG at 112 hours after admission indicated that sinus rhythm was maintained (Figure 1F), although premature ventricular contraction was infrequently observed. On the 10th day, he was transferred to the medical psychiatry unit. In the unit, the patient reported transient suicidal feelings that gradually dissipated. On the 23rd day, he was discharged.
The plasma concentrations of AT at 14, 45, and 131 hours after admission and those of NT and its hydroxyl metabolites at 45 and 131 hours after admission were measured by liquid chromatography‐tandem mass spectrometry (Figure 2). Both AT and NT concentrations decreased over time after resuscitation following CPA. In contrast, the concentration of 10‐OH‐NT increased during this period. The elimination half‐lives of AT and NT estimated after 45 hours of admission were approximately 35 and 89 hours, respectively.
Figure 2 Time profiles of plasma levels of AT and its metabolites, QTc, QRS, heart rate, creatinine clearance, and blood pressure during the monitoring interval. AT, amitriptyline; NT, nortriptyline; 10‐OH‐NT, 10‐hydroxynortriptyline; HR, heart rate; Ccr, creatinine clearance; NIBP, noninvasive blood pressure. The black‐filled arrows under the x‐axis in top panel indicate AC administration at 3, 14, 19, 27, and 35 h after admission. The shaded area means the one above toxic concentration
3 DISCUSSION
In this overdose case with AT, AC was repeatedly administered (five times in total), following resuscitation 20 minutes after CPA. The subsequent concentration levels of AT were, then, reduced compared to the initial concentration. The repeated AC administration can complex with the TCA (doxepin) released following gradual disaggregation of the complex of doxepin with initially administered AC, thus suppressing the subsequent absorption of parent drug and metabolites secreted into the gastrointestinal tract.
13
This study also reported the repeated dosing effect of AC was observed despite the delay of three or more hours in AC administration following doxepin dosing. Although the delay between AT ingestion and AC initiation could not be confirmed in our case report, the initial measured concentration of AT (ie, 1031 ng/mL) was reduced after the repetitive AC administration. Thus, repeated AC administration and/or the clearance of the drug from the patient's system may have contributed to the reduction of AT concentrations. However, the reduction in AT concentrations between 14 and 45 hours after admission was extremely low (only 55 ng/mL). Additionally, the elimination half‐life estimated from this reduction was approximately 390 hours, while another study on AT overdose patients reported a half‐life of <10 hours when patients were treated with repeated AC administration.
14
There are several possible reasons for the discrepancy and slight reduction of AT concentration, including interruption of patient's individual drug clearance because of cellular damage by ischemic‐reperfusion; saturation of metabolic enzymes by the excessive amount of AT ingested; poor metabolism due to genetic polymorphism in CYP2C19 and CYP2D6, or anticholinergic suppression of elimination by AT and NT. Although it is unclear how the repeated AC administration and patient's clearance system effectively functioned, they may have at least partly contributed to the reduction of AT concentration. Thus, the further increase of the subsequent AT concentration would have not been shown. The repeated AC administration may have functioned as suppressing the elevation of peak concentration of AT, rather than accelerating the elimination process. Repetitive AC may have suppressed the potential increase in AT levels that could occur if the complex formed with the initial dose of AC is disaggregated. Additionally, AC may have also prevented the subsequent absorption/reabsorption of AT and its metabolites following their secretions into the gastrointestinal tract, as AT has been known to undergo enterohepatic circulation.
14
While further studies are needed, we suggest that repeated AC administration is a possible optional treatment in severe cases of AT overdose, even if CPA is presented and several hours have elapsed from the time of overdose.
A significant shortening of QRS interval from 124 to 110 ms was observed after approximately 72 hours from admission. Simultaneously, the total concentrations of AT and NT were estimated to be below the toxic range (total of 1000 ng/mL), suggesting the importance of monitoring the total concentrations of AT and NT in AT overdose cases. However, despite the reduction in total concentrations of AT and NT to less than toxic levels at 110 hours after admission, QTc and QRS intervals remained relatively high values. The QRS interval, particularly, did not fall below the upper limit of normal (100 ms). In parallel with these cardiac effects, elevation of the concentration of 10‐OH‐NT was observed, although the creatinine clearance recovered to a normal level, suggesting that 10‐OH‐NT elimination was not impaired.
15
A previous study demonstrates the cardiotoxic potential of 10‐OH‐NT, although it was less toxic than NT.
16
Additionally, the total concentrations of 10‐E‐hydroxynortriptyline and NT of > 300 ng/mL were associated with QRS prolongation.
4
Therefore, we speculated that the high levels of 10‐OH‐NT may have contributed to this sustained prolonged QTc and QRS intervals. Several factors may have contributed to the delayed elevation of 10‐OH‐NT concentration. One of these may be the genetic polymorphism in CYP2C19 and CYP2D6. Then, we estimated the phenotype of our patient, based on previous reports by Mifsud et al and Franssen et al, although the cases reported by Mifsud et al were treated with a normal dose (10 mg daily) of AT.
12
,
17
In a case with a “normal phenotype” of both CYP2C19 and CYP2D6 (ie, case example III in the report by Mifsud et al), the metabolite‐to‐parent rate (MPR; ie, NT/AT) was reported as 0.4. On the other hand, the case with concomitant use of only CYP2C19 inhibitor (ie, omeprazole) but with normal phenotype in both CYP2C19 and CYP2D6 showed the MPR as 0.2. However, another case with “normal phenotype'” in CYP2C19 and CYP2D6 (ie, case example V in the report of Mifsud et al) and concomitant use of inhibitors for CYP2C19 and CYP2D6 (omeprazole and paroxetine, respectively) indicated an MPR as 0.7, which was close to the MPR of our case (calculated as approximately 0.6). AT itself has an inhibitory effect on both CYP2C19 and CYP2D6, although CYP2D6 inhibition is reported to be clinically insignificant at a normal dose.
6
However, in the current case, a massive dose of AT was ingested, suggesting that the inhibitory effect on CYP2D6 may have somewhat functioned. In addition, considering the similarity of MPR between ours (approximately 0.6) and case's mentioned above (0.7), in which the patient had normal phenotype but was concomitantly administered with inhibitors for CYP2C19 and CYP2D6, our patient may also have possessed a normal phenotype and hers CYP2C19 and CYP2D6 may have somewhat inhibited due to the extremely high dose of AT. We also considered the possibility that the patient was a rapid metabolizer of CYP2C19, and this rapid activity was suppressed to normal levels due to the inhibitory effect of the large amount of AT ingested. However, as shown in case example I reported by Mifsud et al, the rapid metabolizer of CYP2C19 indicated a high MPR of 2.0, despite receiving a concurrent CYP2C19 inhibitor (ie, omeprazole). Therefore, with regard to CYP2C19, our patient (with MPR of 0.6) was not considered to correspond to a rapid metabolizer. Regarding CYP2D6, we focused on the ratio of 10‐OH‐NT/NT. In our case study, the ratio was calculated to be approximately 1.4 at 45 hours after admission, which was relatively close to the estimated one in case example III (approximately 3.5) and example IV (approximately 2.0) in the report by Mifsud et al
17
In these two cases, the CYP2D6 and CYP2C19 phenotypes both identified as normal, although the case example IV concomitantly received a CYP2C19 inhibitor (omeprazole). Another case (case example V in the report by Mifsud et al) with concurrent use of CYP2D6 inhibitor (paroxetine) indicated a lower 10‐OH‐NT/NT ratio (approximately 0.3), while a different case with ultra‐rapid metabolism in CYP2D6 indicated a higher 10‐OH‐NT/NT ratio (approximately 8.0). These estimates were far from the 10‐OH‐NT/NT ratio in our patient. Taken together, our analysis indicates that the patient may have possessed a “normal phenotype” in CYP2D6 as well. Levels of AT and its metabolite (ie, NT) following AT overdose may inhibit both CYP2C19 and CYP2D6 in the initial phase. Then, as concentrations of AT and NT decreased with time, the inhibitory effects on CYP may have gradually weakened, while concentrations of 10‐OH‐NT may have been elevated in a delayed manner. Besides, other factors including saturation of metabolic enzymes, dysfunction of metabolic enzymes or elimination systems by ischemic‐reperfusion damage, insufficient alkalization of urine or anticholinergic effect of AT, might have contributed in a complex manner to the delayed elevation of 10‐OH‐NT levels. Although some potential drugs that inhibit CYP2C19 (ie, duloxetine and chlorpromazine) seemed to have been prescribed, their inhibitory effects can be ignored because there was no evidence of their massive ingestion, and the patient did not present relevant toxic effects. The delayed elevation of 10‐OH‐NT levels over 100 hours after admission was also indicated in a fatal case with AT overdose by Franssen et al,
12
supporting our finding. Monitoring the level of 10‐OH‐NT may also be favorable, if possible, in severe AT overdose cases because it has toxic effects on cardiac function and its concentration can be elevated in later.
In this case report, the elimination half‐life of AT and NT was calculated to be approximately 34 and 88 hours, respectively, from the levels measured at 45 and 131 hours. A previous study reported that the elimination half‐lives of nine cases with AT overdose ranged from 15 to 43 hours in patients treated with gastric lavage and 50 g of AC.
18
Even at normal doses, the elimination half‐life of AT is reported to range from 10 to 46 hours.
6
The elimination half‐life of AT (ie, 45 hours) in our patient was approximately same with the ones reported. For NT in the case with normal dose, elimination half‐life has been reported to range from 13 to 90 hours, although shorter in ultra‐metabolizers (13‐35 hours).
6
A case of NT overdose reported an elimination half‐life of 50 hours based on levels measured from 50 to 110 hours after admission,
12
whereas another case showed a half‐life of 184 hours and sustained elevated levels of NT (468 ng/mL) until 6 days after admission.
19
Although both previous overdose cases were not treated with AC, the elimination half‐life of NT (ie, 88 hours) in our patient treated with AC was compatible with the reported ones. The elimination half‐life of 10‐OH‐NT could not be calculated in this study because its elimination phase was not observed during our evaluation period, although its half‐life has been reported to be approximately 8‐10 hours.
20
Thus, taken these, the damage, possibly induced by ischemic‐reperfusion, would have not induced any meaningful anomalous effect on the disposition of AT or NT, despite physiological damage was suspected by the sustained elevation of lactate dehydrogenase (Figure S1).
21
,
22
As long as CPA is recovered within approximately 20 minutes, as seen in our study, and appropriate treatment is provided, a patient with AT/NT overdose can survive and be managed clinically.
4 CONCLUSION
It would be desired to monitor not only the concentration of AT and NT but also those of its hydroxyl metabolites, especially in severe AT/NT overdose because 10‐OH‐NT has toxic effects on cardiac function and its blood concentration can increase behind the reduction of AT and NT concentrations. Although further studies are needed, repeated AC administration may be a possible optional treatment in severe cases of AT overdose, even after several hours have elapsed from overdose. If the patient experiences CPA, as long as appropriate treatment is provided, AT/NT‐poisoned patient can survivable and may be clinically managed like a typical AT/NT overdose case. These experiences would be beneficial for other workers if they encounter a similar AT overdose case with CPA.
CONFLICT OF INTEREST
No conflicts of interest have been declared.
AUTHORS’ CONTRIBUTION
MA, RT, and ST measured the concentrations of amitriptyline, nortriptyline, and 10‐hydroxynortriptyline and evaluated their relationship with the patient's clinical outcome. MY, KS, and MS provided technical support in quantification by a validated method. KA provided several useful medical considerations as an emergency physician. RT and SN provided several useful pharmaceutical considerations as pharmacists engaged in the treatment of this patient. SF, NS, and TH provided helpful guidance and pharmacokinetic expertise in the area of pharmaceutical sciences. All authors have read and approved the final manuscript.
ETHICAL APPROVAL
Through the provision of a chance to opt‐out, the study and reporting were approved by the ethics review board of our hospital (Approval #: k181033).
Supporting information
Supinfo
Click here for additional data file.
ACKNOWLEDGMENTS
We would like to thank Editage (www.editage.com) for English language editing. Published with written consent of the patient.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request. | Not recovered | ReactionOutcome | CC BY-NC-ND | 33598249 | 18,711,570 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug reaction with eosinophilia and systemic symptoms'. | Chronic persistent HHV-6B infection after sulfasalazine-induced DRESS with demonstration of HHV-6 encoded small noncoding RNAs (sncRNAs) in Crohn's-like colitis: Case report.
A sulfasalazine-induced DRESS (Drug Reactivation with Eosinophilia and Systemic Symptoms) was complicated by a Crohn's-like colitis. We demonstrated HHV-6 reactivation with presence of HHV-6 DNA and small noncoding RNA in colonic lesions. This observation confirms the major role of HHV-6 reactivation in DRESS manifestations and the importance of looking for HHV-6 reactivation in DRESS.
1 INTRODUCTION
Drug reaction with eosinophilia and systemic symptoms (DRESS), also referred to as drug‐induced hypersensitivity syndrome (DIHS), is a severe hypersensitivity drug reaction associating skin eruption and organ involvement. We report a 32‐year‐old man with sulfasalazine‐induced DRESS with reactivation of human herpesvirus 6B (HHV‐6B). His case is remarkable because he had chronic persistent HHV‐6 infection with colonic infection and development of Crohn's disease.
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug hypersensitivity syndrome.
1
,
2
The pathophysiology of this syndrome is not fully understood, but human herpesvirus 6 (HHV‐6) reactivation plays a major role in its development.
1
,
2
,
3
,
4
In most cases, duration of HHV‐6 reactivation is limited.
We report a typical case of sulfasalazine‐induced DRESS with reactivation of HHV‐6B in a patient with spondyloarthritis who developed a Crohn's‐like colitis after DRESS. We demonstrated a chronic persistent HHV‐6 infection with the presence of HHV‐6 DNA and encoded small noncoding RNA (sncRNA) in colonic lesions.
2 CASE REPORT
A 32‐year‐old man was treated for axial and peripheral spondyloarthritis by sulfasalazine without any symptom suggestive of Crohn's disease. He presented 3 weeks after the beginning of sulfasalazine on August 2009 with exanthema, facial edema, high fever, and diffuse lymphadenopathy. The first blood tests confirmed an eosinophilia (3200 cells/µL), a mononucleosis syndrome with atypical lymphocytes and an hepatitis with a drop of prothrombin ratio to 65%. He subsequently developed pneumonitis and colitis. A diagnosis of sulfasalazine‐induced DRESS was made, and sulfasalazine was discontinued. The patient was treated by intravenous methylprednisolone and intravenous immunoglobulins. Intravenous corticosteroids were changed for oral prednisone (1 mg/kg/d). Visceral manifestations progressively improved. HHV‐6B viral load in whole blood was at a high level (23 495 gec/M cells).
5
,
6
,
7
Epstein‐Barr virus and cytomegalovirus viral loads measured by PCR remained negative.
Corticosteroids were progressively tapered within 6‐month period, and HHV‐6 viral load was monitored. The patient developed diarrhea with bloody bowel movement. On February 2010, HHV‐6 viral load was high at 32 737 gec/M cells (genomic DNA per million cells). Endoscopy examination and colonic biopsy demonstrated clinical and microscopic features of Crohn's disease (Figure 1). HHV‐6B DNA PCR was positive in colonic biopsy (1808 gec/M cells) with high levels of virus encoded sncRNAs (Figure 2). Antivirals were started with a monitoring of HHV‐6 viremia. The patient was treated by 14 days of ganciclovir. The whole blood viral load decreased from 7051 to 3675 gec/M cells. HHV‐6 DNA test was negative in hair follicles. The colitis manifestations resolved. Cidofovir treatment was proposed for the treatment of this persistent HHV‐6 infection. He received six infusions of 400 mg each without significant effect on HHV‐6 viral load (3934 gec/M cells). Six months later, on February 2011, it remained 8061 gec/M cells. Colitis manifestations resumed, and a new endoscopy confirmed luminal stenosis of the transverse colon. At that time, a treatment with TNF alpha blocker (adalimumab) was started. After 8‐year treatment with adalimumab, HHV‐6 viral load in whole blood remained stable at 905‐1084 gec/M cells. The patient did not develop any flare of DRESS. The Crohn's‐like colitis was under control.
FIGURE 1 Histological examination of a biopsy of large intestine. A, Hematein eosin saffron: original magnification x 5: The mucosa contains a dense inflammatory infiltrate with focal crypt architectural distortion. B, Hematein eosin saffron: original magnification x 200: A focal active colitis with crypt abscess formation (star) and numerous lymphocytes and eosinophils (arrow)
FIGURE 2 Demonstration of transcription of HHV‐6 encoded sncRNA‐U14 in colon (the study was done on 2019 on stored biopsy samples from 2010). A, Detection of HHV‐6 encoded sncRNA‐U14 in the colonic biopsy of the DRESS patient. FFPE colonic tissue biopsies were used for the analysis. Three different representative images from different regions of the tissue have been shown. Imaging was done using an epifluorescence microscope. The scale bars represent 100 m. B, Detection of HHV‐6 encoded sncRNA‐U14 in HHV‐6 negative colonic biopsy. Two representative images are shown from different regions of a single biopsy. C, Detection of sncRNA‐U14 by FISH in various in vivo cell types. HHV‐6A infected HSB‐2 cells were used as positive control for sncRNA‐U14 FISH analysis. Uninfected HSB‐2 cells were used as negative control. Human small RNA U6 was used as a FISH positive control. At the same time, a scrambled small RNA probe was used as a FISH negative control. Imaging was done on a SP5 confocal microscope. The scale bars represent 100 m
Subsequently, the cellular localization of HHV‐6 genome in leukocyte subpopulations was studied by flow cytometry and PCR because the patient had an unusual persistent HHV‐6 infection after DRESS. HHV‐6 DNA was present only in T lymphocytes fraction with 1212 gec/M cells and was absent from all other fractions (B lymphocytes, monocytes, NK cells, polymorphonuclear cells). Apart from this high HHV‐6 load, the patient had no clinical manifestation and all biological tests were normal.
3 DISCUSSION
This case illustrates a severe case of sulfasalazine‐induced DRESS with Regiscar criteria score of 7 having reactivation of HHV‐6B.
9
HHV‐6 is a lymphotropic virus that predominantly infects T‐cell lymphocyte. It possesses telomere‐like repeats at the terminal regions of its genome that facilitate latency by a unique mechanism of viral latency, integration into the host telomeres, rather than by episome formation. HHV‐6 reactivation plays a major role in DRESS syndrome.
This observation is of great interest because the patient had a persistent HHV‐6 infection after DRESS and developed a Crohn's‐like colitis. Relapsing course of DRESS is usual, and flares are frequently associated with short duration HHV‐6 reactivations.
1
,
4
In this case, HHV‐6 was regularly detected even a long time after DRESS. Persistent HHV‐6 infection was confirmed by a high level of viral DNA in whole blood but HHV‐6B being present only in T lymphocytes. The viral loads below 6 log gec/M cells and negative in hair follicles excluded the presence of inherited chromosomally integrated HHV‐6. Miyagawa et al recently reported 3 cases of DRESS in which HHV‐6 DNA was detected mainly in peripheral T lymphocytes long after resolution of DRESS (until 700 days with HHV‐6 viral DNA up to 3 log copies/million cells).
10
The major point in our case was the demonstration of HHV‐6‐induced colitis. High HHV‐6 DNA load and more interestingly a very high level of viral sncRNA confirmed HHV‐6 reactivation in colon (Figure 1, 2). Antiviral drugs induced a control of colitis symptoms but did not significantly decrease HHV‐6 viral load in whole blood. It may be possible that the antiviral treatment controlled HHV‐6 DNA replication that marks classical active viral infection. However, transient viral reactivation characterized by transcription of HHV‐6 sncRNA‐U14, in the absence of viral DNA replication, cannot be controlled by current antiherpesvirus drugs that target only the viral DNA replication.
8
The residual HHV‐6 viral load possibly represents a latent HHV‐6 infection that can persist as episomal or integrated form in T lymphocytes and other cells.
Crohn's disease and more globally inflammatory bowed diseases may be associated with spondylarthritis and stay silent for a long time. Crohn's disease has not been reported as a consequence of DRESS. Patient with Crohn's disease is at risk for the development of DRESS because they are frequently treated by sulfasalazine or azathrioprine which are well known inducers of DRESS. A previous control study did not find evidence of HHV‐6 infection in patients with Crohn's disease as compared to the controls.
11
In another study HHV‐6B antigen positivity and intensity of immunohistochemistry correlated with endoscopy severity of Crohn's disease.
12
We postulate that HHV‐6 could trigger a previous asymptomatic Crohn's disease. In our patient, the Crohn's disease remained and was subsequently treated by TNF alpha blocker without any relapse of DRESS.
4 CONCLUSION
Through this case report, we would like to emphasize on the advantage of new tools (demonstration of HHV6 sncRNA in tissue sample) for the diagnosis of HHV‐6 reactivation.
CONFLICT OF INTEREST
The authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
DV: involved in the diagnosis and care of the patient and wrote the manuscript. GDA: involved in the virological tests and their interpretation. PAL: involved in the diagnosis and care of the patient. BP: involved in the virological tests and their interpretation. DL: performed the pathological analysis. PBK: performed the HHV‐6 snc‐RNA study and its interpretation. All authors: involved in the critical revision and final approval of the manuscript.
ETHICAL APPROVAL
The article describes a case report. Therefore, no additional permission from our Ethics Committee was required.
ACKNOWLEDGMENTS
Informed consent was obtained for this case.
DATA AVAILABILITY STATEMENT
All data that support the findings of this study are included in this case report. Details are available on request from the corresponding author. | SULFASALAZINE | DrugsGivenReaction | CC BY-NC-ND | 33598255 | 18,874,347 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Face oedema'. | Chronic persistent HHV-6B infection after sulfasalazine-induced DRESS with demonstration of HHV-6 encoded small noncoding RNAs (sncRNAs) in Crohn's-like colitis: Case report.
A sulfasalazine-induced DRESS (Drug Reactivation with Eosinophilia and Systemic Symptoms) was complicated by a Crohn's-like colitis. We demonstrated HHV-6 reactivation with presence of HHV-6 DNA and small noncoding RNA in colonic lesions. This observation confirms the major role of HHV-6 reactivation in DRESS manifestations and the importance of looking for HHV-6 reactivation in DRESS.
1 INTRODUCTION
Drug reaction with eosinophilia and systemic symptoms (DRESS), also referred to as drug‐induced hypersensitivity syndrome (DIHS), is a severe hypersensitivity drug reaction associating skin eruption and organ involvement. We report a 32‐year‐old man with sulfasalazine‐induced DRESS with reactivation of human herpesvirus 6B (HHV‐6B). His case is remarkable because he had chronic persistent HHV‐6 infection with colonic infection and development of Crohn's disease.
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug hypersensitivity syndrome.
1
,
2
The pathophysiology of this syndrome is not fully understood, but human herpesvirus 6 (HHV‐6) reactivation plays a major role in its development.
1
,
2
,
3
,
4
In most cases, duration of HHV‐6 reactivation is limited.
We report a typical case of sulfasalazine‐induced DRESS with reactivation of HHV‐6B in a patient with spondyloarthritis who developed a Crohn's‐like colitis after DRESS. We demonstrated a chronic persistent HHV‐6 infection with the presence of HHV‐6 DNA and encoded small noncoding RNA (sncRNA) in colonic lesions.
2 CASE REPORT
A 32‐year‐old man was treated for axial and peripheral spondyloarthritis by sulfasalazine without any symptom suggestive of Crohn's disease. He presented 3 weeks after the beginning of sulfasalazine on August 2009 with exanthema, facial edema, high fever, and diffuse lymphadenopathy. The first blood tests confirmed an eosinophilia (3200 cells/µL), a mononucleosis syndrome with atypical lymphocytes and an hepatitis with a drop of prothrombin ratio to 65%. He subsequently developed pneumonitis and colitis. A diagnosis of sulfasalazine‐induced DRESS was made, and sulfasalazine was discontinued. The patient was treated by intravenous methylprednisolone and intravenous immunoglobulins. Intravenous corticosteroids were changed for oral prednisone (1 mg/kg/d). Visceral manifestations progressively improved. HHV‐6B viral load in whole blood was at a high level (23 495 gec/M cells).
5
,
6
,
7
Epstein‐Barr virus and cytomegalovirus viral loads measured by PCR remained negative.
Corticosteroids were progressively tapered within 6‐month period, and HHV‐6 viral load was monitored. The patient developed diarrhea with bloody bowel movement. On February 2010, HHV‐6 viral load was high at 32 737 gec/M cells (genomic DNA per million cells). Endoscopy examination and colonic biopsy demonstrated clinical and microscopic features of Crohn's disease (Figure 1). HHV‐6B DNA PCR was positive in colonic biopsy (1808 gec/M cells) with high levels of virus encoded sncRNAs (Figure 2). Antivirals were started with a monitoring of HHV‐6 viremia. The patient was treated by 14 days of ganciclovir. The whole blood viral load decreased from 7051 to 3675 gec/M cells. HHV‐6 DNA test was negative in hair follicles. The colitis manifestations resolved. Cidofovir treatment was proposed for the treatment of this persistent HHV‐6 infection. He received six infusions of 400 mg each without significant effect on HHV‐6 viral load (3934 gec/M cells). Six months later, on February 2011, it remained 8061 gec/M cells. Colitis manifestations resumed, and a new endoscopy confirmed luminal stenosis of the transverse colon. At that time, a treatment with TNF alpha blocker (adalimumab) was started. After 8‐year treatment with adalimumab, HHV‐6 viral load in whole blood remained stable at 905‐1084 gec/M cells. The patient did not develop any flare of DRESS. The Crohn's‐like colitis was under control.
FIGURE 1 Histological examination of a biopsy of large intestine. A, Hematein eosin saffron: original magnification x 5: The mucosa contains a dense inflammatory infiltrate with focal crypt architectural distortion. B, Hematein eosin saffron: original magnification x 200: A focal active colitis with crypt abscess formation (star) and numerous lymphocytes and eosinophils (arrow)
FIGURE 2 Demonstration of transcription of HHV‐6 encoded sncRNA‐U14 in colon (the study was done on 2019 on stored biopsy samples from 2010). A, Detection of HHV‐6 encoded sncRNA‐U14 in the colonic biopsy of the DRESS patient. FFPE colonic tissue biopsies were used for the analysis. Three different representative images from different regions of the tissue have been shown. Imaging was done using an epifluorescence microscope. The scale bars represent 100 m. B, Detection of HHV‐6 encoded sncRNA‐U14 in HHV‐6 negative colonic biopsy. Two representative images are shown from different regions of a single biopsy. C, Detection of sncRNA‐U14 by FISH in various in vivo cell types. HHV‐6A infected HSB‐2 cells were used as positive control for sncRNA‐U14 FISH analysis. Uninfected HSB‐2 cells were used as negative control. Human small RNA U6 was used as a FISH positive control. At the same time, a scrambled small RNA probe was used as a FISH negative control. Imaging was done on a SP5 confocal microscope. The scale bars represent 100 m
Subsequently, the cellular localization of HHV‐6 genome in leukocyte subpopulations was studied by flow cytometry and PCR because the patient had an unusual persistent HHV‐6 infection after DRESS. HHV‐6 DNA was present only in T lymphocytes fraction with 1212 gec/M cells and was absent from all other fractions (B lymphocytes, monocytes, NK cells, polymorphonuclear cells). Apart from this high HHV‐6 load, the patient had no clinical manifestation and all biological tests were normal.
3 DISCUSSION
This case illustrates a severe case of sulfasalazine‐induced DRESS with Regiscar criteria score of 7 having reactivation of HHV‐6B.
9
HHV‐6 is a lymphotropic virus that predominantly infects T‐cell lymphocyte. It possesses telomere‐like repeats at the terminal regions of its genome that facilitate latency by a unique mechanism of viral latency, integration into the host telomeres, rather than by episome formation. HHV‐6 reactivation plays a major role in DRESS syndrome.
This observation is of great interest because the patient had a persistent HHV‐6 infection after DRESS and developed a Crohn's‐like colitis. Relapsing course of DRESS is usual, and flares are frequently associated with short duration HHV‐6 reactivations.
1
,
4
In this case, HHV‐6 was regularly detected even a long time after DRESS. Persistent HHV‐6 infection was confirmed by a high level of viral DNA in whole blood but HHV‐6B being present only in T lymphocytes. The viral loads below 6 log gec/M cells and negative in hair follicles excluded the presence of inherited chromosomally integrated HHV‐6. Miyagawa et al recently reported 3 cases of DRESS in which HHV‐6 DNA was detected mainly in peripheral T lymphocytes long after resolution of DRESS (until 700 days with HHV‐6 viral DNA up to 3 log copies/million cells).
10
The major point in our case was the demonstration of HHV‐6‐induced colitis. High HHV‐6 DNA load and more interestingly a very high level of viral sncRNA confirmed HHV‐6 reactivation in colon (Figure 1, 2). Antiviral drugs induced a control of colitis symptoms but did not significantly decrease HHV‐6 viral load in whole blood. It may be possible that the antiviral treatment controlled HHV‐6 DNA replication that marks classical active viral infection. However, transient viral reactivation characterized by transcription of HHV‐6 sncRNA‐U14, in the absence of viral DNA replication, cannot be controlled by current antiherpesvirus drugs that target only the viral DNA replication.
8
The residual HHV‐6 viral load possibly represents a latent HHV‐6 infection that can persist as episomal or integrated form in T lymphocytes and other cells.
Crohn's disease and more globally inflammatory bowed diseases may be associated with spondylarthritis and stay silent for a long time. Crohn's disease has not been reported as a consequence of DRESS. Patient with Crohn's disease is at risk for the development of DRESS because they are frequently treated by sulfasalazine or azathrioprine which are well known inducers of DRESS. A previous control study did not find evidence of HHV‐6 infection in patients with Crohn's disease as compared to the controls.
11
In another study HHV‐6B antigen positivity and intensity of immunohistochemistry correlated with endoscopy severity of Crohn's disease.
12
We postulate that HHV‐6 could trigger a previous asymptomatic Crohn's disease. In our patient, the Crohn's disease remained and was subsequently treated by TNF alpha blocker without any relapse of DRESS.
4 CONCLUSION
Through this case report, we would like to emphasize on the advantage of new tools (demonstration of HHV6 sncRNA in tissue sample) for the diagnosis of HHV‐6 reactivation.
CONFLICT OF INTEREST
The authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
DV: involved in the diagnosis and care of the patient and wrote the manuscript. GDA: involved in the virological tests and their interpretation. PAL: involved in the diagnosis and care of the patient. BP: involved in the virological tests and their interpretation. DL: performed the pathological analysis. PBK: performed the HHV‐6 snc‐RNA study and its interpretation. All authors: involved in the critical revision and final approval of the manuscript.
ETHICAL APPROVAL
The article describes a case report. Therefore, no additional permission from our Ethics Committee was required.
ACKNOWLEDGMENTS
Informed consent was obtained for this case.
DATA AVAILABILITY STATEMENT
All data that support the findings of this study are included in this case report. Details are available on request from the corresponding author. | SULFASALAZINE | DrugsGivenReaction | CC BY-NC-ND | 33598255 | 18,874,347 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatitis'. | Chronic persistent HHV-6B infection after sulfasalazine-induced DRESS with demonstration of HHV-6 encoded small noncoding RNAs (sncRNAs) in Crohn's-like colitis: Case report.
A sulfasalazine-induced DRESS (Drug Reactivation with Eosinophilia and Systemic Symptoms) was complicated by a Crohn's-like colitis. We demonstrated HHV-6 reactivation with presence of HHV-6 DNA and small noncoding RNA in colonic lesions. This observation confirms the major role of HHV-6 reactivation in DRESS manifestations and the importance of looking for HHV-6 reactivation in DRESS.
1 INTRODUCTION
Drug reaction with eosinophilia and systemic symptoms (DRESS), also referred to as drug‐induced hypersensitivity syndrome (DIHS), is a severe hypersensitivity drug reaction associating skin eruption and organ involvement. We report a 32‐year‐old man with sulfasalazine‐induced DRESS with reactivation of human herpesvirus 6B (HHV‐6B). His case is remarkable because he had chronic persistent HHV‐6 infection with colonic infection and development of Crohn's disease.
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug hypersensitivity syndrome.
1
,
2
The pathophysiology of this syndrome is not fully understood, but human herpesvirus 6 (HHV‐6) reactivation plays a major role in its development.
1
,
2
,
3
,
4
In most cases, duration of HHV‐6 reactivation is limited.
We report a typical case of sulfasalazine‐induced DRESS with reactivation of HHV‐6B in a patient with spondyloarthritis who developed a Crohn's‐like colitis after DRESS. We demonstrated a chronic persistent HHV‐6 infection with the presence of HHV‐6 DNA and encoded small noncoding RNA (sncRNA) in colonic lesions.
2 CASE REPORT
A 32‐year‐old man was treated for axial and peripheral spondyloarthritis by sulfasalazine without any symptom suggestive of Crohn's disease. He presented 3 weeks after the beginning of sulfasalazine on August 2009 with exanthema, facial edema, high fever, and diffuse lymphadenopathy. The first blood tests confirmed an eosinophilia (3200 cells/µL), a mononucleosis syndrome with atypical lymphocytes and an hepatitis with a drop of prothrombin ratio to 65%. He subsequently developed pneumonitis and colitis. A diagnosis of sulfasalazine‐induced DRESS was made, and sulfasalazine was discontinued. The patient was treated by intravenous methylprednisolone and intravenous immunoglobulins. Intravenous corticosteroids were changed for oral prednisone (1 mg/kg/d). Visceral manifestations progressively improved. HHV‐6B viral load in whole blood was at a high level (23 495 gec/M cells).
5
,
6
,
7
Epstein‐Barr virus and cytomegalovirus viral loads measured by PCR remained negative.
Corticosteroids were progressively tapered within 6‐month period, and HHV‐6 viral load was monitored. The patient developed diarrhea with bloody bowel movement. On February 2010, HHV‐6 viral load was high at 32 737 gec/M cells (genomic DNA per million cells). Endoscopy examination and colonic biopsy demonstrated clinical and microscopic features of Crohn's disease (Figure 1). HHV‐6B DNA PCR was positive in colonic biopsy (1808 gec/M cells) with high levels of virus encoded sncRNAs (Figure 2). Antivirals were started with a monitoring of HHV‐6 viremia. The patient was treated by 14 days of ganciclovir. The whole blood viral load decreased from 7051 to 3675 gec/M cells. HHV‐6 DNA test was negative in hair follicles. The colitis manifestations resolved. Cidofovir treatment was proposed for the treatment of this persistent HHV‐6 infection. He received six infusions of 400 mg each without significant effect on HHV‐6 viral load (3934 gec/M cells). Six months later, on February 2011, it remained 8061 gec/M cells. Colitis manifestations resumed, and a new endoscopy confirmed luminal stenosis of the transverse colon. At that time, a treatment with TNF alpha blocker (adalimumab) was started. After 8‐year treatment with adalimumab, HHV‐6 viral load in whole blood remained stable at 905‐1084 gec/M cells. The patient did not develop any flare of DRESS. The Crohn's‐like colitis was under control.
FIGURE 1 Histological examination of a biopsy of large intestine. A, Hematein eosin saffron: original magnification x 5: The mucosa contains a dense inflammatory infiltrate with focal crypt architectural distortion. B, Hematein eosin saffron: original magnification x 200: A focal active colitis with crypt abscess formation (star) and numerous lymphocytes and eosinophils (arrow)
FIGURE 2 Demonstration of transcription of HHV‐6 encoded sncRNA‐U14 in colon (the study was done on 2019 on stored biopsy samples from 2010). A, Detection of HHV‐6 encoded sncRNA‐U14 in the colonic biopsy of the DRESS patient. FFPE colonic tissue biopsies were used for the analysis. Three different representative images from different regions of the tissue have been shown. Imaging was done using an epifluorescence microscope. The scale bars represent 100 m. B, Detection of HHV‐6 encoded sncRNA‐U14 in HHV‐6 negative colonic biopsy. Two representative images are shown from different regions of a single biopsy. C, Detection of sncRNA‐U14 by FISH in various in vivo cell types. HHV‐6A infected HSB‐2 cells were used as positive control for sncRNA‐U14 FISH analysis. Uninfected HSB‐2 cells were used as negative control. Human small RNA U6 was used as a FISH positive control. At the same time, a scrambled small RNA probe was used as a FISH negative control. Imaging was done on a SP5 confocal microscope. The scale bars represent 100 m
Subsequently, the cellular localization of HHV‐6 genome in leukocyte subpopulations was studied by flow cytometry and PCR because the patient had an unusual persistent HHV‐6 infection after DRESS. HHV‐6 DNA was present only in T lymphocytes fraction with 1212 gec/M cells and was absent from all other fractions (B lymphocytes, monocytes, NK cells, polymorphonuclear cells). Apart from this high HHV‐6 load, the patient had no clinical manifestation and all biological tests were normal.
3 DISCUSSION
This case illustrates a severe case of sulfasalazine‐induced DRESS with Regiscar criteria score of 7 having reactivation of HHV‐6B.
9
HHV‐6 is a lymphotropic virus that predominantly infects T‐cell lymphocyte. It possesses telomere‐like repeats at the terminal regions of its genome that facilitate latency by a unique mechanism of viral latency, integration into the host telomeres, rather than by episome formation. HHV‐6 reactivation plays a major role in DRESS syndrome.
This observation is of great interest because the patient had a persistent HHV‐6 infection after DRESS and developed a Crohn's‐like colitis. Relapsing course of DRESS is usual, and flares are frequently associated with short duration HHV‐6 reactivations.
1
,
4
In this case, HHV‐6 was regularly detected even a long time after DRESS. Persistent HHV‐6 infection was confirmed by a high level of viral DNA in whole blood but HHV‐6B being present only in T lymphocytes. The viral loads below 6 log gec/M cells and negative in hair follicles excluded the presence of inherited chromosomally integrated HHV‐6. Miyagawa et al recently reported 3 cases of DRESS in which HHV‐6 DNA was detected mainly in peripheral T lymphocytes long after resolution of DRESS (until 700 days with HHV‐6 viral DNA up to 3 log copies/million cells).
10
The major point in our case was the demonstration of HHV‐6‐induced colitis. High HHV‐6 DNA load and more interestingly a very high level of viral sncRNA confirmed HHV‐6 reactivation in colon (Figure 1, 2). Antiviral drugs induced a control of colitis symptoms but did not significantly decrease HHV‐6 viral load in whole blood. It may be possible that the antiviral treatment controlled HHV‐6 DNA replication that marks classical active viral infection. However, transient viral reactivation characterized by transcription of HHV‐6 sncRNA‐U14, in the absence of viral DNA replication, cannot be controlled by current antiherpesvirus drugs that target only the viral DNA replication.
8
The residual HHV‐6 viral load possibly represents a latent HHV‐6 infection that can persist as episomal or integrated form in T lymphocytes and other cells.
Crohn's disease and more globally inflammatory bowed diseases may be associated with spondylarthritis and stay silent for a long time. Crohn's disease has not been reported as a consequence of DRESS. Patient with Crohn's disease is at risk for the development of DRESS because they are frequently treated by sulfasalazine or azathrioprine which are well known inducers of DRESS. A previous control study did not find evidence of HHV‐6 infection in patients with Crohn's disease as compared to the controls.
11
In another study HHV‐6B antigen positivity and intensity of immunohistochemistry correlated with endoscopy severity of Crohn's disease.
12
We postulate that HHV‐6 could trigger a previous asymptomatic Crohn's disease. In our patient, the Crohn's disease remained and was subsequently treated by TNF alpha blocker without any relapse of DRESS.
4 CONCLUSION
Through this case report, we would like to emphasize on the advantage of new tools (demonstration of HHV6 sncRNA in tissue sample) for the diagnosis of HHV‐6 reactivation.
CONFLICT OF INTEREST
The authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
DV: involved in the diagnosis and care of the patient and wrote the manuscript. GDA: involved in the virological tests and their interpretation. PAL: involved in the diagnosis and care of the patient. BP: involved in the virological tests and their interpretation. DL: performed the pathological analysis. PBK: performed the HHV‐6 snc‐RNA study and its interpretation. All authors: involved in the critical revision and final approval of the manuscript.
ETHICAL APPROVAL
The article describes a case report. Therefore, no additional permission from our Ethics Committee was required.
ACKNOWLEDGMENTS
Informed consent was obtained for this case.
DATA AVAILABILITY STATEMENT
All data that support the findings of this study are included in this case report. Details are available on request from the corresponding author. | SULFASALAZINE | DrugsGivenReaction | CC BY-NC-ND | 33598255 | 18,874,347 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Human herpesvirus 6 infection reactivation'. | Chronic persistent HHV-6B infection after sulfasalazine-induced DRESS with demonstration of HHV-6 encoded small noncoding RNAs (sncRNAs) in Crohn's-like colitis: Case report.
A sulfasalazine-induced DRESS (Drug Reactivation with Eosinophilia and Systemic Symptoms) was complicated by a Crohn's-like colitis. We demonstrated HHV-6 reactivation with presence of HHV-6 DNA and small noncoding RNA in colonic lesions. This observation confirms the major role of HHV-6 reactivation in DRESS manifestations and the importance of looking for HHV-6 reactivation in DRESS.
1 INTRODUCTION
Drug reaction with eosinophilia and systemic symptoms (DRESS), also referred to as drug‐induced hypersensitivity syndrome (DIHS), is a severe hypersensitivity drug reaction associating skin eruption and organ involvement. We report a 32‐year‐old man with sulfasalazine‐induced DRESS with reactivation of human herpesvirus 6B (HHV‐6B). His case is remarkable because he had chronic persistent HHV‐6 infection with colonic infection and development of Crohn's disease.
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug hypersensitivity syndrome.
1
,
2
The pathophysiology of this syndrome is not fully understood, but human herpesvirus 6 (HHV‐6) reactivation plays a major role in its development.
1
,
2
,
3
,
4
In most cases, duration of HHV‐6 reactivation is limited.
We report a typical case of sulfasalazine‐induced DRESS with reactivation of HHV‐6B in a patient with spondyloarthritis who developed a Crohn's‐like colitis after DRESS. We demonstrated a chronic persistent HHV‐6 infection with the presence of HHV‐6 DNA and encoded small noncoding RNA (sncRNA) in colonic lesions.
2 CASE REPORT
A 32‐year‐old man was treated for axial and peripheral spondyloarthritis by sulfasalazine without any symptom suggestive of Crohn's disease. He presented 3 weeks after the beginning of sulfasalazine on August 2009 with exanthema, facial edema, high fever, and diffuse lymphadenopathy. The first blood tests confirmed an eosinophilia (3200 cells/µL), a mononucleosis syndrome with atypical lymphocytes and an hepatitis with a drop of prothrombin ratio to 65%. He subsequently developed pneumonitis and colitis. A diagnosis of sulfasalazine‐induced DRESS was made, and sulfasalazine was discontinued. The patient was treated by intravenous methylprednisolone and intravenous immunoglobulins. Intravenous corticosteroids were changed for oral prednisone (1 mg/kg/d). Visceral manifestations progressively improved. HHV‐6B viral load in whole blood was at a high level (23 495 gec/M cells).
5
,
6
,
7
Epstein‐Barr virus and cytomegalovirus viral loads measured by PCR remained negative.
Corticosteroids were progressively tapered within 6‐month period, and HHV‐6 viral load was monitored. The patient developed diarrhea with bloody bowel movement. On February 2010, HHV‐6 viral load was high at 32 737 gec/M cells (genomic DNA per million cells). Endoscopy examination and colonic biopsy demonstrated clinical and microscopic features of Crohn's disease (Figure 1). HHV‐6B DNA PCR was positive in colonic biopsy (1808 gec/M cells) with high levels of virus encoded sncRNAs (Figure 2). Antivirals were started with a monitoring of HHV‐6 viremia. The patient was treated by 14 days of ganciclovir. The whole blood viral load decreased from 7051 to 3675 gec/M cells. HHV‐6 DNA test was negative in hair follicles. The colitis manifestations resolved. Cidofovir treatment was proposed for the treatment of this persistent HHV‐6 infection. He received six infusions of 400 mg each without significant effect on HHV‐6 viral load (3934 gec/M cells). Six months later, on February 2011, it remained 8061 gec/M cells. Colitis manifestations resumed, and a new endoscopy confirmed luminal stenosis of the transverse colon. At that time, a treatment with TNF alpha blocker (adalimumab) was started. After 8‐year treatment with adalimumab, HHV‐6 viral load in whole blood remained stable at 905‐1084 gec/M cells. The patient did not develop any flare of DRESS. The Crohn's‐like colitis was under control.
FIGURE 1 Histological examination of a biopsy of large intestine. A, Hematein eosin saffron: original magnification x 5: The mucosa contains a dense inflammatory infiltrate with focal crypt architectural distortion. B, Hematein eosin saffron: original magnification x 200: A focal active colitis with crypt abscess formation (star) and numerous lymphocytes and eosinophils (arrow)
FIGURE 2 Demonstration of transcription of HHV‐6 encoded sncRNA‐U14 in colon (the study was done on 2019 on stored biopsy samples from 2010). A, Detection of HHV‐6 encoded sncRNA‐U14 in the colonic biopsy of the DRESS patient. FFPE colonic tissue biopsies were used for the analysis. Three different representative images from different regions of the tissue have been shown. Imaging was done using an epifluorescence microscope. The scale bars represent 100 m. B, Detection of HHV‐6 encoded sncRNA‐U14 in HHV‐6 negative colonic biopsy. Two representative images are shown from different regions of a single biopsy. C, Detection of sncRNA‐U14 by FISH in various in vivo cell types. HHV‐6A infected HSB‐2 cells were used as positive control for sncRNA‐U14 FISH analysis. Uninfected HSB‐2 cells were used as negative control. Human small RNA U6 was used as a FISH positive control. At the same time, a scrambled small RNA probe was used as a FISH negative control. Imaging was done on a SP5 confocal microscope. The scale bars represent 100 m
Subsequently, the cellular localization of HHV‐6 genome in leukocyte subpopulations was studied by flow cytometry and PCR because the patient had an unusual persistent HHV‐6 infection after DRESS. HHV‐6 DNA was present only in T lymphocytes fraction with 1212 gec/M cells and was absent from all other fractions (B lymphocytes, monocytes, NK cells, polymorphonuclear cells). Apart from this high HHV‐6 load, the patient had no clinical manifestation and all biological tests were normal.
3 DISCUSSION
This case illustrates a severe case of sulfasalazine‐induced DRESS with Regiscar criteria score of 7 having reactivation of HHV‐6B.
9
HHV‐6 is a lymphotropic virus that predominantly infects T‐cell lymphocyte. It possesses telomere‐like repeats at the terminal regions of its genome that facilitate latency by a unique mechanism of viral latency, integration into the host telomeres, rather than by episome formation. HHV‐6 reactivation plays a major role in DRESS syndrome.
This observation is of great interest because the patient had a persistent HHV‐6 infection after DRESS and developed a Crohn's‐like colitis. Relapsing course of DRESS is usual, and flares are frequently associated with short duration HHV‐6 reactivations.
1
,
4
In this case, HHV‐6 was regularly detected even a long time after DRESS. Persistent HHV‐6 infection was confirmed by a high level of viral DNA in whole blood but HHV‐6B being present only in T lymphocytes. The viral loads below 6 log gec/M cells and negative in hair follicles excluded the presence of inherited chromosomally integrated HHV‐6. Miyagawa et al recently reported 3 cases of DRESS in which HHV‐6 DNA was detected mainly in peripheral T lymphocytes long after resolution of DRESS (until 700 days with HHV‐6 viral DNA up to 3 log copies/million cells).
10
The major point in our case was the demonstration of HHV‐6‐induced colitis. High HHV‐6 DNA load and more interestingly a very high level of viral sncRNA confirmed HHV‐6 reactivation in colon (Figure 1, 2). Antiviral drugs induced a control of colitis symptoms but did not significantly decrease HHV‐6 viral load in whole blood. It may be possible that the antiviral treatment controlled HHV‐6 DNA replication that marks classical active viral infection. However, transient viral reactivation characterized by transcription of HHV‐6 sncRNA‐U14, in the absence of viral DNA replication, cannot be controlled by current antiherpesvirus drugs that target only the viral DNA replication.
8
The residual HHV‐6 viral load possibly represents a latent HHV‐6 infection that can persist as episomal or integrated form in T lymphocytes and other cells.
Crohn's disease and more globally inflammatory bowed diseases may be associated with spondylarthritis and stay silent for a long time. Crohn's disease has not been reported as a consequence of DRESS. Patient with Crohn's disease is at risk for the development of DRESS because they are frequently treated by sulfasalazine or azathrioprine which are well known inducers of DRESS. A previous control study did not find evidence of HHV‐6 infection in patients with Crohn's disease as compared to the controls.
11
In another study HHV‐6B antigen positivity and intensity of immunohistochemistry correlated with endoscopy severity of Crohn's disease.
12
We postulate that HHV‐6 could trigger a previous asymptomatic Crohn's disease. In our patient, the Crohn's disease remained and was subsequently treated by TNF alpha blocker without any relapse of DRESS.
4 CONCLUSION
Through this case report, we would like to emphasize on the advantage of new tools (demonstration of HHV6 sncRNA in tissue sample) for the diagnosis of HHV‐6 reactivation.
CONFLICT OF INTEREST
The authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
DV: involved in the diagnosis and care of the patient and wrote the manuscript. GDA: involved in the virological tests and their interpretation. PAL: involved in the diagnosis and care of the patient. BP: involved in the virological tests and their interpretation. DL: performed the pathological analysis. PBK: performed the HHV‐6 snc‐RNA study and its interpretation. All authors: involved in the critical revision and final approval of the manuscript.
ETHICAL APPROVAL
The article describes a case report. Therefore, no additional permission from our Ethics Committee was required.
ACKNOWLEDGMENTS
Informed consent was obtained for this case.
DATA AVAILABILITY STATEMENT
All data that support the findings of this study are included in this case report. Details are available on request from the corresponding author. | SULFASALAZINE | DrugsGivenReaction | CC BY-NC-ND | 33598255 | 20,563,226 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Mononucleosis syndrome'. | Chronic persistent HHV-6B infection after sulfasalazine-induced DRESS with demonstration of HHV-6 encoded small noncoding RNAs (sncRNAs) in Crohn's-like colitis: Case report.
A sulfasalazine-induced DRESS (Drug Reactivation with Eosinophilia and Systemic Symptoms) was complicated by a Crohn's-like colitis. We demonstrated HHV-6 reactivation with presence of HHV-6 DNA and small noncoding RNA in colonic lesions. This observation confirms the major role of HHV-6 reactivation in DRESS manifestations and the importance of looking for HHV-6 reactivation in DRESS.
1 INTRODUCTION
Drug reaction with eosinophilia and systemic symptoms (DRESS), also referred to as drug‐induced hypersensitivity syndrome (DIHS), is a severe hypersensitivity drug reaction associating skin eruption and organ involvement. We report a 32‐year‐old man with sulfasalazine‐induced DRESS with reactivation of human herpesvirus 6B (HHV‐6B). His case is remarkable because he had chronic persistent HHV‐6 infection with colonic infection and development of Crohn's disease.
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug hypersensitivity syndrome.
1
,
2
The pathophysiology of this syndrome is not fully understood, but human herpesvirus 6 (HHV‐6) reactivation plays a major role in its development.
1
,
2
,
3
,
4
In most cases, duration of HHV‐6 reactivation is limited.
We report a typical case of sulfasalazine‐induced DRESS with reactivation of HHV‐6B in a patient with spondyloarthritis who developed a Crohn's‐like colitis after DRESS. We demonstrated a chronic persistent HHV‐6 infection with the presence of HHV‐6 DNA and encoded small noncoding RNA (sncRNA) in colonic lesions.
2 CASE REPORT
A 32‐year‐old man was treated for axial and peripheral spondyloarthritis by sulfasalazine without any symptom suggestive of Crohn's disease. He presented 3 weeks after the beginning of sulfasalazine on August 2009 with exanthema, facial edema, high fever, and diffuse lymphadenopathy. The first blood tests confirmed an eosinophilia (3200 cells/µL), a mononucleosis syndrome with atypical lymphocytes and an hepatitis with a drop of prothrombin ratio to 65%. He subsequently developed pneumonitis and colitis. A diagnosis of sulfasalazine‐induced DRESS was made, and sulfasalazine was discontinued. The patient was treated by intravenous methylprednisolone and intravenous immunoglobulins. Intravenous corticosteroids were changed for oral prednisone (1 mg/kg/d). Visceral manifestations progressively improved. HHV‐6B viral load in whole blood was at a high level (23 495 gec/M cells).
5
,
6
,
7
Epstein‐Barr virus and cytomegalovirus viral loads measured by PCR remained negative.
Corticosteroids were progressively tapered within 6‐month period, and HHV‐6 viral load was monitored. The patient developed diarrhea with bloody bowel movement. On February 2010, HHV‐6 viral load was high at 32 737 gec/M cells (genomic DNA per million cells). Endoscopy examination and colonic biopsy demonstrated clinical and microscopic features of Crohn's disease (Figure 1). HHV‐6B DNA PCR was positive in colonic biopsy (1808 gec/M cells) with high levels of virus encoded sncRNAs (Figure 2). Antivirals were started with a monitoring of HHV‐6 viremia. The patient was treated by 14 days of ganciclovir. The whole blood viral load decreased from 7051 to 3675 gec/M cells. HHV‐6 DNA test was negative in hair follicles. The colitis manifestations resolved. Cidofovir treatment was proposed for the treatment of this persistent HHV‐6 infection. He received six infusions of 400 mg each without significant effect on HHV‐6 viral load (3934 gec/M cells). Six months later, on February 2011, it remained 8061 gec/M cells. Colitis manifestations resumed, and a new endoscopy confirmed luminal stenosis of the transverse colon. At that time, a treatment with TNF alpha blocker (adalimumab) was started. After 8‐year treatment with adalimumab, HHV‐6 viral load in whole blood remained stable at 905‐1084 gec/M cells. The patient did not develop any flare of DRESS. The Crohn's‐like colitis was under control.
FIGURE 1 Histological examination of a biopsy of large intestine. A, Hematein eosin saffron: original magnification x 5: The mucosa contains a dense inflammatory infiltrate with focal crypt architectural distortion. B, Hematein eosin saffron: original magnification x 200: A focal active colitis with crypt abscess formation (star) and numerous lymphocytes and eosinophils (arrow)
FIGURE 2 Demonstration of transcription of HHV‐6 encoded sncRNA‐U14 in colon (the study was done on 2019 on stored biopsy samples from 2010). A, Detection of HHV‐6 encoded sncRNA‐U14 in the colonic biopsy of the DRESS patient. FFPE colonic tissue biopsies were used for the analysis. Three different representative images from different regions of the tissue have been shown. Imaging was done using an epifluorescence microscope. The scale bars represent 100 m. B, Detection of HHV‐6 encoded sncRNA‐U14 in HHV‐6 negative colonic biopsy. Two representative images are shown from different regions of a single biopsy. C, Detection of sncRNA‐U14 by FISH in various in vivo cell types. HHV‐6A infected HSB‐2 cells were used as positive control for sncRNA‐U14 FISH analysis. Uninfected HSB‐2 cells were used as negative control. Human small RNA U6 was used as a FISH positive control. At the same time, a scrambled small RNA probe was used as a FISH negative control. Imaging was done on a SP5 confocal microscope. The scale bars represent 100 m
Subsequently, the cellular localization of HHV‐6 genome in leukocyte subpopulations was studied by flow cytometry and PCR because the patient had an unusual persistent HHV‐6 infection after DRESS. HHV‐6 DNA was present only in T lymphocytes fraction with 1212 gec/M cells and was absent from all other fractions (B lymphocytes, monocytes, NK cells, polymorphonuclear cells). Apart from this high HHV‐6 load, the patient had no clinical manifestation and all biological tests were normal.
3 DISCUSSION
This case illustrates a severe case of sulfasalazine‐induced DRESS with Regiscar criteria score of 7 having reactivation of HHV‐6B.
9
HHV‐6 is a lymphotropic virus that predominantly infects T‐cell lymphocyte. It possesses telomere‐like repeats at the terminal regions of its genome that facilitate latency by a unique mechanism of viral latency, integration into the host telomeres, rather than by episome formation. HHV‐6 reactivation plays a major role in DRESS syndrome.
This observation is of great interest because the patient had a persistent HHV‐6 infection after DRESS and developed a Crohn's‐like colitis. Relapsing course of DRESS is usual, and flares are frequently associated with short duration HHV‐6 reactivations.
1
,
4
In this case, HHV‐6 was regularly detected even a long time after DRESS. Persistent HHV‐6 infection was confirmed by a high level of viral DNA in whole blood but HHV‐6B being present only in T lymphocytes. The viral loads below 6 log gec/M cells and negative in hair follicles excluded the presence of inherited chromosomally integrated HHV‐6. Miyagawa et al recently reported 3 cases of DRESS in which HHV‐6 DNA was detected mainly in peripheral T lymphocytes long after resolution of DRESS (until 700 days with HHV‐6 viral DNA up to 3 log copies/million cells).
10
The major point in our case was the demonstration of HHV‐6‐induced colitis. High HHV‐6 DNA load and more interestingly a very high level of viral sncRNA confirmed HHV‐6 reactivation in colon (Figure 1, 2). Antiviral drugs induced a control of colitis symptoms but did not significantly decrease HHV‐6 viral load in whole blood. It may be possible that the antiviral treatment controlled HHV‐6 DNA replication that marks classical active viral infection. However, transient viral reactivation characterized by transcription of HHV‐6 sncRNA‐U14, in the absence of viral DNA replication, cannot be controlled by current antiherpesvirus drugs that target only the viral DNA replication.
8
The residual HHV‐6 viral load possibly represents a latent HHV‐6 infection that can persist as episomal or integrated form in T lymphocytes and other cells.
Crohn's disease and more globally inflammatory bowed diseases may be associated with spondylarthritis and stay silent for a long time. Crohn's disease has not been reported as a consequence of DRESS. Patient with Crohn's disease is at risk for the development of DRESS because they are frequently treated by sulfasalazine or azathrioprine which are well known inducers of DRESS. A previous control study did not find evidence of HHV‐6 infection in patients with Crohn's disease as compared to the controls.
11
In another study HHV‐6B antigen positivity and intensity of immunohistochemistry correlated with endoscopy severity of Crohn's disease.
12
We postulate that HHV‐6 could trigger a previous asymptomatic Crohn's disease. In our patient, the Crohn's disease remained and was subsequently treated by TNF alpha blocker without any relapse of DRESS.
4 CONCLUSION
Through this case report, we would like to emphasize on the advantage of new tools (demonstration of HHV6 sncRNA in tissue sample) for the diagnosis of HHV‐6 reactivation.
CONFLICT OF INTEREST
The authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
DV: involved in the diagnosis and care of the patient and wrote the manuscript. GDA: involved in the virological tests and their interpretation. PAL: involved in the diagnosis and care of the patient. BP: involved in the virological tests and their interpretation. DL: performed the pathological analysis. PBK: performed the HHV‐6 snc‐RNA study and its interpretation. All authors: involved in the critical revision and final approval of the manuscript.
ETHICAL APPROVAL
The article describes a case report. Therefore, no additional permission from our Ethics Committee was required.
ACKNOWLEDGMENTS
Informed consent was obtained for this case.
DATA AVAILABILITY STATEMENT
All data that support the findings of this study are included in this case report. Details are available on request from the corresponding author. | SULFASALAZINE | DrugsGivenReaction | CC BY-NC-ND | 33598255 | 18,874,347 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonitis'. | Chronic persistent HHV-6B infection after sulfasalazine-induced DRESS with demonstration of HHV-6 encoded small noncoding RNAs (sncRNAs) in Crohn's-like colitis: Case report.
A sulfasalazine-induced DRESS (Drug Reactivation with Eosinophilia and Systemic Symptoms) was complicated by a Crohn's-like colitis. We demonstrated HHV-6 reactivation with presence of HHV-6 DNA and small noncoding RNA in colonic lesions. This observation confirms the major role of HHV-6 reactivation in DRESS manifestations and the importance of looking for HHV-6 reactivation in DRESS.
1 INTRODUCTION
Drug reaction with eosinophilia and systemic symptoms (DRESS), also referred to as drug‐induced hypersensitivity syndrome (DIHS), is a severe hypersensitivity drug reaction associating skin eruption and organ involvement. We report a 32‐year‐old man with sulfasalazine‐induced DRESS with reactivation of human herpesvirus 6B (HHV‐6B). His case is remarkable because he had chronic persistent HHV‐6 infection with colonic infection and development of Crohn's disease.
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug hypersensitivity syndrome.
1
,
2
The pathophysiology of this syndrome is not fully understood, but human herpesvirus 6 (HHV‐6) reactivation plays a major role in its development.
1
,
2
,
3
,
4
In most cases, duration of HHV‐6 reactivation is limited.
We report a typical case of sulfasalazine‐induced DRESS with reactivation of HHV‐6B in a patient with spondyloarthritis who developed a Crohn's‐like colitis after DRESS. We demonstrated a chronic persistent HHV‐6 infection with the presence of HHV‐6 DNA and encoded small noncoding RNA (sncRNA) in colonic lesions.
2 CASE REPORT
A 32‐year‐old man was treated for axial and peripheral spondyloarthritis by sulfasalazine without any symptom suggestive of Crohn's disease. He presented 3 weeks after the beginning of sulfasalazine on August 2009 with exanthema, facial edema, high fever, and diffuse lymphadenopathy. The first blood tests confirmed an eosinophilia (3200 cells/µL), a mononucleosis syndrome with atypical lymphocytes and an hepatitis with a drop of prothrombin ratio to 65%. He subsequently developed pneumonitis and colitis. A diagnosis of sulfasalazine‐induced DRESS was made, and sulfasalazine was discontinued. The patient was treated by intravenous methylprednisolone and intravenous immunoglobulins. Intravenous corticosteroids were changed for oral prednisone (1 mg/kg/d). Visceral manifestations progressively improved. HHV‐6B viral load in whole blood was at a high level (23 495 gec/M cells).
5
,
6
,
7
Epstein‐Barr virus and cytomegalovirus viral loads measured by PCR remained negative.
Corticosteroids were progressively tapered within 6‐month period, and HHV‐6 viral load was monitored. The patient developed diarrhea with bloody bowel movement. On February 2010, HHV‐6 viral load was high at 32 737 gec/M cells (genomic DNA per million cells). Endoscopy examination and colonic biopsy demonstrated clinical and microscopic features of Crohn's disease (Figure 1). HHV‐6B DNA PCR was positive in colonic biopsy (1808 gec/M cells) with high levels of virus encoded sncRNAs (Figure 2). Antivirals were started with a monitoring of HHV‐6 viremia. The patient was treated by 14 days of ganciclovir. The whole blood viral load decreased from 7051 to 3675 gec/M cells. HHV‐6 DNA test was negative in hair follicles. The colitis manifestations resolved. Cidofovir treatment was proposed for the treatment of this persistent HHV‐6 infection. He received six infusions of 400 mg each without significant effect on HHV‐6 viral load (3934 gec/M cells). Six months later, on February 2011, it remained 8061 gec/M cells. Colitis manifestations resumed, and a new endoscopy confirmed luminal stenosis of the transverse colon. At that time, a treatment with TNF alpha blocker (adalimumab) was started. After 8‐year treatment with adalimumab, HHV‐6 viral load in whole blood remained stable at 905‐1084 gec/M cells. The patient did not develop any flare of DRESS. The Crohn's‐like colitis was under control.
FIGURE 1 Histological examination of a biopsy of large intestine. A, Hematein eosin saffron: original magnification x 5: The mucosa contains a dense inflammatory infiltrate with focal crypt architectural distortion. B, Hematein eosin saffron: original magnification x 200: A focal active colitis with crypt abscess formation (star) and numerous lymphocytes and eosinophils (arrow)
FIGURE 2 Demonstration of transcription of HHV‐6 encoded sncRNA‐U14 in colon (the study was done on 2019 on stored biopsy samples from 2010). A, Detection of HHV‐6 encoded sncRNA‐U14 in the colonic biopsy of the DRESS patient. FFPE colonic tissue biopsies were used for the analysis. Three different representative images from different regions of the tissue have been shown. Imaging was done using an epifluorescence microscope. The scale bars represent 100 m. B, Detection of HHV‐6 encoded sncRNA‐U14 in HHV‐6 negative colonic biopsy. Two representative images are shown from different regions of a single biopsy. C, Detection of sncRNA‐U14 by FISH in various in vivo cell types. HHV‐6A infected HSB‐2 cells were used as positive control for sncRNA‐U14 FISH analysis. Uninfected HSB‐2 cells were used as negative control. Human small RNA U6 was used as a FISH positive control. At the same time, a scrambled small RNA probe was used as a FISH negative control. Imaging was done on a SP5 confocal microscope. The scale bars represent 100 m
Subsequently, the cellular localization of HHV‐6 genome in leukocyte subpopulations was studied by flow cytometry and PCR because the patient had an unusual persistent HHV‐6 infection after DRESS. HHV‐6 DNA was present only in T lymphocytes fraction with 1212 gec/M cells and was absent from all other fractions (B lymphocytes, monocytes, NK cells, polymorphonuclear cells). Apart from this high HHV‐6 load, the patient had no clinical manifestation and all biological tests were normal.
3 DISCUSSION
This case illustrates a severe case of sulfasalazine‐induced DRESS with Regiscar criteria score of 7 having reactivation of HHV‐6B.
9
HHV‐6 is a lymphotropic virus that predominantly infects T‐cell lymphocyte. It possesses telomere‐like repeats at the terminal regions of its genome that facilitate latency by a unique mechanism of viral latency, integration into the host telomeres, rather than by episome formation. HHV‐6 reactivation plays a major role in DRESS syndrome.
This observation is of great interest because the patient had a persistent HHV‐6 infection after DRESS and developed a Crohn's‐like colitis. Relapsing course of DRESS is usual, and flares are frequently associated with short duration HHV‐6 reactivations.
1
,
4
In this case, HHV‐6 was regularly detected even a long time after DRESS. Persistent HHV‐6 infection was confirmed by a high level of viral DNA in whole blood but HHV‐6B being present only in T lymphocytes. The viral loads below 6 log gec/M cells and negative in hair follicles excluded the presence of inherited chromosomally integrated HHV‐6. Miyagawa et al recently reported 3 cases of DRESS in which HHV‐6 DNA was detected mainly in peripheral T lymphocytes long after resolution of DRESS (until 700 days with HHV‐6 viral DNA up to 3 log copies/million cells).
10
The major point in our case was the demonstration of HHV‐6‐induced colitis. High HHV‐6 DNA load and more interestingly a very high level of viral sncRNA confirmed HHV‐6 reactivation in colon (Figure 1, 2). Antiviral drugs induced a control of colitis symptoms but did not significantly decrease HHV‐6 viral load in whole blood. It may be possible that the antiviral treatment controlled HHV‐6 DNA replication that marks classical active viral infection. However, transient viral reactivation characterized by transcription of HHV‐6 sncRNA‐U14, in the absence of viral DNA replication, cannot be controlled by current antiherpesvirus drugs that target only the viral DNA replication.
8
The residual HHV‐6 viral load possibly represents a latent HHV‐6 infection that can persist as episomal or integrated form in T lymphocytes and other cells.
Crohn's disease and more globally inflammatory bowed diseases may be associated with spondylarthritis and stay silent for a long time. Crohn's disease has not been reported as a consequence of DRESS. Patient with Crohn's disease is at risk for the development of DRESS because they are frequently treated by sulfasalazine or azathrioprine which are well known inducers of DRESS. A previous control study did not find evidence of HHV‐6 infection in patients with Crohn's disease as compared to the controls.
11
In another study HHV‐6B antigen positivity and intensity of immunohistochemistry correlated with endoscopy severity of Crohn's disease.
12
We postulate that HHV‐6 could trigger a previous asymptomatic Crohn's disease. In our patient, the Crohn's disease remained and was subsequently treated by TNF alpha blocker without any relapse of DRESS.
4 CONCLUSION
Through this case report, we would like to emphasize on the advantage of new tools (demonstration of HHV6 sncRNA in tissue sample) for the diagnosis of HHV‐6 reactivation.
CONFLICT OF INTEREST
The authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
DV: involved in the diagnosis and care of the patient and wrote the manuscript. GDA: involved in the virological tests and their interpretation. PAL: involved in the diagnosis and care of the patient. BP: involved in the virological tests and their interpretation. DL: performed the pathological analysis. PBK: performed the HHV‐6 snc‐RNA study and its interpretation. All authors: involved in the critical revision and final approval of the manuscript.
ETHICAL APPROVAL
The article describes a case report. Therefore, no additional permission from our Ethics Committee was required.
ACKNOWLEDGMENTS
Informed consent was obtained for this case.
DATA AVAILABILITY STATEMENT
All data that support the findings of this study are included in this case report. Details are available on request from the corresponding author. | SULFASALAZINE | DrugsGivenReaction | CC BY-NC-ND | 33598255 | 18,874,347 | 2021-02 |
What was the administration route of drug 'SULFASALAZINE'? | Chronic persistent HHV-6B infection after sulfasalazine-induced DRESS with demonstration of HHV-6 encoded small noncoding RNAs (sncRNAs) in Crohn's-like colitis: Case report.
A sulfasalazine-induced DRESS (Drug Reactivation with Eosinophilia and Systemic Symptoms) was complicated by a Crohn's-like colitis. We demonstrated HHV-6 reactivation with presence of HHV-6 DNA and small noncoding RNA in colonic lesions. This observation confirms the major role of HHV-6 reactivation in DRESS manifestations and the importance of looking for HHV-6 reactivation in DRESS.
1 INTRODUCTION
Drug reaction with eosinophilia and systemic symptoms (DRESS), also referred to as drug‐induced hypersensitivity syndrome (DIHS), is a severe hypersensitivity drug reaction associating skin eruption and organ involvement. We report a 32‐year‐old man with sulfasalazine‐induced DRESS with reactivation of human herpesvirus 6B (HHV‐6B). His case is remarkable because he had chronic persistent HHV‐6 infection with colonic infection and development of Crohn's disease.
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug hypersensitivity syndrome.
1
,
2
The pathophysiology of this syndrome is not fully understood, but human herpesvirus 6 (HHV‐6) reactivation plays a major role in its development.
1
,
2
,
3
,
4
In most cases, duration of HHV‐6 reactivation is limited.
We report a typical case of sulfasalazine‐induced DRESS with reactivation of HHV‐6B in a patient with spondyloarthritis who developed a Crohn's‐like colitis after DRESS. We demonstrated a chronic persistent HHV‐6 infection with the presence of HHV‐6 DNA and encoded small noncoding RNA (sncRNA) in colonic lesions.
2 CASE REPORT
A 32‐year‐old man was treated for axial and peripheral spondyloarthritis by sulfasalazine without any symptom suggestive of Crohn's disease. He presented 3 weeks after the beginning of sulfasalazine on August 2009 with exanthema, facial edema, high fever, and diffuse lymphadenopathy. The first blood tests confirmed an eosinophilia (3200 cells/µL), a mononucleosis syndrome with atypical lymphocytes and an hepatitis with a drop of prothrombin ratio to 65%. He subsequently developed pneumonitis and colitis. A diagnosis of sulfasalazine‐induced DRESS was made, and sulfasalazine was discontinued. The patient was treated by intravenous methylprednisolone and intravenous immunoglobulins. Intravenous corticosteroids were changed for oral prednisone (1 mg/kg/d). Visceral manifestations progressively improved. HHV‐6B viral load in whole blood was at a high level (23 495 gec/M cells).
5
,
6
,
7
Epstein‐Barr virus and cytomegalovirus viral loads measured by PCR remained negative.
Corticosteroids were progressively tapered within 6‐month period, and HHV‐6 viral load was monitored. The patient developed diarrhea with bloody bowel movement. On February 2010, HHV‐6 viral load was high at 32 737 gec/M cells (genomic DNA per million cells). Endoscopy examination and colonic biopsy demonstrated clinical and microscopic features of Crohn's disease (Figure 1). HHV‐6B DNA PCR was positive in colonic biopsy (1808 gec/M cells) with high levels of virus encoded sncRNAs (Figure 2). Antivirals were started with a monitoring of HHV‐6 viremia. The patient was treated by 14 days of ganciclovir. The whole blood viral load decreased from 7051 to 3675 gec/M cells. HHV‐6 DNA test was negative in hair follicles. The colitis manifestations resolved. Cidofovir treatment was proposed for the treatment of this persistent HHV‐6 infection. He received six infusions of 400 mg each without significant effect on HHV‐6 viral load (3934 gec/M cells). Six months later, on February 2011, it remained 8061 gec/M cells. Colitis manifestations resumed, and a new endoscopy confirmed luminal stenosis of the transverse colon. At that time, a treatment with TNF alpha blocker (adalimumab) was started. After 8‐year treatment with adalimumab, HHV‐6 viral load in whole blood remained stable at 905‐1084 gec/M cells. The patient did not develop any flare of DRESS. The Crohn's‐like colitis was under control.
FIGURE 1 Histological examination of a biopsy of large intestine. A, Hematein eosin saffron: original magnification x 5: The mucosa contains a dense inflammatory infiltrate with focal crypt architectural distortion. B, Hematein eosin saffron: original magnification x 200: A focal active colitis with crypt abscess formation (star) and numerous lymphocytes and eosinophils (arrow)
FIGURE 2 Demonstration of transcription of HHV‐6 encoded sncRNA‐U14 in colon (the study was done on 2019 on stored biopsy samples from 2010). A, Detection of HHV‐6 encoded sncRNA‐U14 in the colonic biopsy of the DRESS patient. FFPE colonic tissue biopsies were used for the analysis. Three different representative images from different regions of the tissue have been shown. Imaging was done using an epifluorescence microscope. The scale bars represent 100 m. B, Detection of HHV‐6 encoded sncRNA‐U14 in HHV‐6 negative colonic biopsy. Two representative images are shown from different regions of a single biopsy. C, Detection of sncRNA‐U14 by FISH in various in vivo cell types. HHV‐6A infected HSB‐2 cells were used as positive control for sncRNA‐U14 FISH analysis. Uninfected HSB‐2 cells were used as negative control. Human small RNA U6 was used as a FISH positive control. At the same time, a scrambled small RNA probe was used as a FISH negative control. Imaging was done on a SP5 confocal microscope. The scale bars represent 100 m
Subsequently, the cellular localization of HHV‐6 genome in leukocyte subpopulations was studied by flow cytometry and PCR because the patient had an unusual persistent HHV‐6 infection after DRESS. HHV‐6 DNA was present only in T lymphocytes fraction with 1212 gec/M cells and was absent from all other fractions (B lymphocytes, monocytes, NK cells, polymorphonuclear cells). Apart from this high HHV‐6 load, the patient had no clinical manifestation and all biological tests were normal.
3 DISCUSSION
This case illustrates a severe case of sulfasalazine‐induced DRESS with Regiscar criteria score of 7 having reactivation of HHV‐6B.
9
HHV‐6 is a lymphotropic virus that predominantly infects T‐cell lymphocyte. It possesses telomere‐like repeats at the terminal regions of its genome that facilitate latency by a unique mechanism of viral latency, integration into the host telomeres, rather than by episome formation. HHV‐6 reactivation plays a major role in DRESS syndrome.
This observation is of great interest because the patient had a persistent HHV‐6 infection after DRESS and developed a Crohn's‐like colitis. Relapsing course of DRESS is usual, and flares are frequently associated with short duration HHV‐6 reactivations.
1
,
4
In this case, HHV‐6 was regularly detected even a long time after DRESS. Persistent HHV‐6 infection was confirmed by a high level of viral DNA in whole blood but HHV‐6B being present only in T lymphocytes. The viral loads below 6 log gec/M cells and negative in hair follicles excluded the presence of inherited chromosomally integrated HHV‐6. Miyagawa et al recently reported 3 cases of DRESS in which HHV‐6 DNA was detected mainly in peripheral T lymphocytes long after resolution of DRESS (until 700 days with HHV‐6 viral DNA up to 3 log copies/million cells).
10
The major point in our case was the demonstration of HHV‐6‐induced colitis. High HHV‐6 DNA load and more interestingly a very high level of viral sncRNA confirmed HHV‐6 reactivation in colon (Figure 1, 2). Antiviral drugs induced a control of colitis symptoms but did not significantly decrease HHV‐6 viral load in whole blood. It may be possible that the antiviral treatment controlled HHV‐6 DNA replication that marks classical active viral infection. However, transient viral reactivation characterized by transcription of HHV‐6 sncRNA‐U14, in the absence of viral DNA replication, cannot be controlled by current antiherpesvirus drugs that target only the viral DNA replication.
8
The residual HHV‐6 viral load possibly represents a latent HHV‐6 infection that can persist as episomal or integrated form in T lymphocytes and other cells.
Crohn's disease and more globally inflammatory bowed diseases may be associated with spondylarthritis and stay silent for a long time. Crohn's disease has not been reported as a consequence of DRESS. Patient with Crohn's disease is at risk for the development of DRESS because they are frequently treated by sulfasalazine or azathrioprine which are well known inducers of DRESS. A previous control study did not find evidence of HHV‐6 infection in patients with Crohn's disease as compared to the controls.
11
In another study HHV‐6B antigen positivity and intensity of immunohistochemistry correlated with endoscopy severity of Crohn's disease.
12
We postulate that HHV‐6 could trigger a previous asymptomatic Crohn's disease. In our patient, the Crohn's disease remained and was subsequently treated by TNF alpha blocker without any relapse of DRESS.
4 CONCLUSION
Through this case report, we would like to emphasize on the advantage of new tools (demonstration of HHV6 sncRNA in tissue sample) for the diagnosis of HHV‐6 reactivation.
CONFLICT OF INTEREST
The authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
DV: involved in the diagnosis and care of the patient and wrote the manuscript. GDA: involved in the virological tests and their interpretation. PAL: involved in the diagnosis and care of the patient. BP: involved in the virological tests and their interpretation. DL: performed the pathological analysis. PBK: performed the HHV‐6 snc‐RNA study and its interpretation. All authors: involved in the critical revision and final approval of the manuscript.
ETHICAL APPROVAL
The article describes a case report. Therefore, no additional permission from our Ethics Committee was required.
ACKNOWLEDGMENTS
Informed consent was obtained for this case.
DATA AVAILABILITY STATEMENT
All data that support the findings of this study are included in this case report. Details are available on request from the corresponding author. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33598255 | 20,563,226 | 2021-02 |
What was the outcome of reaction 'Drug reaction with eosinophilia and systemic symptoms'? | Chronic persistent HHV-6B infection after sulfasalazine-induced DRESS with demonstration of HHV-6 encoded small noncoding RNAs (sncRNAs) in Crohn's-like colitis: Case report.
A sulfasalazine-induced DRESS (Drug Reactivation with Eosinophilia and Systemic Symptoms) was complicated by a Crohn's-like colitis. We demonstrated HHV-6 reactivation with presence of HHV-6 DNA and small noncoding RNA in colonic lesions. This observation confirms the major role of HHV-6 reactivation in DRESS manifestations and the importance of looking for HHV-6 reactivation in DRESS.
1 INTRODUCTION
Drug reaction with eosinophilia and systemic symptoms (DRESS), also referred to as drug‐induced hypersensitivity syndrome (DIHS), is a severe hypersensitivity drug reaction associating skin eruption and organ involvement. We report a 32‐year‐old man with sulfasalazine‐induced DRESS with reactivation of human herpesvirus 6B (HHV‐6B). His case is remarkable because he had chronic persistent HHV‐6 infection with colonic infection and development of Crohn's disease.
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug hypersensitivity syndrome.
1
,
2
The pathophysiology of this syndrome is not fully understood, but human herpesvirus 6 (HHV‐6) reactivation plays a major role in its development.
1
,
2
,
3
,
4
In most cases, duration of HHV‐6 reactivation is limited.
We report a typical case of sulfasalazine‐induced DRESS with reactivation of HHV‐6B in a patient with spondyloarthritis who developed a Crohn's‐like colitis after DRESS. We demonstrated a chronic persistent HHV‐6 infection with the presence of HHV‐6 DNA and encoded small noncoding RNA (sncRNA) in colonic lesions.
2 CASE REPORT
A 32‐year‐old man was treated for axial and peripheral spondyloarthritis by sulfasalazine without any symptom suggestive of Crohn's disease. He presented 3 weeks after the beginning of sulfasalazine on August 2009 with exanthema, facial edema, high fever, and diffuse lymphadenopathy. The first blood tests confirmed an eosinophilia (3200 cells/µL), a mononucleosis syndrome with atypical lymphocytes and an hepatitis with a drop of prothrombin ratio to 65%. He subsequently developed pneumonitis and colitis. A diagnosis of sulfasalazine‐induced DRESS was made, and sulfasalazine was discontinued. The patient was treated by intravenous methylprednisolone and intravenous immunoglobulins. Intravenous corticosteroids were changed for oral prednisone (1 mg/kg/d). Visceral manifestations progressively improved. HHV‐6B viral load in whole blood was at a high level (23 495 gec/M cells).
5
,
6
,
7
Epstein‐Barr virus and cytomegalovirus viral loads measured by PCR remained negative.
Corticosteroids were progressively tapered within 6‐month period, and HHV‐6 viral load was monitored. The patient developed diarrhea with bloody bowel movement. On February 2010, HHV‐6 viral load was high at 32 737 gec/M cells (genomic DNA per million cells). Endoscopy examination and colonic biopsy demonstrated clinical and microscopic features of Crohn's disease (Figure 1). HHV‐6B DNA PCR was positive in colonic biopsy (1808 gec/M cells) with high levels of virus encoded sncRNAs (Figure 2). Antivirals were started with a monitoring of HHV‐6 viremia. The patient was treated by 14 days of ganciclovir. The whole blood viral load decreased from 7051 to 3675 gec/M cells. HHV‐6 DNA test was negative in hair follicles. The colitis manifestations resolved. Cidofovir treatment was proposed for the treatment of this persistent HHV‐6 infection. He received six infusions of 400 mg each without significant effect on HHV‐6 viral load (3934 gec/M cells). Six months later, on February 2011, it remained 8061 gec/M cells. Colitis manifestations resumed, and a new endoscopy confirmed luminal stenosis of the transverse colon. At that time, a treatment with TNF alpha blocker (adalimumab) was started. After 8‐year treatment with adalimumab, HHV‐6 viral load in whole blood remained stable at 905‐1084 gec/M cells. The patient did not develop any flare of DRESS. The Crohn's‐like colitis was under control.
FIGURE 1 Histological examination of a biopsy of large intestine. A, Hematein eosin saffron: original magnification x 5: The mucosa contains a dense inflammatory infiltrate with focal crypt architectural distortion. B, Hematein eosin saffron: original magnification x 200: A focal active colitis with crypt abscess formation (star) and numerous lymphocytes and eosinophils (arrow)
FIGURE 2 Demonstration of transcription of HHV‐6 encoded sncRNA‐U14 in colon (the study was done on 2019 on stored biopsy samples from 2010). A, Detection of HHV‐6 encoded sncRNA‐U14 in the colonic biopsy of the DRESS patient. FFPE colonic tissue biopsies were used for the analysis. Three different representative images from different regions of the tissue have been shown. Imaging was done using an epifluorescence microscope. The scale bars represent 100 m. B, Detection of HHV‐6 encoded sncRNA‐U14 in HHV‐6 negative colonic biopsy. Two representative images are shown from different regions of a single biopsy. C, Detection of sncRNA‐U14 by FISH in various in vivo cell types. HHV‐6A infected HSB‐2 cells were used as positive control for sncRNA‐U14 FISH analysis. Uninfected HSB‐2 cells were used as negative control. Human small RNA U6 was used as a FISH positive control. At the same time, a scrambled small RNA probe was used as a FISH negative control. Imaging was done on a SP5 confocal microscope. The scale bars represent 100 m
Subsequently, the cellular localization of HHV‐6 genome in leukocyte subpopulations was studied by flow cytometry and PCR because the patient had an unusual persistent HHV‐6 infection after DRESS. HHV‐6 DNA was present only in T lymphocytes fraction with 1212 gec/M cells and was absent from all other fractions (B lymphocytes, monocytes, NK cells, polymorphonuclear cells). Apart from this high HHV‐6 load, the patient had no clinical manifestation and all biological tests were normal.
3 DISCUSSION
This case illustrates a severe case of sulfasalazine‐induced DRESS with Regiscar criteria score of 7 having reactivation of HHV‐6B.
9
HHV‐6 is a lymphotropic virus that predominantly infects T‐cell lymphocyte. It possesses telomere‐like repeats at the terminal regions of its genome that facilitate latency by a unique mechanism of viral latency, integration into the host telomeres, rather than by episome formation. HHV‐6 reactivation plays a major role in DRESS syndrome.
This observation is of great interest because the patient had a persistent HHV‐6 infection after DRESS and developed a Crohn's‐like colitis. Relapsing course of DRESS is usual, and flares are frequently associated with short duration HHV‐6 reactivations.
1
,
4
In this case, HHV‐6 was regularly detected even a long time after DRESS. Persistent HHV‐6 infection was confirmed by a high level of viral DNA in whole blood but HHV‐6B being present only in T lymphocytes. The viral loads below 6 log gec/M cells and negative in hair follicles excluded the presence of inherited chromosomally integrated HHV‐6. Miyagawa et al recently reported 3 cases of DRESS in which HHV‐6 DNA was detected mainly in peripheral T lymphocytes long after resolution of DRESS (until 700 days with HHV‐6 viral DNA up to 3 log copies/million cells).
10
The major point in our case was the demonstration of HHV‐6‐induced colitis. High HHV‐6 DNA load and more interestingly a very high level of viral sncRNA confirmed HHV‐6 reactivation in colon (Figure 1, 2). Antiviral drugs induced a control of colitis symptoms but did not significantly decrease HHV‐6 viral load in whole blood. It may be possible that the antiviral treatment controlled HHV‐6 DNA replication that marks classical active viral infection. However, transient viral reactivation characterized by transcription of HHV‐6 sncRNA‐U14, in the absence of viral DNA replication, cannot be controlled by current antiherpesvirus drugs that target only the viral DNA replication.
8
The residual HHV‐6 viral load possibly represents a latent HHV‐6 infection that can persist as episomal or integrated form in T lymphocytes and other cells.
Crohn's disease and more globally inflammatory bowed diseases may be associated with spondylarthritis and stay silent for a long time. Crohn's disease has not been reported as a consequence of DRESS. Patient with Crohn's disease is at risk for the development of DRESS because they are frequently treated by sulfasalazine or azathrioprine which are well known inducers of DRESS. A previous control study did not find evidence of HHV‐6 infection in patients with Crohn's disease as compared to the controls.
11
In another study HHV‐6B antigen positivity and intensity of immunohistochemistry correlated with endoscopy severity of Crohn's disease.
12
We postulate that HHV‐6 could trigger a previous asymptomatic Crohn's disease. In our patient, the Crohn's disease remained and was subsequently treated by TNF alpha blocker without any relapse of DRESS.
4 CONCLUSION
Through this case report, we would like to emphasize on the advantage of new tools (demonstration of HHV6 sncRNA in tissue sample) for the diagnosis of HHV‐6 reactivation.
CONFLICT OF INTEREST
The authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
DV: involved in the diagnosis and care of the patient and wrote the manuscript. GDA: involved in the virological tests and their interpretation. PAL: involved in the diagnosis and care of the patient. BP: involved in the virological tests and their interpretation. DL: performed the pathological analysis. PBK: performed the HHV‐6 snc‐RNA study and its interpretation. All authors: involved in the critical revision and final approval of the manuscript.
ETHICAL APPROVAL
The article describes a case report. Therefore, no additional permission from our Ethics Committee was required.
ACKNOWLEDGMENTS
Informed consent was obtained for this case.
DATA AVAILABILITY STATEMENT
All data that support the findings of this study are included in this case report. Details are available on request from the corresponding author. | Recovered | ReactionOutcome | CC BY-NC-ND | 33598255 | 18,874,347 | 2021-02 |
What was the outcome of reaction 'Face oedema'? | Chronic persistent HHV-6B infection after sulfasalazine-induced DRESS with demonstration of HHV-6 encoded small noncoding RNAs (sncRNAs) in Crohn's-like colitis: Case report.
A sulfasalazine-induced DRESS (Drug Reactivation with Eosinophilia and Systemic Symptoms) was complicated by a Crohn's-like colitis. We demonstrated HHV-6 reactivation with presence of HHV-6 DNA and small noncoding RNA in colonic lesions. This observation confirms the major role of HHV-6 reactivation in DRESS manifestations and the importance of looking for HHV-6 reactivation in DRESS.
1 INTRODUCTION
Drug reaction with eosinophilia and systemic symptoms (DRESS), also referred to as drug‐induced hypersensitivity syndrome (DIHS), is a severe hypersensitivity drug reaction associating skin eruption and organ involvement. We report a 32‐year‐old man with sulfasalazine‐induced DRESS with reactivation of human herpesvirus 6B (HHV‐6B). His case is remarkable because he had chronic persistent HHV‐6 infection with colonic infection and development of Crohn's disease.
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug hypersensitivity syndrome.
1
,
2
The pathophysiology of this syndrome is not fully understood, but human herpesvirus 6 (HHV‐6) reactivation plays a major role in its development.
1
,
2
,
3
,
4
In most cases, duration of HHV‐6 reactivation is limited.
We report a typical case of sulfasalazine‐induced DRESS with reactivation of HHV‐6B in a patient with spondyloarthritis who developed a Crohn's‐like colitis after DRESS. We demonstrated a chronic persistent HHV‐6 infection with the presence of HHV‐6 DNA and encoded small noncoding RNA (sncRNA) in colonic lesions.
2 CASE REPORT
A 32‐year‐old man was treated for axial and peripheral spondyloarthritis by sulfasalazine without any symptom suggestive of Crohn's disease. He presented 3 weeks after the beginning of sulfasalazine on August 2009 with exanthema, facial edema, high fever, and diffuse lymphadenopathy. The first blood tests confirmed an eosinophilia (3200 cells/µL), a mononucleosis syndrome with atypical lymphocytes and an hepatitis with a drop of prothrombin ratio to 65%. He subsequently developed pneumonitis and colitis. A diagnosis of sulfasalazine‐induced DRESS was made, and sulfasalazine was discontinued. The patient was treated by intravenous methylprednisolone and intravenous immunoglobulins. Intravenous corticosteroids were changed for oral prednisone (1 mg/kg/d). Visceral manifestations progressively improved. HHV‐6B viral load in whole blood was at a high level (23 495 gec/M cells).
5
,
6
,
7
Epstein‐Barr virus and cytomegalovirus viral loads measured by PCR remained negative.
Corticosteroids were progressively tapered within 6‐month period, and HHV‐6 viral load was monitored. The patient developed diarrhea with bloody bowel movement. On February 2010, HHV‐6 viral load was high at 32 737 gec/M cells (genomic DNA per million cells). Endoscopy examination and colonic biopsy demonstrated clinical and microscopic features of Crohn's disease (Figure 1). HHV‐6B DNA PCR was positive in colonic biopsy (1808 gec/M cells) with high levels of virus encoded sncRNAs (Figure 2). Antivirals were started with a monitoring of HHV‐6 viremia. The patient was treated by 14 days of ganciclovir. The whole blood viral load decreased from 7051 to 3675 gec/M cells. HHV‐6 DNA test was negative in hair follicles. The colitis manifestations resolved. Cidofovir treatment was proposed for the treatment of this persistent HHV‐6 infection. He received six infusions of 400 mg each without significant effect on HHV‐6 viral load (3934 gec/M cells). Six months later, on February 2011, it remained 8061 gec/M cells. Colitis manifestations resumed, and a new endoscopy confirmed luminal stenosis of the transverse colon. At that time, a treatment with TNF alpha blocker (adalimumab) was started. After 8‐year treatment with adalimumab, HHV‐6 viral load in whole blood remained stable at 905‐1084 gec/M cells. The patient did not develop any flare of DRESS. The Crohn's‐like colitis was under control.
FIGURE 1 Histological examination of a biopsy of large intestine. A, Hematein eosin saffron: original magnification x 5: The mucosa contains a dense inflammatory infiltrate with focal crypt architectural distortion. B, Hematein eosin saffron: original magnification x 200: A focal active colitis with crypt abscess formation (star) and numerous lymphocytes and eosinophils (arrow)
FIGURE 2 Demonstration of transcription of HHV‐6 encoded sncRNA‐U14 in colon (the study was done on 2019 on stored biopsy samples from 2010). A, Detection of HHV‐6 encoded sncRNA‐U14 in the colonic biopsy of the DRESS patient. FFPE colonic tissue biopsies were used for the analysis. Three different representative images from different regions of the tissue have been shown. Imaging was done using an epifluorescence microscope. The scale bars represent 100 m. B, Detection of HHV‐6 encoded sncRNA‐U14 in HHV‐6 negative colonic biopsy. Two representative images are shown from different regions of a single biopsy. C, Detection of sncRNA‐U14 by FISH in various in vivo cell types. HHV‐6A infected HSB‐2 cells were used as positive control for sncRNA‐U14 FISH analysis. Uninfected HSB‐2 cells were used as negative control. Human small RNA U6 was used as a FISH positive control. At the same time, a scrambled small RNA probe was used as a FISH negative control. Imaging was done on a SP5 confocal microscope. The scale bars represent 100 m
Subsequently, the cellular localization of HHV‐6 genome in leukocyte subpopulations was studied by flow cytometry and PCR because the patient had an unusual persistent HHV‐6 infection after DRESS. HHV‐6 DNA was present only in T lymphocytes fraction with 1212 gec/M cells and was absent from all other fractions (B lymphocytes, monocytes, NK cells, polymorphonuclear cells). Apart from this high HHV‐6 load, the patient had no clinical manifestation and all biological tests were normal.
3 DISCUSSION
This case illustrates a severe case of sulfasalazine‐induced DRESS with Regiscar criteria score of 7 having reactivation of HHV‐6B.
9
HHV‐6 is a lymphotropic virus that predominantly infects T‐cell lymphocyte. It possesses telomere‐like repeats at the terminal regions of its genome that facilitate latency by a unique mechanism of viral latency, integration into the host telomeres, rather than by episome formation. HHV‐6 reactivation plays a major role in DRESS syndrome.
This observation is of great interest because the patient had a persistent HHV‐6 infection after DRESS and developed a Crohn's‐like colitis. Relapsing course of DRESS is usual, and flares are frequently associated with short duration HHV‐6 reactivations.
1
,
4
In this case, HHV‐6 was regularly detected even a long time after DRESS. Persistent HHV‐6 infection was confirmed by a high level of viral DNA in whole blood but HHV‐6B being present only in T lymphocytes. The viral loads below 6 log gec/M cells and negative in hair follicles excluded the presence of inherited chromosomally integrated HHV‐6. Miyagawa et al recently reported 3 cases of DRESS in which HHV‐6 DNA was detected mainly in peripheral T lymphocytes long after resolution of DRESS (until 700 days with HHV‐6 viral DNA up to 3 log copies/million cells).
10
The major point in our case was the demonstration of HHV‐6‐induced colitis. High HHV‐6 DNA load and more interestingly a very high level of viral sncRNA confirmed HHV‐6 reactivation in colon (Figure 1, 2). Antiviral drugs induced a control of colitis symptoms but did not significantly decrease HHV‐6 viral load in whole blood. It may be possible that the antiviral treatment controlled HHV‐6 DNA replication that marks classical active viral infection. However, transient viral reactivation characterized by transcription of HHV‐6 sncRNA‐U14, in the absence of viral DNA replication, cannot be controlled by current antiherpesvirus drugs that target only the viral DNA replication.
8
The residual HHV‐6 viral load possibly represents a latent HHV‐6 infection that can persist as episomal or integrated form in T lymphocytes and other cells.
Crohn's disease and more globally inflammatory bowed diseases may be associated with spondylarthritis and stay silent for a long time. Crohn's disease has not been reported as a consequence of DRESS. Patient with Crohn's disease is at risk for the development of DRESS because they are frequently treated by sulfasalazine or azathrioprine which are well known inducers of DRESS. A previous control study did not find evidence of HHV‐6 infection in patients with Crohn's disease as compared to the controls.
11
In another study HHV‐6B antigen positivity and intensity of immunohistochemistry correlated with endoscopy severity of Crohn's disease.
12
We postulate that HHV‐6 could trigger a previous asymptomatic Crohn's disease. In our patient, the Crohn's disease remained and was subsequently treated by TNF alpha blocker without any relapse of DRESS.
4 CONCLUSION
Through this case report, we would like to emphasize on the advantage of new tools (demonstration of HHV6 sncRNA in tissue sample) for the diagnosis of HHV‐6 reactivation.
CONFLICT OF INTEREST
The authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
DV: involved in the diagnosis and care of the patient and wrote the manuscript. GDA: involved in the virological tests and their interpretation. PAL: involved in the diagnosis and care of the patient. BP: involved in the virological tests and their interpretation. DL: performed the pathological analysis. PBK: performed the HHV‐6 snc‐RNA study and its interpretation. All authors: involved in the critical revision and final approval of the manuscript.
ETHICAL APPROVAL
The article describes a case report. Therefore, no additional permission from our Ethics Committee was required.
ACKNOWLEDGMENTS
Informed consent was obtained for this case.
DATA AVAILABILITY STATEMENT
All data that support the findings of this study are included in this case report. Details are available on request from the corresponding author. | Recovered | ReactionOutcome | CC BY-NC-ND | 33598255 | 18,874,347 | 2021-02 |
What was the outcome of reaction 'Mononucleosis syndrome'? | Chronic persistent HHV-6B infection after sulfasalazine-induced DRESS with demonstration of HHV-6 encoded small noncoding RNAs (sncRNAs) in Crohn's-like colitis: Case report.
A sulfasalazine-induced DRESS (Drug Reactivation with Eosinophilia and Systemic Symptoms) was complicated by a Crohn's-like colitis. We demonstrated HHV-6 reactivation with presence of HHV-6 DNA and small noncoding RNA in colonic lesions. This observation confirms the major role of HHV-6 reactivation in DRESS manifestations and the importance of looking for HHV-6 reactivation in DRESS.
1 INTRODUCTION
Drug reaction with eosinophilia and systemic symptoms (DRESS), also referred to as drug‐induced hypersensitivity syndrome (DIHS), is a severe hypersensitivity drug reaction associating skin eruption and organ involvement. We report a 32‐year‐old man with sulfasalazine‐induced DRESS with reactivation of human herpesvirus 6B (HHV‐6B). His case is remarkable because he had chronic persistent HHV‐6 infection with colonic infection and development of Crohn's disease.
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug hypersensitivity syndrome.
1
,
2
The pathophysiology of this syndrome is not fully understood, but human herpesvirus 6 (HHV‐6) reactivation plays a major role in its development.
1
,
2
,
3
,
4
In most cases, duration of HHV‐6 reactivation is limited.
We report a typical case of sulfasalazine‐induced DRESS with reactivation of HHV‐6B in a patient with spondyloarthritis who developed a Crohn's‐like colitis after DRESS. We demonstrated a chronic persistent HHV‐6 infection with the presence of HHV‐6 DNA and encoded small noncoding RNA (sncRNA) in colonic lesions.
2 CASE REPORT
A 32‐year‐old man was treated for axial and peripheral spondyloarthritis by sulfasalazine without any symptom suggestive of Crohn's disease. He presented 3 weeks after the beginning of sulfasalazine on August 2009 with exanthema, facial edema, high fever, and diffuse lymphadenopathy. The first blood tests confirmed an eosinophilia (3200 cells/µL), a mononucleosis syndrome with atypical lymphocytes and an hepatitis with a drop of prothrombin ratio to 65%. He subsequently developed pneumonitis and colitis. A diagnosis of sulfasalazine‐induced DRESS was made, and sulfasalazine was discontinued. The patient was treated by intravenous methylprednisolone and intravenous immunoglobulins. Intravenous corticosteroids were changed for oral prednisone (1 mg/kg/d). Visceral manifestations progressively improved. HHV‐6B viral load in whole blood was at a high level (23 495 gec/M cells).
5
,
6
,
7
Epstein‐Barr virus and cytomegalovirus viral loads measured by PCR remained negative.
Corticosteroids were progressively tapered within 6‐month period, and HHV‐6 viral load was monitored. The patient developed diarrhea with bloody bowel movement. On February 2010, HHV‐6 viral load was high at 32 737 gec/M cells (genomic DNA per million cells). Endoscopy examination and colonic biopsy demonstrated clinical and microscopic features of Crohn's disease (Figure 1). HHV‐6B DNA PCR was positive in colonic biopsy (1808 gec/M cells) with high levels of virus encoded sncRNAs (Figure 2). Antivirals were started with a monitoring of HHV‐6 viremia. The patient was treated by 14 days of ganciclovir. The whole blood viral load decreased from 7051 to 3675 gec/M cells. HHV‐6 DNA test was negative in hair follicles. The colitis manifestations resolved. Cidofovir treatment was proposed for the treatment of this persistent HHV‐6 infection. He received six infusions of 400 mg each without significant effect on HHV‐6 viral load (3934 gec/M cells). Six months later, on February 2011, it remained 8061 gec/M cells. Colitis manifestations resumed, and a new endoscopy confirmed luminal stenosis of the transverse colon. At that time, a treatment with TNF alpha blocker (adalimumab) was started. After 8‐year treatment with adalimumab, HHV‐6 viral load in whole blood remained stable at 905‐1084 gec/M cells. The patient did not develop any flare of DRESS. The Crohn's‐like colitis was under control.
FIGURE 1 Histological examination of a biopsy of large intestine. A, Hematein eosin saffron: original magnification x 5: The mucosa contains a dense inflammatory infiltrate with focal crypt architectural distortion. B, Hematein eosin saffron: original magnification x 200: A focal active colitis with crypt abscess formation (star) and numerous lymphocytes and eosinophils (arrow)
FIGURE 2 Demonstration of transcription of HHV‐6 encoded sncRNA‐U14 in colon (the study was done on 2019 on stored biopsy samples from 2010). A, Detection of HHV‐6 encoded sncRNA‐U14 in the colonic biopsy of the DRESS patient. FFPE colonic tissue biopsies were used for the analysis. Three different representative images from different regions of the tissue have been shown. Imaging was done using an epifluorescence microscope. The scale bars represent 100 m. B, Detection of HHV‐6 encoded sncRNA‐U14 in HHV‐6 negative colonic biopsy. Two representative images are shown from different regions of a single biopsy. C, Detection of sncRNA‐U14 by FISH in various in vivo cell types. HHV‐6A infected HSB‐2 cells were used as positive control for sncRNA‐U14 FISH analysis. Uninfected HSB‐2 cells were used as negative control. Human small RNA U6 was used as a FISH positive control. At the same time, a scrambled small RNA probe was used as a FISH negative control. Imaging was done on a SP5 confocal microscope. The scale bars represent 100 m
Subsequently, the cellular localization of HHV‐6 genome in leukocyte subpopulations was studied by flow cytometry and PCR because the patient had an unusual persistent HHV‐6 infection after DRESS. HHV‐6 DNA was present only in T lymphocytes fraction with 1212 gec/M cells and was absent from all other fractions (B lymphocytes, monocytes, NK cells, polymorphonuclear cells). Apart from this high HHV‐6 load, the patient had no clinical manifestation and all biological tests were normal.
3 DISCUSSION
This case illustrates a severe case of sulfasalazine‐induced DRESS with Regiscar criteria score of 7 having reactivation of HHV‐6B.
9
HHV‐6 is a lymphotropic virus that predominantly infects T‐cell lymphocyte. It possesses telomere‐like repeats at the terminal regions of its genome that facilitate latency by a unique mechanism of viral latency, integration into the host telomeres, rather than by episome formation. HHV‐6 reactivation plays a major role in DRESS syndrome.
This observation is of great interest because the patient had a persistent HHV‐6 infection after DRESS and developed a Crohn's‐like colitis. Relapsing course of DRESS is usual, and flares are frequently associated with short duration HHV‐6 reactivations.
1
,
4
In this case, HHV‐6 was regularly detected even a long time after DRESS. Persistent HHV‐6 infection was confirmed by a high level of viral DNA in whole blood but HHV‐6B being present only in T lymphocytes. The viral loads below 6 log gec/M cells and negative in hair follicles excluded the presence of inherited chromosomally integrated HHV‐6. Miyagawa et al recently reported 3 cases of DRESS in which HHV‐6 DNA was detected mainly in peripheral T lymphocytes long after resolution of DRESS (until 700 days with HHV‐6 viral DNA up to 3 log copies/million cells).
10
The major point in our case was the demonstration of HHV‐6‐induced colitis. High HHV‐6 DNA load and more interestingly a very high level of viral sncRNA confirmed HHV‐6 reactivation in colon (Figure 1, 2). Antiviral drugs induced a control of colitis symptoms but did not significantly decrease HHV‐6 viral load in whole blood. It may be possible that the antiviral treatment controlled HHV‐6 DNA replication that marks classical active viral infection. However, transient viral reactivation characterized by transcription of HHV‐6 sncRNA‐U14, in the absence of viral DNA replication, cannot be controlled by current antiherpesvirus drugs that target only the viral DNA replication.
8
The residual HHV‐6 viral load possibly represents a latent HHV‐6 infection that can persist as episomal or integrated form in T lymphocytes and other cells.
Crohn's disease and more globally inflammatory bowed diseases may be associated with spondylarthritis and stay silent for a long time. Crohn's disease has not been reported as a consequence of DRESS. Patient with Crohn's disease is at risk for the development of DRESS because they are frequently treated by sulfasalazine or azathrioprine which are well known inducers of DRESS. A previous control study did not find evidence of HHV‐6 infection in patients with Crohn's disease as compared to the controls.
11
In another study HHV‐6B antigen positivity and intensity of immunohistochemistry correlated with endoscopy severity of Crohn's disease.
12
We postulate that HHV‐6 could trigger a previous asymptomatic Crohn's disease. In our patient, the Crohn's disease remained and was subsequently treated by TNF alpha blocker without any relapse of DRESS.
4 CONCLUSION
Through this case report, we would like to emphasize on the advantage of new tools (demonstration of HHV6 sncRNA in tissue sample) for the diagnosis of HHV‐6 reactivation.
CONFLICT OF INTEREST
The authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
DV: involved in the diagnosis and care of the patient and wrote the manuscript. GDA: involved in the virological tests and their interpretation. PAL: involved in the diagnosis and care of the patient. BP: involved in the virological tests and their interpretation. DL: performed the pathological analysis. PBK: performed the HHV‐6 snc‐RNA study and its interpretation. All authors: involved in the critical revision and final approval of the manuscript.
ETHICAL APPROVAL
The article describes a case report. Therefore, no additional permission from our Ethics Committee was required.
ACKNOWLEDGMENTS
Informed consent was obtained for this case.
DATA AVAILABILITY STATEMENT
All data that support the findings of this study are included in this case report. Details are available on request from the corresponding author. | Recovered | ReactionOutcome | CC BY-NC-ND | 33598255 | 18,874,347 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Febrile neutropenia'. | Toxic epidermal necrolysis associated with nivolumab treatment for head and neck cancer.
This report is the first to document TEN caused by nivolumab treatment in head and neck cancer. We believe this article can contribute significantly in understanding the principles of nivolumab treatment in patients with head and neck cancer.
1 INTRODUCTION
Nivolumab, an antiprogrammed death‐1 (PD‐1) antibody, is an immune‐checkpoint inhibitor. According to the results of the CheckMate‐141 study, which compared nivolumab and a physician‐selected treatment modality for recurrent/metastatic head and neck squamous cell carcinoma with a history of chemotherapy including platinum, nivolumab significantly increases the overall survival rate.
1
Considering the results of this report, nivolumab was approved in the United States in November 2016 and in Japan in March 2017 as a treatment modality for patients with recurrent/metastatic head and neck cancer, who had been previously treated with platinum‐containing drugs. Currently, the clinical benefits of nivolumab therapy have been recognized not only in head and neck cancers but also in other types of cancers such as malignant melanoma, non‐small cell lung cancer, renal cell cancer, gastric cancer, and Hodgkin's lymphoma. Various immune‐related adverse events associated with nivolumab have been reported, because the mechanism of action of the drug is different from that of conventional anticancer drugs. However, the frequency of severe skin complications is considerably less.
Toxic epidermal necrosis (TEN) is a disease with fever and widespread erythema, erosion, blisters, and mucosal rash on the skin. TEN is a rare, albeit serious disease with a mortality rate of approximately 30%.
2
We herein report a patient with squamous cell carcinoma of the tongue who developed TEN after nivolumab treatment.
2 CASE REPORT
A 76‐year‐old man with cancer of the right side of the tongue (cT3N2bM0) underwent hemiglossectomy of the right side and dissection of the right side of the neck followed by reconstruction using anterolateral thigh flap. Postoperative pathological examination showed pT3N2b and negative surgical margins and extranodal invasion. The patient was treated with 60 Gy/30 Fr postoperative radiation therapy, because a vertical margin of only 4 mm could be obtained. Five months after surgery, multiple cavitatory lesions were detected in the lungs in the computed tomography (CT) scans. Bronchoscopic biopsy revealed that the tongue cancer had metastasized to the lungs (Figure 1). Six months after the surgery, chemotherapy with cisplatin plus 5‐FU (PF, CDDP 60 mg/m2, 5‐FU 750 mg/m2, a reduced dosage was used due to renal dysfunction) was initiated. Considering the possibility of chronic obstructive pulmonary disease and cavitatory lesions in the lung, cetuximab was not administered. He developed febrile neutropenia 13 days after the initiation of PF treatment and was urgently hospitalized. CT scans showed the progression of the lung metastases. Considering the possibility of platinum resistance, the first dose of nivolumab (240 mg/body) was administered 7 months after the surgery and the second dose was administered 2 weeks later. A rash appeared on the trunk region on the 27th day after the administration of the first dose of Nivolumab. Since fever of more than 38°C also developed on the 28th day, we suspected drug eruption and antihistamines were administered to the patient. Due to the exacerbation of the skin rash and fever, he was hospitalized on the 29th day. On the 31st day, a dermatologist diagnosed the patient with Stevens‐Johnson syndrome (SJS) (Figure 2A). Pathological examination of a skin specimen showed the presence of necrotic keratinocytes and vacuolar degeneration in the epidermis (Figure 2B). There was no history of usage of any drug other than Nivolumab. Hence, nivolumab was suspected to be the cause of SJS. On the same day, steroid pulse therapy with 1000 mg methylprednisolone was initiated, and cefepime was administered to prevent secondary infection. Steroid pulse therapy was continued for 3 days, after which it was transferred to oral administration with 50 mg prednisolone. On the 35th day, the dermatologist diagnosed the patient with TEN considering the spread of erythema and erosion (Figure 2C). According to the diagnostic criteria for TEN, the presence of three major items (a) Blisters and erosions exceeding 10% of the body surface area, (b) Fever, (c) Staphylococcal scalded skin syndrome, toxic shock syndrome, contagious impetigo, acute generalized exanthematous pustulosis, or autoimmune blistering) and of four sub‐items (a) Flat, atypical target legions initially, (b) Mucosal lesions at the skin mucosa transition, (c) Objective generalized symptoms, subjective malaise, or eating disorders, and (d) Histopathological changes in the epidermis such as necrosis 200 times more than 10 epidermal cell necrosis in a visual field) was confirmed. From the 37th day, intravenous immunoglobulin 40 mg/kg/d was administered for 5 days. From the 43rd day, symptoms improved. On the 49th day, the reduction in dose of predonin was initiated, and on the 66th day, treatment with predonin was completed. All skin eruptions had epithelialized, and only pigmentations were evident. However, his respiratory condition worsened from the 42nd day, and treatment with morphine was initiated from the 44th day to relieve the respiratory distress. CT scan advised on the 44th day showed increased lung metastatic lesions and pleural effusion (Figure 3). We believed that the deterioration of respiratory function occurred due to increase in cancerous lesions. Hence, a ventilator was not used. His respiratory condition continued to worsen, and he died on the 67th day. The clinical course of the case is depicted in Figure 4.
Figure 1 Computed tomography and positron emission tomography (PET) images of the lung metastases. Multiple metastases with cavity formation in the lungs. PET also shows fluorodeoxyglucose accumulation at the same sites
Figure 2 Skin photograph and histological image at the onset of Stevens‐Johnson syndrome (SJS)/ Toxic epidermal necrolysis (TEN). A, Skin photograph at the onset of SJS. B, Necrotic changes in epidermal keratinocytes, vacuolar degeneration in the epidermal layer (arrow), and lymphocyte infiltration into the epidermal layer (arrow head). C, Skin photograph at the onset of TEN
Figure 3 Computed tomography image of lungs on day 44. Increase in lung metastasis with cavitation and pleural effusion
Figure 4 Schema of symptom transition. The upper row shows the course of the respiratory condition and skin symptoms of the patient. The bottom row outlines the details of the instituted treatment
3 DISCUSSION
SJS and TEN present as widespread erythema, erosion, blisters, mucosal rash, and fever. Frequently, they are caused by drugs, but can also be caused by infections from mycoplasma or certain viruses.
2
Apoptosis of epidermal and mucosal epithelial cells induced by CD8+ T cells is considered as the etiology of both SJS and TEN. However, the detailed mechanism of development of SJS and TEN has not been elucidated. These diseases are rare but serious. In particular, the mortality rate associated with the most severe form of TEN is as high as 30%. Most cases of TEN develop from SJS. According to the Japanese diagnostic criteria for SJS and TEN, SJS is diagnosed if erosion involves less than 10% body surface area, and TEN is diagnosed if it involves 10% or more. Our patient was initially diagnosed with SJS and subsequently with TEN after worsening of skin symptoms.
When SJS or TEN are caused by a drug, they develop within 1‐2 weeks from the beginning of drug therapy. In our patient, skin symptoms appeared on the 27th day after administration of the first dose of nivolumab. A relatively long time had passed from the administration of nivolumab until the appearance of skin symptoms. However, as no new drug therapy, apart from nivolumab, was ongoing, nivolumab was determined to be the causative drug for the onset of TEN. In ALDEN, an algorithm developed for determining the drug causality in SJS and TEN, a period of onset of 5 to 28 days after the drug administration is “suggestive,” which is consistent with the course of this patient.
3
However, we must understand that severe skin adverse events can occur even 4 weeks after drug administration.
SCORTEN is an assessment of the severity of SJS and TEN, and we performed a retrospective study on this case.
4
On admission, age and the presence of a malignancy were positive items, and the area of epidermal exfoliation, pulse, blood urea nitrogen (BUN), and blood glucose were negative items. HCO3
‐ in the blood was not measured. As a result, SCORTEN in this case was 2 or 3, and the severity was judged to be at the mild to moderate level. In the RegiSCAR study, the mortality rate of acute SJS and TEN was determined to be 23%.
5
The acute cause of death is sepsis, which occurs due to secondary bacterial and fungal infections in the skin and mucous membrane lesions. Pneumonia is a major complication of SJS and TEN, with approximately half of the patients requiring a ventilator, which is often associated with a poor prognosis.
6
Our patient showed improvement in skin symptoms, but died due to worsening of the respiratory function. Increase in lung metastatic lesions and associated pleural effusion were the principal causes of respiratory deterioration. Furthermore, it was determined that respiratory function was further deteriorated due to pneumonia caused by SJS or TEN. However, it is difficult to arrange ventilators for patients with cancer that cannot be cured.
SJS and TEN caused by nivolumab have been reported in patients with melanoma, hepatocellular carcinoma, non‐small cell lung cancer, and lymphoma, but this is the first reported case of SJS or TEN associated with head and neck cancer.
7
,
8
,
9
,
10
SJS or TEN was not observed in adverse event reports in the CheckMate‐141 study.
1
In addition, only 2 cases of grade 3 or grade 4 skin adverse events were reported in the international randomized phase 3 study (n = 945) with nivolumab and ipilimumab for advanced melanoma.
11
Deaths caused by TEN have been reported with nivolumab use for metastatic melanoma and lymphoma.
7
,
9
The mechanism by which immune‐checkpoint inhibitors such as anti‐PD‐1 antibody and anticytotoxic T lymphocyte‐associated‐4 antibody cause SJS and TEN has not been elucidated. Several drugs such as antibacterial, antiepileptic, and nonsteroidal anti‐inflammatory drugs, and allopurinol are listed as high‐risk drugs for the development of SJS and TEN. Currently, molecular‐targeting drugs and immune‐checkpoint inhibitors used for cancer treatment are not classified as risk drugs but are expected to be assessed for risk after the documentation of adequate cases treated with these anticancer agents in the future.
In head and neck cancer, nivolumab is approved as a treatment modality for patients with platinum‐resistant recurrence/metastasis. Several patients show distant metastasis or local recurrence with a compromised general medical condition. Prior chemotherapy is also a factor that can affect the general condition. If SJS or TEN develops in such patients, it will be fatal. In addition, treatment guidelines for SJS and TEN recommend plasma‐exchange therapy in cases of resistance to steroid pulse therapy. However, plasma‐exchange therapy should be carefully used in patients with cancer. In our patient, steroid pulse therapy was not effective immediately, and hence, plasma‐exchange therapy was considered. However, due to the increase in lung metastatic lesions and worsening of the respiratory condition, plasma‐exchange therapy was not initiated, and intravenous immunoglobulin was administered. Infliximab, an antitumor necrosis factor‐α antibody, may be administered for severe skin adverse events, but no reports on its use in patients with adverse skin events caused by nivolumab have been documented.
11
It is necessary to determine a suitable treatment modality for TEN considering the prognosis and disease control status of each case.
With the progress of immunotherapy for cancer, many patients are treated with immunotherapeutic agents worldwide. In the future, the number of patients developing severe skin adverse events, such as SJS or TEN, is expected to increase. For immunotherapy, the patient's general medical condition should be evaluated to manage the adverse events by early detection and appropriate treatment planning.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
KK: involved in conceptualization and writing; DS, MS, YM, SH, TS, and NK: involved in investigation and review; MN, TH: involved in supervision and review.
Funding information
This study was supported by JSPS KAKENHI, 19K18795.
ETHICAL APPROVAL
Written informed consent was obtained from the patient in the Japanese language to publish his clinical details including his photograph.
ACKNOWLEDGMENTS
Published with written consent of the patient. | CISPLATIN, FLUOROURACIL | DrugsGivenReaction | CC BY-NC | 33598257 | 19,034,916 | 2021-02 |
What was the dosage of drug 'CISPLATIN'? | Toxic epidermal necrolysis associated with nivolumab treatment for head and neck cancer.
This report is the first to document TEN caused by nivolumab treatment in head and neck cancer. We believe this article can contribute significantly in understanding the principles of nivolumab treatment in patients with head and neck cancer.
1 INTRODUCTION
Nivolumab, an antiprogrammed death‐1 (PD‐1) antibody, is an immune‐checkpoint inhibitor. According to the results of the CheckMate‐141 study, which compared nivolumab and a physician‐selected treatment modality for recurrent/metastatic head and neck squamous cell carcinoma with a history of chemotherapy including platinum, nivolumab significantly increases the overall survival rate.
1
Considering the results of this report, nivolumab was approved in the United States in November 2016 and in Japan in March 2017 as a treatment modality for patients with recurrent/metastatic head and neck cancer, who had been previously treated with platinum‐containing drugs. Currently, the clinical benefits of nivolumab therapy have been recognized not only in head and neck cancers but also in other types of cancers such as malignant melanoma, non‐small cell lung cancer, renal cell cancer, gastric cancer, and Hodgkin's lymphoma. Various immune‐related adverse events associated with nivolumab have been reported, because the mechanism of action of the drug is different from that of conventional anticancer drugs. However, the frequency of severe skin complications is considerably less.
Toxic epidermal necrosis (TEN) is a disease with fever and widespread erythema, erosion, blisters, and mucosal rash on the skin. TEN is a rare, albeit serious disease with a mortality rate of approximately 30%.
2
We herein report a patient with squamous cell carcinoma of the tongue who developed TEN after nivolumab treatment.
2 CASE REPORT
A 76‐year‐old man with cancer of the right side of the tongue (cT3N2bM0) underwent hemiglossectomy of the right side and dissection of the right side of the neck followed by reconstruction using anterolateral thigh flap. Postoperative pathological examination showed pT3N2b and negative surgical margins and extranodal invasion. The patient was treated with 60 Gy/30 Fr postoperative radiation therapy, because a vertical margin of only 4 mm could be obtained. Five months after surgery, multiple cavitatory lesions were detected in the lungs in the computed tomography (CT) scans. Bronchoscopic biopsy revealed that the tongue cancer had metastasized to the lungs (Figure 1). Six months after the surgery, chemotherapy with cisplatin plus 5‐FU (PF, CDDP 60 mg/m2, 5‐FU 750 mg/m2, a reduced dosage was used due to renal dysfunction) was initiated. Considering the possibility of chronic obstructive pulmonary disease and cavitatory lesions in the lung, cetuximab was not administered. He developed febrile neutropenia 13 days after the initiation of PF treatment and was urgently hospitalized. CT scans showed the progression of the lung metastases. Considering the possibility of platinum resistance, the first dose of nivolumab (240 mg/body) was administered 7 months after the surgery and the second dose was administered 2 weeks later. A rash appeared on the trunk region on the 27th day after the administration of the first dose of Nivolumab. Since fever of more than 38°C also developed on the 28th day, we suspected drug eruption and antihistamines were administered to the patient. Due to the exacerbation of the skin rash and fever, he was hospitalized on the 29th day. On the 31st day, a dermatologist diagnosed the patient with Stevens‐Johnson syndrome (SJS) (Figure 2A). Pathological examination of a skin specimen showed the presence of necrotic keratinocytes and vacuolar degeneration in the epidermis (Figure 2B). There was no history of usage of any drug other than Nivolumab. Hence, nivolumab was suspected to be the cause of SJS. On the same day, steroid pulse therapy with 1000 mg methylprednisolone was initiated, and cefepime was administered to prevent secondary infection. Steroid pulse therapy was continued for 3 days, after which it was transferred to oral administration with 50 mg prednisolone. On the 35th day, the dermatologist diagnosed the patient with TEN considering the spread of erythema and erosion (Figure 2C). According to the diagnostic criteria for TEN, the presence of three major items (a) Blisters and erosions exceeding 10% of the body surface area, (b) Fever, (c) Staphylococcal scalded skin syndrome, toxic shock syndrome, contagious impetigo, acute generalized exanthematous pustulosis, or autoimmune blistering) and of four sub‐items (a) Flat, atypical target legions initially, (b) Mucosal lesions at the skin mucosa transition, (c) Objective generalized symptoms, subjective malaise, or eating disorders, and (d) Histopathological changes in the epidermis such as necrosis 200 times more than 10 epidermal cell necrosis in a visual field) was confirmed. From the 37th day, intravenous immunoglobulin 40 mg/kg/d was administered for 5 days. From the 43rd day, symptoms improved. On the 49th day, the reduction in dose of predonin was initiated, and on the 66th day, treatment with predonin was completed. All skin eruptions had epithelialized, and only pigmentations were evident. However, his respiratory condition worsened from the 42nd day, and treatment with morphine was initiated from the 44th day to relieve the respiratory distress. CT scan advised on the 44th day showed increased lung metastatic lesions and pleural effusion (Figure 3). We believed that the deterioration of respiratory function occurred due to increase in cancerous lesions. Hence, a ventilator was not used. His respiratory condition continued to worsen, and he died on the 67th day. The clinical course of the case is depicted in Figure 4.
Figure 1 Computed tomography and positron emission tomography (PET) images of the lung metastases. Multiple metastases with cavity formation in the lungs. PET also shows fluorodeoxyglucose accumulation at the same sites
Figure 2 Skin photograph and histological image at the onset of Stevens‐Johnson syndrome (SJS)/ Toxic epidermal necrolysis (TEN). A, Skin photograph at the onset of SJS. B, Necrotic changes in epidermal keratinocytes, vacuolar degeneration in the epidermal layer (arrow), and lymphocyte infiltration into the epidermal layer (arrow head). C, Skin photograph at the onset of TEN
Figure 3 Computed tomography image of lungs on day 44. Increase in lung metastasis with cavitation and pleural effusion
Figure 4 Schema of symptom transition. The upper row shows the course of the respiratory condition and skin symptoms of the patient. The bottom row outlines the details of the instituted treatment
3 DISCUSSION
SJS and TEN present as widespread erythema, erosion, blisters, mucosal rash, and fever. Frequently, they are caused by drugs, but can also be caused by infections from mycoplasma or certain viruses.
2
Apoptosis of epidermal and mucosal epithelial cells induced by CD8+ T cells is considered as the etiology of both SJS and TEN. However, the detailed mechanism of development of SJS and TEN has not been elucidated. These diseases are rare but serious. In particular, the mortality rate associated with the most severe form of TEN is as high as 30%. Most cases of TEN develop from SJS. According to the Japanese diagnostic criteria for SJS and TEN, SJS is diagnosed if erosion involves less than 10% body surface area, and TEN is diagnosed if it involves 10% or more. Our patient was initially diagnosed with SJS and subsequently with TEN after worsening of skin symptoms.
When SJS or TEN are caused by a drug, they develop within 1‐2 weeks from the beginning of drug therapy. In our patient, skin symptoms appeared on the 27th day after administration of the first dose of nivolumab. A relatively long time had passed from the administration of nivolumab until the appearance of skin symptoms. However, as no new drug therapy, apart from nivolumab, was ongoing, nivolumab was determined to be the causative drug for the onset of TEN. In ALDEN, an algorithm developed for determining the drug causality in SJS and TEN, a period of onset of 5 to 28 days after the drug administration is “suggestive,” which is consistent with the course of this patient.
3
However, we must understand that severe skin adverse events can occur even 4 weeks after drug administration.
SCORTEN is an assessment of the severity of SJS and TEN, and we performed a retrospective study on this case.
4
On admission, age and the presence of a malignancy were positive items, and the area of epidermal exfoliation, pulse, blood urea nitrogen (BUN), and blood glucose were negative items. HCO3
‐ in the blood was not measured. As a result, SCORTEN in this case was 2 or 3, and the severity was judged to be at the mild to moderate level. In the RegiSCAR study, the mortality rate of acute SJS and TEN was determined to be 23%.
5
The acute cause of death is sepsis, which occurs due to secondary bacterial and fungal infections in the skin and mucous membrane lesions. Pneumonia is a major complication of SJS and TEN, with approximately half of the patients requiring a ventilator, which is often associated with a poor prognosis.
6
Our patient showed improvement in skin symptoms, but died due to worsening of the respiratory function. Increase in lung metastatic lesions and associated pleural effusion were the principal causes of respiratory deterioration. Furthermore, it was determined that respiratory function was further deteriorated due to pneumonia caused by SJS or TEN. However, it is difficult to arrange ventilators for patients with cancer that cannot be cured.
SJS and TEN caused by nivolumab have been reported in patients with melanoma, hepatocellular carcinoma, non‐small cell lung cancer, and lymphoma, but this is the first reported case of SJS or TEN associated with head and neck cancer.
7
,
8
,
9
,
10
SJS or TEN was not observed in adverse event reports in the CheckMate‐141 study.
1
In addition, only 2 cases of grade 3 or grade 4 skin adverse events were reported in the international randomized phase 3 study (n = 945) with nivolumab and ipilimumab for advanced melanoma.
11
Deaths caused by TEN have been reported with nivolumab use for metastatic melanoma and lymphoma.
7
,
9
The mechanism by which immune‐checkpoint inhibitors such as anti‐PD‐1 antibody and anticytotoxic T lymphocyte‐associated‐4 antibody cause SJS and TEN has not been elucidated. Several drugs such as antibacterial, antiepileptic, and nonsteroidal anti‐inflammatory drugs, and allopurinol are listed as high‐risk drugs for the development of SJS and TEN. Currently, molecular‐targeting drugs and immune‐checkpoint inhibitors used for cancer treatment are not classified as risk drugs but are expected to be assessed for risk after the documentation of adequate cases treated with these anticancer agents in the future.
In head and neck cancer, nivolumab is approved as a treatment modality for patients with platinum‐resistant recurrence/metastasis. Several patients show distant metastasis or local recurrence with a compromised general medical condition. Prior chemotherapy is also a factor that can affect the general condition. If SJS or TEN develops in such patients, it will be fatal. In addition, treatment guidelines for SJS and TEN recommend plasma‐exchange therapy in cases of resistance to steroid pulse therapy. However, plasma‐exchange therapy should be carefully used in patients with cancer. In our patient, steroid pulse therapy was not effective immediately, and hence, plasma‐exchange therapy was considered. However, due to the increase in lung metastatic lesions and worsening of the respiratory condition, plasma‐exchange therapy was not initiated, and intravenous immunoglobulin was administered. Infliximab, an antitumor necrosis factor‐α antibody, may be administered for severe skin adverse events, but no reports on its use in patients with adverse skin events caused by nivolumab have been documented.
11
It is necessary to determine a suitable treatment modality for TEN considering the prognosis and disease control status of each case.
With the progress of immunotherapy for cancer, many patients are treated with immunotherapeutic agents worldwide. In the future, the number of patients developing severe skin adverse events, such as SJS or TEN, is expected to increase. For immunotherapy, the patient's general medical condition should be evaluated to manage the adverse events by early detection and appropriate treatment planning.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
KK: involved in conceptualization and writing; DS, MS, YM, SH, TS, and NK: involved in investigation and review; MN, TH: involved in supervision and review.
Funding information
This study was supported by JSPS KAKENHI, 19K18795.
ETHICAL APPROVAL
Written informed consent was obtained from the patient in the Japanese language to publish his clinical details including his photograph.
ACKNOWLEDGMENTS
Published with written consent of the patient. | A REDUCED DOSAGE WAS USED | DrugDosageText | CC BY-NC | 33598257 | 19,034,916 | 2021-02 |
What was the dosage of drug 'FLUOROURACIL'? | Toxic epidermal necrolysis associated with nivolumab treatment for head and neck cancer.
This report is the first to document TEN caused by nivolumab treatment in head and neck cancer. We believe this article can contribute significantly in understanding the principles of nivolumab treatment in patients with head and neck cancer.
1 INTRODUCTION
Nivolumab, an antiprogrammed death‐1 (PD‐1) antibody, is an immune‐checkpoint inhibitor. According to the results of the CheckMate‐141 study, which compared nivolumab and a physician‐selected treatment modality for recurrent/metastatic head and neck squamous cell carcinoma with a history of chemotherapy including platinum, nivolumab significantly increases the overall survival rate.
1
Considering the results of this report, nivolumab was approved in the United States in November 2016 and in Japan in March 2017 as a treatment modality for patients with recurrent/metastatic head and neck cancer, who had been previously treated with platinum‐containing drugs. Currently, the clinical benefits of nivolumab therapy have been recognized not only in head and neck cancers but also in other types of cancers such as malignant melanoma, non‐small cell lung cancer, renal cell cancer, gastric cancer, and Hodgkin's lymphoma. Various immune‐related adverse events associated with nivolumab have been reported, because the mechanism of action of the drug is different from that of conventional anticancer drugs. However, the frequency of severe skin complications is considerably less.
Toxic epidermal necrosis (TEN) is a disease with fever and widespread erythema, erosion, blisters, and mucosal rash on the skin. TEN is a rare, albeit serious disease with a mortality rate of approximately 30%.
2
We herein report a patient with squamous cell carcinoma of the tongue who developed TEN after nivolumab treatment.
2 CASE REPORT
A 76‐year‐old man with cancer of the right side of the tongue (cT3N2bM0) underwent hemiglossectomy of the right side and dissection of the right side of the neck followed by reconstruction using anterolateral thigh flap. Postoperative pathological examination showed pT3N2b and negative surgical margins and extranodal invasion. The patient was treated with 60 Gy/30 Fr postoperative radiation therapy, because a vertical margin of only 4 mm could be obtained. Five months after surgery, multiple cavitatory lesions were detected in the lungs in the computed tomography (CT) scans. Bronchoscopic biopsy revealed that the tongue cancer had metastasized to the lungs (Figure 1). Six months after the surgery, chemotherapy with cisplatin plus 5‐FU (PF, CDDP 60 mg/m2, 5‐FU 750 mg/m2, a reduced dosage was used due to renal dysfunction) was initiated. Considering the possibility of chronic obstructive pulmonary disease and cavitatory lesions in the lung, cetuximab was not administered. He developed febrile neutropenia 13 days after the initiation of PF treatment and was urgently hospitalized. CT scans showed the progression of the lung metastases. Considering the possibility of platinum resistance, the first dose of nivolumab (240 mg/body) was administered 7 months after the surgery and the second dose was administered 2 weeks later. A rash appeared on the trunk region on the 27th day after the administration of the first dose of Nivolumab. Since fever of more than 38°C also developed on the 28th day, we suspected drug eruption and antihistamines were administered to the patient. Due to the exacerbation of the skin rash and fever, he was hospitalized on the 29th day. On the 31st day, a dermatologist diagnosed the patient with Stevens‐Johnson syndrome (SJS) (Figure 2A). Pathological examination of a skin specimen showed the presence of necrotic keratinocytes and vacuolar degeneration in the epidermis (Figure 2B). There was no history of usage of any drug other than Nivolumab. Hence, nivolumab was suspected to be the cause of SJS. On the same day, steroid pulse therapy with 1000 mg methylprednisolone was initiated, and cefepime was administered to prevent secondary infection. Steroid pulse therapy was continued for 3 days, after which it was transferred to oral administration with 50 mg prednisolone. On the 35th day, the dermatologist diagnosed the patient with TEN considering the spread of erythema and erosion (Figure 2C). According to the diagnostic criteria for TEN, the presence of three major items (a) Blisters and erosions exceeding 10% of the body surface area, (b) Fever, (c) Staphylococcal scalded skin syndrome, toxic shock syndrome, contagious impetigo, acute generalized exanthematous pustulosis, or autoimmune blistering) and of four sub‐items (a) Flat, atypical target legions initially, (b) Mucosal lesions at the skin mucosa transition, (c) Objective generalized symptoms, subjective malaise, or eating disorders, and (d) Histopathological changes in the epidermis such as necrosis 200 times more than 10 epidermal cell necrosis in a visual field) was confirmed. From the 37th day, intravenous immunoglobulin 40 mg/kg/d was administered for 5 days. From the 43rd day, symptoms improved. On the 49th day, the reduction in dose of predonin was initiated, and on the 66th day, treatment with predonin was completed. All skin eruptions had epithelialized, and only pigmentations were evident. However, his respiratory condition worsened from the 42nd day, and treatment with morphine was initiated from the 44th day to relieve the respiratory distress. CT scan advised on the 44th day showed increased lung metastatic lesions and pleural effusion (Figure 3). We believed that the deterioration of respiratory function occurred due to increase in cancerous lesions. Hence, a ventilator was not used. His respiratory condition continued to worsen, and he died on the 67th day. The clinical course of the case is depicted in Figure 4.
Figure 1 Computed tomography and positron emission tomography (PET) images of the lung metastases. Multiple metastases with cavity formation in the lungs. PET also shows fluorodeoxyglucose accumulation at the same sites
Figure 2 Skin photograph and histological image at the onset of Stevens‐Johnson syndrome (SJS)/ Toxic epidermal necrolysis (TEN). A, Skin photograph at the onset of SJS. B, Necrotic changes in epidermal keratinocytes, vacuolar degeneration in the epidermal layer (arrow), and lymphocyte infiltration into the epidermal layer (arrow head). C, Skin photograph at the onset of TEN
Figure 3 Computed tomography image of lungs on day 44. Increase in lung metastasis with cavitation and pleural effusion
Figure 4 Schema of symptom transition. The upper row shows the course of the respiratory condition and skin symptoms of the patient. The bottom row outlines the details of the instituted treatment
3 DISCUSSION
SJS and TEN present as widespread erythema, erosion, blisters, mucosal rash, and fever. Frequently, they are caused by drugs, but can also be caused by infections from mycoplasma or certain viruses.
2
Apoptosis of epidermal and mucosal epithelial cells induced by CD8+ T cells is considered as the etiology of both SJS and TEN. However, the detailed mechanism of development of SJS and TEN has not been elucidated. These diseases are rare but serious. In particular, the mortality rate associated with the most severe form of TEN is as high as 30%. Most cases of TEN develop from SJS. According to the Japanese diagnostic criteria for SJS and TEN, SJS is diagnosed if erosion involves less than 10% body surface area, and TEN is diagnosed if it involves 10% or more. Our patient was initially diagnosed with SJS and subsequently with TEN after worsening of skin symptoms.
When SJS or TEN are caused by a drug, they develop within 1‐2 weeks from the beginning of drug therapy. In our patient, skin symptoms appeared on the 27th day after administration of the first dose of nivolumab. A relatively long time had passed from the administration of nivolumab until the appearance of skin symptoms. However, as no new drug therapy, apart from nivolumab, was ongoing, nivolumab was determined to be the causative drug for the onset of TEN. In ALDEN, an algorithm developed for determining the drug causality in SJS and TEN, a period of onset of 5 to 28 days after the drug administration is “suggestive,” which is consistent with the course of this patient.
3
However, we must understand that severe skin adverse events can occur even 4 weeks after drug administration.
SCORTEN is an assessment of the severity of SJS and TEN, and we performed a retrospective study on this case.
4
On admission, age and the presence of a malignancy were positive items, and the area of epidermal exfoliation, pulse, blood urea nitrogen (BUN), and blood glucose were negative items. HCO3
‐ in the blood was not measured. As a result, SCORTEN in this case was 2 or 3, and the severity was judged to be at the mild to moderate level. In the RegiSCAR study, the mortality rate of acute SJS and TEN was determined to be 23%.
5
The acute cause of death is sepsis, which occurs due to secondary bacterial and fungal infections in the skin and mucous membrane lesions. Pneumonia is a major complication of SJS and TEN, with approximately half of the patients requiring a ventilator, which is often associated with a poor prognosis.
6
Our patient showed improvement in skin symptoms, but died due to worsening of the respiratory function. Increase in lung metastatic lesions and associated pleural effusion were the principal causes of respiratory deterioration. Furthermore, it was determined that respiratory function was further deteriorated due to pneumonia caused by SJS or TEN. However, it is difficult to arrange ventilators for patients with cancer that cannot be cured.
SJS and TEN caused by nivolumab have been reported in patients with melanoma, hepatocellular carcinoma, non‐small cell lung cancer, and lymphoma, but this is the first reported case of SJS or TEN associated with head and neck cancer.
7
,
8
,
9
,
10
SJS or TEN was not observed in adverse event reports in the CheckMate‐141 study.
1
In addition, only 2 cases of grade 3 or grade 4 skin adverse events were reported in the international randomized phase 3 study (n = 945) with nivolumab and ipilimumab for advanced melanoma.
11
Deaths caused by TEN have been reported with nivolumab use for metastatic melanoma and lymphoma.
7
,
9
The mechanism by which immune‐checkpoint inhibitors such as anti‐PD‐1 antibody and anticytotoxic T lymphocyte‐associated‐4 antibody cause SJS and TEN has not been elucidated. Several drugs such as antibacterial, antiepileptic, and nonsteroidal anti‐inflammatory drugs, and allopurinol are listed as high‐risk drugs for the development of SJS and TEN. Currently, molecular‐targeting drugs and immune‐checkpoint inhibitors used for cancer treatment are not classified as risk drugs but are expected to be assessed for risk after the documentation of adequate cases treated with these anticancer agents in the future.
In head and neck cancer, nivolumab is approved as a treatment modality for patients with platinum‐resistant recurrence/metastasis. Several patients show distant metastasis or local recurrence with a compromised general medical condition. Prior chemotherapy is also a factor that can affect the general condition. If SJS or TEN develops in such patients, it will be fatal. In addition, treatment guidelines for SJS and TEN recommend plasma‐exchange therapy in cases of resistance to steroid pulse therapy. However, plasma‐exchange therapy should be carefully used in patients with cancer. In our patient, steroid pulse therapy was not effective immediately, and hence, plasma‐exchange therapy was considered. However, due to the increase in lung metastatic lesions and worsening of the respiratory condition, plasma‐exchange therapy was not initiated, and intravenous immunoglobulin was administered. Infliximab, an antitumor necrosis factor‐α antibody, may be administered for severe skin adverse events, but no reports on its use in patients with adverse skin events caused by nivolumab have been documented.
11
It is necessary to determine a suitable treatment modality for TEN considering the prognosis and disease control status of each case.
With the progress of immunotherapy for cancer, many patients are treated with immunotherapeutic agents worldwide. In the future, the number of patients developing severe skin adverse events, such as SJS or TEN, is expected to increase. For immunotherapy, the patient's general medical condition should be evaluated to manage the adverse events by early detection and appropriate treatment planning.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
KK: involved in conceptualization and writing; DS, MS, YM, SH, TS, and NK: involved in investigation and review; MN, TH: involved in supervision and review.
Funding information
This study was supported by JSPS KAKENHI, 19K18795.
ETHICAL APPROVAL
Written informed consent was obtained from the patient in the Japanese language to publish his clinical details including his photograph.
ACKNOWLEDGMENTS
Published with written consent of the patient. | A REDUCED DOSAGE WAS USED | DrugDosageText | CC BY-NC | 33598257 | 19,034,916 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute kidney injury'. | Cryptococcemia in a patient with COVID-19: A case report.
The authors urge clinicians to balance the use of Immunosuppressant drugs and tocilizumab for COVID-19 patients to avoid the development of infections like Cryptococcemia, leading to death within 30 days.
1 BACKGROUND
Cryptococcus neoformans infection is a known cause of meningoencephalitis in immunocompromised patients. However, it is less frequent in immunocompetent individuals. Here, we report a case of a 60‐year‐old COVID‐19 patient with a history of several comorbidities who received tocilizumab and corticosteroids, which lead to Cryptococcemia.
Cryptococcus neoformans are basidiomycetous; encapsulated yeasts are classified into four serotypes according to their capsule.
1
The way of the infection is by inhalation of basidiospore form or small, poorly encapsulated yeasts.
2
Cryptococcus neoformans infection typically happens among immunocompromised patients, and meningoencephalitis is the typical manifestation of cryptococcosis among HIV patients.
3
,
4
In immunocompetent, the infection can be subclinical and a study on postmortem immunocompetent just showed small granulomatous disease in the lung without disseminating the infection.
5
,
6
We describe a case of a patient with COVID‐19 who developed Cryptococcemia while being treated by immunosuppressive treatment.
2 CASE PRESENTATION
A 60‐year‐old man with a history of hypertension, diabetes mellitus, and ischemic heart disease admitted to the intensive care unit (ICU) with confirmed COVID‐19 infection required mechanical ventilation; on the same day of admission, he was pronned for many times due to low PaO2/FiO2 (P/F) ratio. He received three doses of tocilizumab (400 mg/once), (600 mg/once), and (600 mg/once), respectively, due to possible cytokine storm; he received several doses of methylprednisolone as part of the COVID‐19 management and hydrocortisone.
Few days after receiving tocilizumab, his bronchial alveolar lavage was positive for Candida glabrate; he was started on anidulafungin 200 mg q24 hours for 7 days. The patient was sedated and intubated for 22 days, so a tracheostomy was done. He developed acute kidney injury (AKI) after 28 days of ICU admission; hence, hemodialysis was started.
Despite that the patient was on antibiotics, his inflammatory marker is still high. Thus, full septic workups were done, and the patient was having candidemia (Candida parapsilosis) after one month of the admission. For which he was started on anidulafungin 200 mg q24 hours for more than 7 days. Many episodes of gastrointestinal (GI) tract bleeding complicated his course manifested as melena and per rectal bleeding, but all the episodes were managed conservatively by the gastroenterology team. The candidemia persists after 2 weeks of treatment and there was an increase in C‐reactive protein (CRP) level despite that the patient was under antibiotic and antifungal cover. Hence, the ID team recommended giving antifungal (anidulafungin 100 mg) for a total of 14 days to involve an ophthalmologist to rule out fungal ophthalmitis. Still, it was not applicable and to do an echocardiogram to rule out vegetation and it was ruled out by trans‐thoracic echocardiogram.
While the patient was on anidulafungin, his blood culture became positive for Cryptococcus neoformans after 18 days of receiving anidulafungin for previous candida infection, for which he was started on amphotericin (300 mg, q24 hours) and flucytosine (500 mg q12 hours). And there was a recommendation from the ID team to do trans esophageal echo and lumbar puncture to rule out vegetation and brain involvement, respectively, but both tests were not done due to poor prognosis and risk of bleeding because the patient had thrombocytopenia (platelet 21, RR = 150‐400 × 109/L). The Cryptococcemia persist despite the management and he developed sepsis and die within 10 days of the Cryptococcemia.
3 DISCUSSION
Disseminated Cryptococcus neoformans infection is a serious infection that can occur in immunocompromised patients.
7
During the outbreak of COVID‐19 disease, there were many studies about the overwhelming immune response to COVID‐19 infection through the activation of a large number of T lymphocytes and mononuclear macrophages, producing cytokines like interleukin‐6 (IL‐6), which bind to the receptor and cause cytokine storm and severe inflammation in the lung and other tissues. Tocilizumab, as an antihuman IL‐6 receptor monoclonal antibody and immunosuppressant drugs, was recommended by several studies for alleviating the inflammatory response.
8
Jean and colleagues have noted in their study of 52 patients with Cryptococcus neoformans isolated from blood culture; the primary three predisposing for Cryptococcemia are Acquired immunodeficiency syndrome, immunosuppressive therapy, and decompensated liver cirrhosis.
9
And in our case, the Cryptococcus neoformans was isolated from the blood culture. And according to Passerini M et al that Cryptococcus neoformans can affect different organs as meningoencephalitis, which is the most common, followed by pulmonary and cutaneous disease.
10
According to Jean et al that patients with positive blood culture for Cryptococcus neoformans developed sepsis by 81%, including those developed septic shock, the lumbar puncture (LP) was positive in 61.5% of patients with positive blood culture for Cryptococcus neoformans and 84% of those with LP positive showed meningeal involvement, in our case LP was recommended but not done because the patient was critically sick and unstable. Also, it was noted by Jean et al that the fatality within 30 days of Cryptococcemia was 37%.
9
Also, in our case, the patient died within 10 days of Cryptococcemia. Therefore, it is essential to suspect Cryptococcus neoformans infection in an immunocompromised patient and early management, keeping in mind the high morbidity associated with it. Consequently, it is crucial to avoid misdiagnosis and mismanagement, keeping in mind the high morbidity.
4 CONCLUSION
This case highlights the importance of early suspicion of Cryptococcus neoformans infection and other opportunistic infections in immunocompromised patients, putting in mind that patients with Cryptococcaemia have a high risk of mortality within 30 days, which warrants the use of corticosteroid and immunomodulatory drugs in a critically ill patient with COVID‐19. In the current scenario, the use of immunosuppressive therapy should be justified and to be alert for opportunistic infection like Cryptococcus neoformans infection, which can lead to sepsis and mortality.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
AUTHORS' CONTRIBUTIONS
MYK, AAA, SBS, ASM, AJN: involved in data collection, literature search, and manuscript preparation. All authors read and approved the final manuscript.
ETHICAL APPROVAL
The article describes a case report. Therefore, no additional permission from our Ethics Committee was required.
ACKNOWLEDGMENTS
Open Access funding provided by the Qatar National Library. The consent for publication was obtained.
DATA AVAILABILITY STATEMENT
All data generated or analyzed during this study are included in this published article. | HYDROCORTISONE SODIUM SUCCINATE, METHYLPREDNISOLONE, TOCILIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33598258 | 19,012,839 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastrointestinal haemorrhage'. | Cryptococcemia in a patient with COVID-19: A case report.
The authors urge clinicians to balance the use of Immunosuppressant drugs and tocilizumab for COVID-19 patients to avoid the development of infections like Cryptococcemia, leading to death within 30 days.
1 BACKGROUND
Cryptococcus neoformans infection is a known cause of meningoencephalitis in immunocompromised patients. However, it is less frequent in immunocompetent individuals. Here, we report a case of a 60‐year‐old COVID‐19 patient with a history of several comorbidities who received tocilizumab and corticosteroids, which lead to Cryptococcemia.
Cryptococcus neoformans are basidiomycetous; encapsulated yeasts are classified into four serotypes according to their capsule.
1
The way of the infection is by inhalation of basidiospore form or small, poorly encapsulated yeasts.
2
Cryptococcus neoformans infection typically happens among immunocompromised patients, and meningoencephalitis is the typical manifestation of cryptococcosis among HIV patients.
3
,
4
In immunocompetent, the infection can be subclinical and a study on postmortem immunocompetent just showed small granulomatous disease in the lung without disseminating the infection.
5
,
6
We describe a case of a patient with COVID‐19 who developed Cryptococcemia while being treated by immunosuppressive treatment.
2 CASE PRESENTATION
A 60‐year‐old man with a history of hypertension, diabetes mellitus, and ischemic heart disease admitted to the intensive care unit (ICU) with confirmed COVID‐19 infection required mechanical ventilation; on the same day of admission, he was pronned for many times due to low PaO2/FiO2 (P/F) ratio. He received three doses of tocilizumab (400 mg/once), (600 mg/once), and (600 mg/once), respectively, due to possible cytokine storm; he received several doses of methylprednisolone as part of the COVID‐19 management and hydrocortisone.
Few days after receiving tocilizumab, his bronchial alveolar lavage was positive for Candida glabrate; he was started on anidulafungin 200 mg q24 hours for 7 days. The patient was sedated and intubated for 22 days, so a tracheostomy was done. He developed acute kidney injury (AKI) after 28 days of ICU admission; hence, hemodialysis was started.
Despite that the patient was on antibiotics, his inflammatory marker is still high. Thus, full septic workups were done, and the patient was having candidemia (Candida parapsilosis) after one month of the admission. For which he was started on anidulafungin 200 mg q24 hours for more than 7 days. Many episodes of gastrointestinal (GI) tract bleeding complicated his course manifested as melena and per rectal bleeding, but all the episodes were managed conservatively by the gastroenterology team. The candidemia persists after 2 weeks of treatment and there was an increase in C‐reactive protein (CRP) level despite that the patient was under antibiotic and antifungal cover. Hence, the ID team recommended giving antifungal (anidulafungin 100 mg) for a total of 14 days to involve an ophthalmologist to rule out fungal ophthalmitis. Still, it was not applicable and to do an echocardiogram to rule out vegetation and it was ruled out by trans‐thoracic echocardiogram.
While the patient was on anidulafungin, his blood culture became positive for Cryptococcus neoformans after 18 days of receiving anidulafungin for previous candida infection, for which he was started on amphotericin (300 mg, q24 hours) and flucytosine (500 mg q12 hours). And there was a recommendation from the ID team to do trans esophageal echo and lumbar puncture to rule out vegetation and brain involvement, respectively, but both tests were not done due to poor prognosis and risk of bleeding because the patient had thrombocytopenia (platelet 21, RR = 150‐400 × 109/L). The Cryptococcemia persist despite the management and he developed sepsis and die within 10 days of the Cryptococcemia.
3 DISCUSSION
Disseminated Cryptococcus neoformans infection is a serious infection that can occur in immunocompromised patients.
7
During the outbreak of COVID‐19 disease, there were many studies about the overwhelming immune response to COVID‐19 infection through the activation of a large number of T lymphocytes and mononuclear macrophages, producing cytokines like interleukin‐6 (IL‐6), which bind to the receptor and cause cytokine storm and severe inflammation in the lung and other tissues. Tocilizumab, as an antihuman IL‐6 receptor monoclonal antibody and immunosuppressant drugs, was recommended by several studies for alleviating the inflammatory response.
8
Jean and colleagues have noted in their study of 52 patients with Cryptococcus neoformans isolated from blood culture; the primary three predisposing for Cryptococcemia are Acquired immunodeficiency syndrome, immunosuppressive therapy, and decompensated liver cirrhosis.
9
And in our case, the Cryptococcus neoformans was isolated from the blood culture. And according to Passerini M et al that Cryptococcus neoformans can affect different organs as meningoencephalitis, which is the most common, followed by pulmonary and cutaneous disease.
10
According to Jean et al that patients with positive blood culture for Cryptococcus neoformans developed sepsis by 81%, including those developed septic shock, the lumbar puncture (LP) was positive in 61.5% of patients with positive blood culture for Cryptococcus neoformans and 84% of those with LP positive showed meningeal involvement, in our case LP was recommended but not done because the patient was critically sick and unstable. Also, it was noted by Jean et al that the fatality within 30 days of Cryptococcemia was 37%.
9
Also, in our case, the patient died within 10 days of Cryptococcemia. Therefore, it is essential to suspect Cryptococcus neoformans infection in an immunocompromised patient and early management, keeping in mind the high morbidity associated with it. Consequently, it is crucial to avoid misdiagnosis and mismanagement, keeping in mind the high morbidity.
4 CONCLUSION
This case highlights the importance of early suspicion of Cryptococcus neoformans infection and other opportunistic infections in immunocompromised patients, putting in mind that patients with Cryptococcaemia have a high risk of mortality within 30 days, which warrants the use of corticosteroid and immunomodulatory drugs in a critically ill patient with COVID‐19. In the current scenario, the use of immunosuppressive therapy should be justified and to be alert for opportunistic infection like Cryptococcus neoformans infection, which can lead to sepsis and mortality.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
AUTHORS' CONTRIBUTIONS
MYK, AAA, SBS, ASM, AJN: involved in data collection, literature search, and manuscript preparation. All authors read and approved the final manuscript.
ETHICAL APPROVAL
The article describes a case report. Therefore, no additional permission from our Ethics Committee was required.
ACKNOWLEDGMENTS
Open Access funding provided by the Qatar National Library. The consent for publication was obtained.
DATA AVAILABILITY STATEMENT
All data generated or analyzed during this study are included in this published article. | HYDROCORTISONE SODIUM SUCCINATE, METHYLPREDNISOLONE, TOCILIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33598258 | 19,012,839 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Cryptococcemia in a patient with COVID-19: A case report.
The authors urge clinicians to balance the use of Immunosuppressant drugs and tocilizumab for COVID-19 patients to avoid the development of infections like Cryptococcemia, leading to death within 30 days.
1 BACKGROUND
Cryptococcus neoformans infection is a known cause of meningoencephalitis in immunocompromised patients. However, it is less frequent in immunocompetent individuals. Here, we report a case of a 60‐year‐old COVID‐19 patient with a history of several comorbidities who received tocilizumab and corticosteroids, which lead to Cryptococcemia.
Cryptococcus neoformans are basidiomycetous; encapsulated yeasts are classified into four serotypes according to their capsule.
1
The way of the infection is by inhalation of basidiospore form or small, poorly encapsulated yeasts.
2
Cryptococcus neoformans infection typically happens among immunocompromised patients, and meningoencephalitis is the typical manifestation of cryptococcosis among HIV patients.
3
,
4
In immunocompetent, the infection can be subclinical and a study on postmortem immunocompetent just showed small granulomatous disease in the lung without disseminating the infection.
5
,
6
We describe a case of a patient with COVID‐19 who developed Cryptococcemia while being treated by immunosuppressive treatment.
2 CASE PRESENTATION
A 60‐year‐old man with a history of hypertension, diabetes mellitus, and ischemic heart disease admitted to the intensive care unit (ICU) with confirmed COVID‐19 infection required mechanical ventilation; on the same day of admission, he was pronned for many times due to low PaO2/FiO2 (P/F) ratio. He received three doses of tocilizumab (400 mg/once), (600 mg/once), and (600 mg/once), respectively, due to possible cytokine storm; he received several doses of methylprednisolone as part of the COVID‐19 management and hydrocortisone.
Few days after receiving tocilizumab, his bronchial alveolar lavage was positive for Candida glabrate; he was started on anidulafungin 200 mg q24 hours for 7 days. The patient was sedated and intubated for 22 days, so a tracheostomy was done. He developed acute kidney injury (AKI) after 28 days of ICU admission; hence, hemodialysis was started.
Despite that the patient was on antibiotics, his inflammatory marker is still high. Thus, full septic workups were done, and the patient was having candidemia (Candida parapsilosis) after one month of the admission. For which he was started on anidulafungin 200 mg q24 hours for more than 7 days. Many episodes of gastrointestinal (GI) tract bleeding complicated his course manifested as melena and per rectal bleeding, but all the episodes were managed conservatively by the gastroenterology team. The candidemia persists after 2 weeks of treatment and there was an increase in C‐reactive protein (CRP) level despite that the patient was under antibiotic and antifungal cover. Hence, the ID team recommended giving antifungal (anidulafungin 100 mg) for a total of 14 days to involve an ophthalmologist to rule out fungal ophthalmitis. Still, it was not applicable and to do an echocardiogram to rule out vegetation and it was ruled out by trans‐thoracic echocardiogram.
While the patient was on anidulafungin, his blood culture became positive for Cryptococcus neoformans after 18 days of receiving anidulafungin for previous candida infection, for which he was started on amphotericin (300 mg, q24 hours) and flucytosine (500 mg q12 hours). And there was a recommendation from the ID team to do trans esophageal echo and lumbar puncture to rule out vegetation and brain involvement, respectively, but both tests were not done due to poor prognosis and risk of bleeding because the patient had thrombocytopenia (platelet 21, RR = 150‐400 × 109/L). The Cryptococcemia persist despite the management and he developed sepsis and die within 10 days of the Cryptococcemia.
3 DISCUSSION
Disseminated Cryptococcus neoformans infection is a serious infection that can occur in immunocompromised patients.
7
During the outbreak of COVID‐19 disease, there were many studies about the overwhelming immune response to COVID‐19 infection through the activation of a large number of T lymphocytes and mononuclear macrophages, producing cytokines like interleukin‐6 (IL‐6), which bind to the receptor and cause cytokine storm and severe inflammation in the lung and other tissues. Tocilizumab, as an antihuman IL‐6 receptor monoclonal antibody and immunosuppressant drugs, was recommended by several studies for alleviating the inflammatory response.
8
Jean and colleagues have noted in their study of 52 patients with Cryptococcus neoformans isolated from blood culture; the primary three predisposing for Cryptococcemia are Acquired immunodeficiency syndrome, immunosuppressive therapy, and decompensated liver cirrhosis.
9
And in our case, the Cryptococcus neoformans was isolated from the blood culture. And according to Passerini M et al that Cryptococcus neoformans can affect different organs as meningoencephalitis, which is the most common, followed by pulmonary and cutaneous disease.
10
According to Jean et al that patients with positive blood culture for Cryptococcus neoformans developed sepsis by 81%, including those developed septic shock, the lumbar puncture (LP) was positive in 61.5% of patients with positive blood culture for Cryptococcus neoformans and 84% of those with LP positive showed meningeal involvement, in our case LP was recommended but not done because the patient was critically sick and unstable. Also, it was noted by Jean et al that the fatality within 30 days of Cryptococcemia was 37%.
9
Also, in our case, the patient died within 10 days of Cryptococcemia. Therefore, it is essential to suspect Cryptococcus neoformans infection in an immunocompromised patient and early management, keeping in mind the high morbidity associated with it. Consequently, it is crucial to avoid misdiagnosis and mismanagement, keeping in mind the high morbidity.
4 CONCLUSION
This case highlights the importance of early suspicion of Cryptococcus neoformans infection and other opportunistic infections in immunocompromised patients, putting in mind that patients with Cryptococcaemia have a high risk of mortality within 30 days, which warrants the use of corticosteroid and immunomodulatory drugs in a critically ill patient with COVID‐19. In the current scenario, the use of immunosuppressive therapy should be justified and to be alert for opportunistic infection like Cryptococcus neoformans infection, which can lead to sepsis and mortality.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
AUTHORS' CONTRIBUTIONS
MYK, AAA, SBS, ASM, AJN: involved in data collection, literature search, and manuscript preparation. All authors read and approved the final manuscript.
ETHICAL APPROVAL
The article describes a case report. Therefore, no additional permission from our Ethics Committee was required.
ACKNOWLEDGMENTS
Open Access funding provided by the Qatar National Library. The consent for publication was obtained.
DATA AVAILABILITY STATEMENT
All data generated or analyzed during this study are included in this published article. | HYDROCORTISONE SODIUM SUCCINATE, METHYLPREDNISOLONE, TOCILIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33598258 | 19,012,839 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Cryptococcemia in a patient with COVID-19: A case report.
The authors urge clinicians to balance the use of Immunosuppressant drugs and tocilizumab for COVID-19 patients to avoid the development of infections like Cryptococcemia, leading to death within 30 days.
1 BACKGROUND
Cryptococcus neoformans infection is a known cause of meningoencephalitis in immunocompromised patients. However, it is less frequent in immunocompetent individuals. Here, we report a case of a 60‐year‐old COVID‐19 patient with a history of several comorbidities who received tocilizumab and corticosteroids, which lead to Cryptococcemia.
Cryptococcus neoformans are basidiomycetous; encapsulated yeasts are classified into four serotypes according to their capsule.
1
The way of the infection is by inhalation of basidiospore form or small, poorly encapsulated yeasts.
2
Cryptococcus neoformans infection typically happens among immunocompromised patients, and meningoencephalitis is the typical manifestation of cryptococcosis among HIV patients.
3
,
4
In immunocompetent, the infection can be subclinical and a study on postmortem immunocompetent just showed small granulomatous disease in the lung without disseminating the infection.
5
,
6
We describe a case of a patient with COVID‐19 who developed Cryptococcemia while being treated by immunosuppressive treatment.
2 CASE PRESENTATION
A 60‐year‐old man with a history of hypertension, diabetes mellitus, and ischemic heart disease admitted to the intensive care unit (ICU) with confirmed COVID‐19 infection required mechanical ventilation; on the same day of admission, he was pronned for many times due to low PaO2/FiO2 (P/F) ratio. He received three doses of tocilizumab (400 mg/once), (600 mg/once), and (600 mg/once), respectively, due to possible cytokine storm; he received several doses of methylprednisolone as part of the COVID‐19 management and hydrocortisone.
Few days after receiving tocilizumab, his bronchial alveolar lavage was positive for Candida glabrate; he was started on anidulafungin 200 mg q24 hours for 7 days. The patient was sedated and intubated for 22 days, so a tracheostomy was done. He developed acute kidney injury (AKI) after 28 days of ICU admission; hence, hemodialysis was started.
Despite that the patient was on antibiotics, his inflammatory marker is still high. Thus, full septic workups were done, and the patient was having candidemia (Candida parapsilosis) after one month of the admission. For which he was started on anidulafungin 200 mg q24 hours for more than 7 days. Many episodes of gastrointestinal (GI) tract bleeding complicated his course manifested as melena and per rectal bleeding, but all the episodes were managed conservatively by the gastroenterology team. The candidemia persists after 2 weeks of treatment and there was an increase in C‐reactive protein (CRP) level despite that the patient was under antibiotic and antifungal cover. Hence, the ID team recommended giving antifungal (anidulafungin 100 mg) for a total of 14 days to involve an ophthalmologist to rule out fungal ophthalmitis. Still, it was not applicable and to do an echocardiogram to rule out vegetation and it was ruled out by trans‐thoracic echocardiogram.
While the patient was on anidulafungin, his blood culture became positive for Cryptococcus neoformans after 18 days of receiving anidulafungin for previous candida infection, for which he was started on amphotericin (300 mg, q24 hours) and flucytosine (500 mg q12 hours). And there was a recommendation from the ID team to do trans esophageal echo and lumbar puncture to rule out vegetation and brain involvement, respectively, but both tests were not done due to poor prognosis and risk of bleeding because the patient had thrombocytopenia (platelet 21, RR = 150‐400 × 109/L). The Cryptococcemia persist despite the management and he developed sepsis and die within 10 days of the Cryptococcemia.
3 DISCUSSION
Disseminated Cryptococcus neoformans infection is a serious infection that can occur in immunocompromised patients.
7
During the outbreak of COVID‐19 disease, there were many studies about the overwhelming immune response to COVID‐19 infection through the activation of a large number of T lymphocytes and mononuclear macrophages, producing cytokines like interleukin‐6 (IL‐6), which bind to the receptor and cause cytokine storm and severe inflammation in the lung and other tissues. Tocilizumab, as an antihuman IL‐6 receptor monoclonal antibody and immunosuppressant drugs, was recommended by several studies for alleviating the inflammatory response.
8
Jean and colleagues have noted in their study of 52 patients with Cryptococcus neoformans isolated from blood culture; the primary three predisposing for Cryptococcemia are Acquired immunodeficiency syndrome, immunosuppressive therapy, and decompensated liver cirrhosis.
9
And in our case, the Cryptococcus neoformans was isolated from the blood culture. And according to Passerini M et al that Cryptococcus neoformans can affect different organs as meningoencephalitis, which is the most common, followed by pulmonary and cutaneous disease.
10
According to Jean et al that patients with positive blood culture for Cryptococcus neoformans developed sepsis by 81%, including those developed septic shock, the lumbar puncture (LP) was positive in 61.5% of patients with positive blood culture for Cryptococcus neoformans and 84% of those with LP positive showed meningeal involvement, in our case LP was recommended but not done because the patient was critically sick and unstable. Also, it was noted by Jean et al that the fatality within 30 days of Cryptococcemia was 37%.
9
Also, in our case, the patient died within 10 days of Cryptococcemia. Therefore, it is essential to suspect Cryptococcus neoformans infection in an immunocompromised patient and early management, keeping in mind the high morbidity associated with it. Consequently, it is crucial to avoid misdiagnosis and mismanagement, keeping in mind the high morbidity.
4 CONCLUSION
This case highlights the importance of early suspicion of Cryptococcus neoformans infection and other opportunistic infections in immunocompromised patients, putting in mind that patients with Cryptococcaemia have a high risk of mortality within 30 days, which warrants the use of corticosteroid and immunomodulatory drugs in a critically ill patient with COVID‐19. In the current scenario, the use of immunosuppressive therapy should be justified and to be alert for opportunistic infection like Cryptococcus neoformans infection, which can lead to sepsis and mortality.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
AUTHORS' CONTRIBUTIONS
MYK, AAA, SBS, ASM, AJN: involved in data collection, literature search, and manuscript preparation. All authors read and approved the final manuscript.
ETHICAL APPROVAL
The article describes a case report. Therefore, no additional permission from our Ethics Committee was required.
ACKNOWLEDGMENTS
Open Access funding provided by the Qatar National Library. The consent for publication was obtained.
DATA AVAILABILITY STATEMENT
All data generated or analyzed during this study are included in this published article. | HYDROCORTISONE, METHYLPREDNISOLONE, TOCILIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33598258 | 19,029,149 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Systemic candida'. | Cryptococcemia in a patient with COVID-19: A case report.
The authors urge clinicians to balance the use of Immunosuppressant drugs and tocilizumab for COVID-19 patients to avoid the development of infections like Cryptococcemia, leading to death within 30 days.
1 BACKGROUND
Cryptococcus neoformans infection is a known cause of meningoencephalitis in immunocompromised patients. However, it is less frequent in immunocompetent individuals. Here, we report a case of a 60‐year‐old COVID‐19 patient with a history of several comorbidities who received tocilizumab and corticosteroids, which lead to Cryptococcemia.
Cryptococcus neoformans are basidiomycetous; encapsulated yeasts are classified into four serotypes according to their capsule.
1
The way of the infection is by inhalation of basidiospore form or small, poorly encapsulated yeasts.
2
Cryptococcus neoformans infection typically happens among immunocompromised patients, and meningoencephalitis is the typical manifestation of cryptococcosis among HIV patients.
3
,
4
In immunocompetent, the infection can be subclinical and a study on postmortem immunocompetent just showed small granulomatous disease in the lung without disseminating the infection.
5
,
6
We describe a case of a patient with COVID‐19 who developed Cryptococcemia while being treated by immunosuppressive treatment.
2 CASE PRESENTATION
A 60‐year‐old man with a history of hypertension, diabetes mellitus, and ischemic heart disease admitted to the intensive care unit (ICU) with confirmed COVID‐19 infection required mechanical ventilation; on the same day of admission, he was pronned for many times due to low PaO2/FiO2 (P/F) ratio. He received three doses of tocilizumab (400 mg/once), (600 mg/once), and (600 mg/once), respectively, due to possible cytokine storm; he received several doses of methylprednisolone as part of the COVID‐19 management and hydrocortisone.
Few days after receiving tocilizumab, his bronchial alveolar lavage was positive for Candida glabrate; he was started on anidulafungin 200 mg q24 hours for 7 days. The patient was sedated and intubated for 22 days, so a tracheostomy was done. He developed acute kidney injury (AKI) after 28 days of ICU admission; hence, hemodialysis was started.
Despite that the patient was on antibiotics, his inflammatory marker is still high. Thus, full septic workups were done, and the patient was having candidemia (Candida parapsilosis) after one month of the admission. For which he was started on anidulafungin 200 mg q24 hours for more than 7 days. Many episodes of gastrointestinal (GI) tract bleeding complicated his course manifested as melena and per rectal bleeding, but all the episodes were managed conservatively by the gastroenterology team. The candidemia persists after 2 weeks of treatment and there was an increase in C‐reactive protein (CRP) level despite that the patient was under antibiotic and antifungal cover. Hence, the ID team recommended giving antifungal (anidulafungin 100 mg) for a total of 14 days to involve an ophthalmologist to rule out fungal ophthalmitis. Still, it was not applicable and to do an echocardiogram to rule out vegetation and it was ruled out by trans‐thoracic echocardiogram.
While the patient was on anidulafungin, his blood culture became positive for Cryptococcus neoformans after 18 days of receiving anidulafungin for previous candida infection, for which he was started on amphotericin (300 mg, q24 hours) and flucytosine (500 mg q12 hours). And there was a recommendation from the ID team to do trans esophageal echo and lumbar puncture to rule out vegetation and brain involvement, respectively, but both tests were not done due to poor prognosis and risk of bleeding because the patient had thrombocytopenia (platelet 21, RR = 150‐400 × 109/L). The Cryptococcemia persist despite the management and he developed sepsis and die within 10 days of the Cryptococcemia.
3 DISCUSSION
Disseminated Cryptococcus neoformans infection is a serious infection that can occur in immunocompromised patients.
7
During the outbreak of COVID‐19 disease, there were many studies about the overwhelming immune response to COVID‐19 infection through the activation of a large number of T lymphocytes and mononuclear macrophages, producing cytokines like interleukin‐6 (IL‐6), which bind to the receptor and cause cytokine storm and severe inflammation in the lung and other tissues. Tocilizumab, as an antihuman IL‐6 receptor monoclonal antibody and immunosuppressant drugs, was recommended by several studies for alleviating the inflammatory response.
8
Jean and colleagues have noted in their study of 52 patients with Cryptococcus neoformans isolated from blood culture; the primary three predisposing for Cryptococcemia are Acquired immunodeficiency syndrome, immunosuppressive therapy, and decompensated liver cirrhosis.
9
And in our case, the Cryptococcus neoformans was isolated from the blood culture. And according to Passerini M et al that Cryptococcus neoformans can affect different organs as meningoencephalitis, which is the most common, followed by pulmonary and cutaneous disease.
10
According to Jean et al that patients with positive blood culture for Cryptococcus neoformans developed sepsis by 81%, including those developed septic shock, the lumbar puncture (LP) was positive in 61.5% of patients with positive blood culture for Cryptococcus neoformans and 84% of those with LP positive showed meningeal involvement, in our case LP was recommended but not done because the patient was critically sick and unstable. Also, it was noted by Jean et al that the fatality within 30 days of Cryptococcemia was 37%.
9
Also, in our case, the patient died within 10 days of Cryptococcemia. Therefore, it is essential to suspect Cryptococcus neoformans infection in an immunocompromised patient and early management, keeping in mind the high morbidity associated with it. Consequently, it is crucial to avoid misdiagnosis and mismanagement, keeping in mind the high morbidity.
4 CONCLUSION
This case highlights the importance of early suspicion of Cryptococcus neoformans infection and other opportunistic infections in immunocompromised patients, putting in mind that patients with Cryptococcaemia have a high risk of mortality within 30 days, which warrants the use of corticosteroid and immunomodulatory drugs in a critically ill patient with COVID‐19. In the current scenario, the use of immunosuppressive therapy should be justified and to be alert for opportunistic infection like Cryptococcus neoformans infection, which can lead to sepsis and mortality.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
AUTHORS' CONTRIBUTIONS
MYK, AAA, SBS, ASM, AJN: involved in data collection, literature search, and manuscript preparation. All authors read and approved the final manuscript.
ETHICAL APPROVAL
The article describes a case report. Therefore, no additional permission from our Ethics Committee was required.
ACKNOWLEDGMENTS
Open Access funding provided by the Qatar National Library. The consent for publication was obtained.
DATA AVAILABILITY STATEMENT
All data generated or analyzed during this study are included in this published article. | HYDROCORTISONE, METHYLPREDNISOLONE, TOCILIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33598258 | 19,041,516 | 2021-02 |
What is the weight of the patient? | Cryptococcemia in a patient with COVID-19: A case report.
The authors urge clinicians to balance the use of Immunosuppressant drugs and tocilizumab for COVID-19 patients to avoid the development of infections like Cryptococcemia, leading to death within 30 days.
1 BACKGROUND
Cryptococcus neoformans infection is a known cause of meningoencephalitis in immunocompromised patients. However, it is less frequent in immunocompetent individuals. Here, we report a case of a 60‐year‐old COVID‐19 patient with a history of several comorbidities who received tocilizumab and corticosteroids, which lead to Cryptococcemia.
Cryptococcus neoformans are basidiomycetous; encapsulated yeasts are classified into four serotypes according to their capsule.
1
The way of the infection is by inhalation of basidiospore form or small, poorly encapsulated yeasts.
2
Cryptococcus neoformans infection typically happens among immunocompromised patients, and meningoencephalitis is the typical manifestation of cryptococcosis among HIV patients.
3
,
4
In immunocompetent, the infection can be subclinical and a study on postmortem immunocompetent just showed small granulomatous disease in the lung without disseminating the infection.
5
,
6
We describe a case of a patient with COVID‐19 who developed Cryptococcemia while being treated by immunosuppressive treatment.
2 CASE PRESENTATION
A 60‐year‐old man with a history of hypertension, diabetes mellitus, and ischemic heart disease admitted to the intensive care unit (ICU) with confirmed COVID‐19 infection required mechanical ventilation; on the same day of admission, he was pronned for many times due to low PaO2/FiO2 (P/F) ratio. He received three doses of tocilizumab (400 mg/once), (600 mg/once), and (600 mg/once), respectively, due to possible cytokine storm; he received several doses of methylprednisolone as part of the COVID‐19 management and hydrocortisone.
Few days after receiving tocilizumab, his bronchial alveolar lavage was positive for Candida glabrate; he was started on anidulafungin 200 mg q24 hours for 7 days. The patient was sedated and intubated for 22 days, so a tracheostomy was done. He developed acute kidney injury (AKI) after 28 days of ICU admission; hence, hemodialysis was started.
Despite that the patient was on antibiotics, his inflammatory marker is still high. Thus, full septic workups were done, and the patient was having candidemia (Candida parapsilosis) after one month of the admission. For which he was started on anidulafungin 200 mg q24 hours for more than 7 days. Many episodes of gastrointestinal (GI) tract bleeding complicated his course manifested as melena and per rectal bleeding, but all the episodes were managed conservatively by the gastroenterology team. The candidemia persists after 2 weeks of treatment and there was an increase in C‐reactive protein (CRP) level despite that the patient was under antibiotic and antifungal cover. Hence, the ID team recommended giving antifungal (anidulafungin 100 mg) for a total of 14 days to involve an ophthalmologist to rule out fungal ophthalmitis. Still, it was not applicable and to do an echocardiogram to rule out vegetation and it was ruled out by trans‐thoracic echocardiogram.
While the patient was on anidulafungin, his blood culture became positive for Cryptococcus neoformans after 18 days of receiving anidulafungin for previous candida infection, for which he was started on amphotericin (300 mg, q24 hours) and flucytosine (500 mg q12 hours). And there was a recommendation from the ID team to do trans esophageal echo and lumbar puncture to rule out vegetation and brain involvement, respectively, but both tests were not done due to poor prognosis and risk of bleeding because the patient had thrombocytopenia (platelet 21, RR = 150‐400 × 109/L). The Cryptococcemia persist despite the management and he developed sepsis and die within 10 days of the Cryptococcemia.
3 DISCUSSION
Disseminated Cryptococcus neoformans infection is a serious infection that can occur in immunocompromised patients.
7
During the outbreak of COVID‐19 disease, there were many studies about the overwhelming immune response to COVID‐19 infection through the activation of a large number of T lymphocytes and mononuclear macrophages, producing cytokines like interleukin‐6 (IL‐6), which bind to the receptor and cause cytokine storm and severe inflammation in the lung and other tissues. Tocilizumab, as an antihuman IL‐6 receptor monoclonal antibody and immunosuppressant drugs, was recommended by several studies for alleviating the inflammatory response.
8
Jean and colleagues have noted in their study of 52 patients with Cryptococcus neoformans isolated from blood culture; the primary three predisposing for Cryptococcemia are Acquired immunodeficiency syndrome, immunosuppressive therapy, and decompensated liver cirrhosis.
9
And in our case, the Cryptococcus neoformans was isolated from the blood culture. And according to Passerini M et al that Cryptococcus neoformans can affect different organs as meningoencephalitis, which is the most common, followed by pulmonary and cutaneous disease.
10
According to Jean et al that patients with positive blood culture for Cryptococcus neoformans developed sepsis by 81%, including those developed septic shock, the lumbar puncture (LP) was positive in 61.5% of patients with positive blood culture for Cryptococcus neoformans and 84% of those with LP positive showed meningeal involvement, in our case LP was recommended but not done because the patient was critically sick and unstable. Also, it was noted by Jean et al that the fatality within 30 days of Cryptococcemia was 37%.
9
Also, in our case, the patient died within 10 days of Cryptococcemia. Therefore, it is essential to suspect Cryptococcus neoformans infection in an immunocompromised patient and early management, keeping in mind the high morbidity associated with it. Consequently, it is crucial to avoid misdiagnosis and mismanagement, keeping in mind the high morbidity.
4 CONCLUSION
This case highlights the importance of early suspicion of Cryptococcus neoformans infection and other opportunistic infections in immunocompromised patients, putting in mind that patients with Cryptococcaemia have a high risk of mortality within 30 days, which warrants the use of corticosteroid and immunomodulatory drugs in a critically ill patient with COVID‐19. In the current scenario, the use of immunosuppressive therapy should be justified and to be alert for opportunistic infection like Cryptococcus neoformans infection, which can lead to sepsis and mortality.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
AUTHORS' CONTRIBUTIONS
MYK, AAA, SBS, ASM, AJN: involved in data collection, literature search, and manuscript preparation. All authors read and approved the final manuscript.
ETHICAL APPROVAL
The article describes a case report. Therefore, no additional permission from our Ethics Committee was required.
ACKNOWLEDGMENTS
Open Access funding provided by the Qatar National Library. The consent for publication was obtained.
DATA AVAILABILITY STATEMENT
All data generated or analyzed during this study are included in this published article. | 72 kg. | Weight | CC BY-NC-ND | 33598258 | 19,029,149 | 2021-02 |
What was the dosage of drug 'METHYLPREDNISOLONE'? | Cryptococcemia in a patient with COVID-19: A case report.
The authors urge clinicians to balance the use of Immunosuppressant drugs and tocilizumab for COVID-19 patients to avoid the development of infections like Cryptococcemia, leading to death within 30 days.
1 BACKGROUND
Cryptococcus neoformans infection is a known cause of meningoencephalitis in immunocompromised patients. However, it is less frequent in immunocompetent individuals. Here, we report a case of a 60‐year‐old COVID‐19 patient with a history of several comorbidities who received tocilizumab and corticosteroids, which lead to Cryptococcemia.
Cryptococcus neoformans are basidiomycetous; encapsulated yeasts are classified into four serotypes according to their capsule.
1
The way of the infection is by inhalation of basidiospore form or small, poorly encapsulated yeasts.
2
Cryptococcus neoformans infection typically happens among immunocompromised patients, and meningoencephalitis is the typical manifestation of cryptococcosis among HIV patients.
3
,
4
In immunocompetent, the infection can be subclinical and a study on postmortem immunocompetent just showed small granulomatous disease in the lung without disseminating the infection.
5
,
6
We describe a case of a patient with COVID‐19 who developed Cryptococcemia while being treated by immunosuppressive treatment.
2 CASE PRESENTATION
A 60‐year‐old man with a history of hypertension, diabetes mellitus, and ischemic heart disease admitted to the intensive care unit (ICU) with confirmed COVID‐19 infection required mechanical ventilation; on the same day of admission, he was pronned for many times due to low PaO2/FiO2 (P/F) ratio. He received three doses of tocilizumab (400 mg/once), (600 mg/once), and (600 mg/once), respectively, due to possible cytokine storm; he received several doses of methylprednisolone as part of the COVID‐19 management and hydrocortisone.
Few days after receiving tocilizumab, his bronchial alveolar lavage was positive for Candida glabrate; he was started on anidulafungin 200 mg q24 hours for 7 days. The patient was sedated and intubated for 22 days, so a tracheostomy was done. He developed acute kidney injury (AKI) after 28 days of ICU admission; hence, hemodialysis was started.
Despite that the patient was on antibiotics, his inflammatory marker is still high. Thus, full septic workups were done, and the patient was having candidemia (Candida parapsilosis) after one month of the admission. For which he was started on anidulafungin 200 mg q24 hours for more than 7 days. Many episodes of gastrointestinal (GI) tract bleeding complicated his course manifested as melena and per rectal bleeding, but all the episodes were managed conservatively by the gastroenterology team. The candidemia persists after 2 weeks of treatment and there was an increase in C‐reactive protein (CRP) level despite that the patient was under antibiotic and antifungal cover. Hence, the ID team recommended giving antifungal (anidulafungin 100 mg) for a total of 14 days to involve an ophthalmologist to rule out fungal ophthalmitis. Still, it was not applicable and to do an echocardiogram to rule out vegetation and it was ruled out by trans‐thoracic echocardiogram.
While the patient was on anidulafungin, his blood culture became positive for Cryptococcus neoformans after 18 days of receiving anidulafungin for previous candida infection, for which he was started on amphotericin (300 mg, q24 hours) and flucytosine (500 mg q12 hours). And there was a recommendation from the ID team to do trans esophageal echo and lumbar puncture to rule out vegetation and brain involvement, respectively, but both tests were not done due to poor prognosis and risk of bleeding because the patient had thrombocytopenia (platelet 21, RR = 150‐400 × 109/L). The Cryptococcemia persist despite the management and he developed sepsis and die within 10 days of the Cryptococcemia.
3 DISCUSSION
Disseminated Cryptococcus neoformans infection is a serious infection that can occur in immunocompromised patients.
7
During the outbreak of COVID‐19 disease, there were many studies about the overwhelming immune response to COVID‐19 infection through the activation of a large number of T lymphocytes and mononuclear macrophages, producing cytokines like interleukin‐6 (IL‐6), which bind to the receptor and cause cytokine storm and severe inflammation in the lung and other tissues. Tocilizumab, as an antihuman IL‐6 receptor monoclonal antibody and immunosuppressant drugs, was recommended by several studies for alleviating the inflammatory response.
8
Jean and colleagues have noted in their study of 52 patients with Cryptococcus neoformans isolated from blood culture; the primary three predisposing for Cryptococcemia are Acquired immunodeficiency syndrome, immunosuppressive therapy, and decompensated liver cirrhosis.
9
And in our case, the Cryptococcus neoformans was isolated from the blood culture. And according to Passerini M et al that Cryptococcus neoformans can affect different organs as meningoencephalitis, which is the most common, followed by pulmonary and cutaneous disease.
10
According to Jean et al that patients with positive blood culture for Cryptococcus neoformans developed sepsis by 81%, including those developed septic shock, the lumbar puncture (LP) was positive in 61.5% of patients with positive blood culture for Cryptococcus neoformans and 84% of those with LP positive showed meningeal involvement, in our case LP was recommended but not done because the patient was critically sick and unstable. Also, it was noted by Jean et al that the fatality within 30 days of Cryptococcemia was 37%.
9
Also, in our case, the patient died within 10 days of Cryptococcemia. Therefore, it is essential to suspect Cryptococcus neoformans infection in an immunocompromised patient and early management, keeping in mind the high morbidity associated with it. Consequently, it is crucial to avoid misdiagnosis and mismanagement, keeping in mind the high morbidity.
4 CONCLUSION
This case highlights the importance of early suspicion of Cryptococcus neoformans infection and other opportunistic infections in immunocompromised patients, putting in mind that patients with Cryptococcaemia have a high risk of mortality within 30 days, which warrants the use of corticosteroid and immunomodulatory drugs in a critically ill patient with COVID‐19. In the current scenario, the use of immunosuppressive therapy should be justified and to be alert for opportunistic infection like Cryptococcus neoformans infection, which can lead to sepsis and mortality.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
AUTHORS' CONTRIBUTIONS
MYK, AAA, SBS, ASM, AJN: involved in data collection, literature search, and manuscript preparation. All authors read and approved the final manuscript.
ETHICAL APPROVAL
The article describes a case report. Therefore, no additional permission from our Ethics Committee was required.
ACKNOWLEDGMENTS
Open Access funding provided by the Qatar National Library. The consent for publication was obtained.
DATA AVAILABILITY STATEMENT
All data generated or analyzed during this study are included in this published article. | RECEIVED SEVERAL DOSES | DrugDosageText | CC BY-NC-ND | 33598258 | 19,029,149 | 2021-02 |
What was the outcome of reaction 'Acute kidney injury'? | Cryptococcemia in a patient with COVID-19: A case report.
The authors urge clinicians to balance the use of Immunosuppressant drugs and tocilizumab for COVID-19 patients to avoid the development of infections like Cryptococcemia, leading to death within 30 days.
1 BACKGROUND
Cryptococcus neoformans infection is a known cause of meningoencephalitis in immunocompromised patients. However, it is less frequent in immunocompetent individuals. Here, we report a case of a 60‐year‐old COVID‐19 patient with a history of several comorbidities who received tocilizumab and corticosteroids, which lead to Cryptococcemia.
Cryptococcus neoformans are basidiomycetous; encapsulated yeasts are classified into four serotypes according to their capsule.
1
The way of the infection is by inhalation of basidiospore form or small, poorly encapsulated yeasts.
2
Cryptococcus neoformans infection typically happens among immunocompromised patients, and meningoencephalitis is the typical manifestation of cryptococcosis among HIV patients.
3
,
4
In immunocompetent, the infection can be subclinical and a study on postmortem immunocompetent just showed small granulomatous disease in the lung without disseminating the infection.
5
,
6
We describe a case of a patient with COVID‐19 who developed Cryptococcemia while being treated by immunosuppressive treatment.
2 CASE PRESENTATION
A 60‐year‐old man with a history of hypertension, diabetes mellitus, and ischemic heart disease admitted to the intensive care unit (ICU) with confirmed COVID‐19 infection required mechanical ventilation; on the same day of admission, he was pronned for many times due to low PaO2/FiO2 (P/F) ratio. He received three doses of tocilizumab (400 mg/once), (600 mg/once), and (600 mg/once), respectively, due to possible cytokine storm; he received several doses of methylprednisolone as part of the COVID‐19 management and hydrocortisone.
Few days after receiving tocilizumab, his bronchial alveolar lavage was positive for Candida glabrate; he was started on anidulafungin 200 mg q24 hours for 7 days. The patient was sedated and intubated for 22 days, so a tracheostomy was done. He developed acute kidney injury (AKI) after 28 days of ICU admission; hence, hemodialysis was started.
Despite that the patient was on antibiotics, his inflammatory marker is still high. Thus, full septic workups were done, and the patient was having candidemia (Candida parapsilosis) after one month of the admission. For which he was started on anidulafungin 200 mg q24 hours for more than 7 days. Many episodes of gastrointestinal (GI) tract bleeding complicated his course manifested as melena and per rectal bleeding, but all the episodes were managed conservatively by the gastroenterology team. The candidemia persists after 2 weeks of treatment and there was an increase in C‐reactive protein (CRP) level despite that the patient was under antibiotic and antifungal cover. Hence, the ID team recommended giving antifungal (anidulafungin 100 mg) for a total of 14 days to involve an ophthalmologist to rule out fungal ophthalmitis. Still, it was not applicable and to do an echocardiogram to rule out vegetation and it was ruled out by trans‐thoracic echocardiogram.
While the patient was on anidulafungin, his blood culture became positive for Cryptococcus neoformans after 18 days of receiving anidulafungin for previous candida infection, for which he was started on amphotericin (300 mg, q24 hours) and flucytosine (500 mg q12 hours). And there was a recommendation from the ID team to do trans esophageal echo and lumbar puncture to rule out vegetation and brain involvement, respectively, but both tests were not done due to poor prognosis and risk of bleeding because the patient had thrombocytopenia (platelet 21, RR = 150‐400 × 109/L). The Cryptococcemia persist despite the management and he developed sepsis and die within 10 days of the Cryptococcemia.
3 DISCUSSION
Disseminated Cryptococcus neoformans infection is a serious infection that can occur in immunocompromised patients.
7
During the outbreak of COVID‐19 disease, there were many studies about the overwhelming immune response to COVID‐19 infection through the activation of a large number of T lymphocytes and mononuclear macrophages, producing cytokines like interleukin‐6 (IL‐6), which bind to the receptor and cause cytokine storm and severe inflammation in the lung and other tissues. Tocilizumab, as an antihuman IL‐6 receptor monoclonal antibody and immunosuppressant drugs, was recommended by several studies for alleviating the inflammatory response.
8
Jean and colleagues have noted in their study of 52 patients with Cryptococcus neoformans isolated from blood culture; the primary three predisposing for Cryptococcemia are Acquired immunodeficiency syndrome, immunosuppressive therapy, and decompensated liver cirrhosis.
9
And in our case, the Cryptococcus neoformans was isolated from the blood culture. And according to Passerini M et al that Cryptococcus neoformans can affect different organs as meningoencephalitis, which is the most common, followed by pulmonary and cutaneous disease.
10
According to Jean et al that patients with positive blood culture for Cryptococcus neoformans developed sepsis by 81%, including those developed septic shock, the lumbar puncture (LP) was positive in 61.5% of patients with positive blood culture for Cryptococcus neoformans and 84% of those with LP positive showed meningeal involvement, in our case LP was recommended but not done because the patient was critically sick and unstable. Also, it was noted by Jean et al that the fatality within 30 days of Cryptococcemia was 37%.
9
Also, in our case, the patient died within 10 days of Cryptococcemia. Therefore, it is essential to suspect Cryptococcus neoformans infection in an immunocompromised patient and early management, keeping in mind the high morbidity associated with it. Consequently, it is crucial to avoid misdiagnosis and mismanagement, keeping in mind the high morbidity.
4 CONCLUSION
This case highlights the importance of early suspicion of Cryptococcus neoformans infection and other opportunistic infections in immunocompromised patients, putting in mind that patients with Cryptococcaemia have a high risk of mortality within 30 days, which warrants the use of corticosteroid and immunomodulatory drugs in a critically ill patient with COVID‐19. In the current scenario, the use of immunosuppressive therapy should be justified and to be alert for opportunistic infection like Cryptococcus neoformans infection, which can lead to sepsis and mortality.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
AUTHORS' CONTRIBUTIONS
MYK, AAA, SBS, ASM, AJN: involved in data collection, literature search, and manuscript preparation. All authors read and approved the final manuscript.
ETHICAL APPROVAL
The article describes a case report. Therefore, no additional permission from our Ethics Committee was required.
ACKNOWLEDGMENTS
Open Access funding provided by the Qatar National Library. The consent for publication was obtained.
DATA AVAILABILITY STATEMENT
All data generated or analyzed during this study are included in this published article. | Not recovered | ReactionOutcome | CC BY-NC-ND | 33598258 | 19,012,839 | 2021-02 |
What was the outcome of reaction 'Candida infection'? | Cryptococcemia in a patient with COVID-19: A case report.
The authors urge clinicians to balance the use of Immunosuppressant drugs and tocilizumab for COVID-19 patients to avoid the development of infections like Cryptococcemia, leading to death within 30 days.
1 BACKGROUND
Cryptococcus neoformans infection is a known cause of meningoencephalitis in immunocompromised patients. However, it is less frequent in immunocompetent individuals. Here, we report a case of a 60‐year‐old COVID‐19 patient with a history of several comorbidities who received tocilizumab and corticosteroids, which lead to Cryptococcemia.
Cryptococcus neoformans are basidiomycetous; encapsulated yeasts are classified into four serotypes according to their capsule.
1
The way of the infection is by inhalation of basidiospore form or small, poorly encapsulated yeasts.
2
Cryptococcus neoformans infection typically happens among immunocompromised patients, and meningoencephalitis is the typical manifestation of cryptococcosis among HIV patients.
3
,
4
In immunocompetent, the infection can be subclinical and a study on postmortem immunocompetent just showed small granulomatous disease in the lung without disseminating the infection.
5
,
6
We describe a case of a patient with COVID‐19 who developed Cryptococcemia while being treated by immunosuppressive treatment.
2 CASE PRESENTATION
A 60‐year‐old man with a history of hypertension, diabetes mellitus, and ischemic heart disease admitted to the intensive care unit (ICU) with confirmed COVID‐19 infection required mechanical ventilation; on the same day of admission, he was pronned for many times due to low PaO2/FiO2 (P/F) ratio. He received three doses of tocilizumab (400 mg/once), (600 mg/once), and (600 mg/once), respectively, due to possible cytokine storm; he received several doses of methylprednisolone as part of the COVID‐19 management and hydrocortisone.
Few days after receiving tocilizumab, his bronchial alveolar lavage was positive for Candida glabrate; he was started on anidulafungin 200 mg q24 hours for 7 days. The patient was sedated and intubated for 22 days, so a tracheostomy was done. He developed acute kidney injury (AKI) after 28 days of ICU admission; hence, hemodialysis was started.
Despite that the patient was on antibiotics, his inflammatory marker is still high. Thus, full septic workups were done, and the patient was having candidemia (Candida parapsilosis) after one month of the admission. For which he was started on anidulafungin 200 mg q24 hours for more than 7 days. Many episodes of gastrointestinal (GI) tract bleeding complicated his course manifested as melena and per rectal bleeding, but all the episodes were managed conservatively by the gastroenterology team. The candidemia persists after 2 weeks of treatment and there was an increase in C‐reactive protein (CRP) level despite that the patient was under antibiotic and antifungal cover. Hence, the ID team recommended giving antifungal (anidulafungin 100 mg) for a total of 14 days to involve an ophthalmologist to rule out fungal ophthalmitis. Still, it was not applicable and to do an echocardiogram to rule out vegetation and it was ruled out by trans‐thoracic echocardiogram.
While the patient was on anidulafungin, his blood culture became positive for Cryptococcus neoformans after 18 days of receiving anidulafungin for previous candida infection, for which he was started on amphotericin (300 mg, q24 hours) and flucytosine (500 mg q12 hours). And there was a recommendation from the ID team to do trans esophageal echo and lumbar puncture to rule out vegetation and brain involvement, respectively, but both tests were not done due to poor prognosis and risk of bleeding because the patient had thrombocytopenia (platelet 21, RR = 150‐400 × 109/L). The Cryptococcemia persist despite the management and he developed sepsis and die within 10 days of the Cryptococcemia.
3 DISCUSSION
Disseminated Cryptococcus neoformans infection is a serious infection that can occur in immunocompromised patients.
7
During the outbreak of COVID‐19 disease, there were many studies about the overwhelming immune response to COVID‐19 infection through the activation of a large number of T lymphocytes and mononuclear macrophages, producing cytokines like interleukin‐6 (IL‐6), which bind to the receptor and cause cytokine storm and severe inflammation in the lung and other tissues. Tocilizumab, as an antihuman IL‐6 receptor monoclonal antibody and immunosuppressant drugs, was recommended by several studies for alleviating the inflammatory response.
8
Jean and colleagues have noted in their study of 52 patients with Cryptococcus neoformans isolated from blood culture; the primary three predisposing for Cryptococcemia are Acquired immunodeficiency syndrome, immunosuppressive therapy, and decompensated liver cirrhosis.
9
And in our case, the Cryptococcus neoformans was isolated from the blood culture. And according to Passerini M et al that Cryptococcus neoformans can affect different organs as meningoencephalitis, which is the most common, followed by pulmonary and cutaneous disease.
10
According to Jean et al that patients with positive blood culture for Cryptococcus neoformans developed sepsis by 81%, including those developed septic shock, the lumbar puncture (LP) was positive in 61.5% of patients with positive blood culture for Cryptococcus neoformans and 84% of those with LP positive showed meningeal involvement, in our case LP was recommended but not done because the patient was critically sick and unstable. Also, it was noted by Jean et al that the fatality within 30 days of Cryptococcemia was 37%.
9
Also, in our case, the patient died within 10 days of Cryptococcemia. Therefore, it is essential to suspect Cryptococcus neoformans infection in an immunocompromised patient and early management, keeping in mind the high morbidity associated with it. Consequently, it is crucial to avoid misdiagnosis and mismanagement, keeping in mind the high morbidity.
4 CONCLUSION
This case highlights the importance of early suspicion of Cryptococcus neoformans infection and other opportunistic infections in immunocompromised patients, putting in mind that patients with Cryptococcaemia have a high risk of mortality within 30 days, which warrants the use of corticosteroid and immunomodulatory drugs in a critically ill patient with COVID‐19. In the current scenario, the use of immunosuppressive therapy should be justified and to be alert for opportunistic infection like Cryptococcus neoformans infection, which can lead to sepsis and mortality.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
AUTHORS' CONTRIBUTIONS
MYK, AAA, SBS, ASM, AJN: involved in data collection, literature search, and manuscript preparation. All authors read and approved the final manuscript.
ETHICAL APPROVAL
The article describes a case report. Therefore, no additional permission from our Ethics Committee was required.
ACKNOWLEDGMENTS
Open Access funding provided by the Qatar National Library. The consent for publication was obtained.
DATA AVAILABILITY STATEMENT
All data generated or analyzed during this study are included in this published article. | Recovered | ReactionOutcome | CC BY-NC-ND | 33598258 | 19,012,839 | 2021-02 |
What was the outcome of reaction 'Cryptococcosis'? | Cryptococcemia in a patient with COVID-19: A case report.
The authors urge clinicians to balance the use of Immunosuppressant drugs and tocilizumab for COVID-19 patients to avoid the development of infections like Cryptococcemia, leading to death within 30 days.
1 BACKGROUND
Cryptococcus neoformans infection is a known cause of meningoencephalitis in immunocompromised patients. However, it is less frequent in immunocompetent individuals. Here, we report a case of a 60‐year‐old COVID‐19 patient with a history of several comorbidities who received tocilizumab and corticosteroids, which lead to Cryptococcemia.
Cryptococcus neoformans are basidiomycetous; encapsulated yeasts are classified into four serotypes according to their capsule.
1
The way of the infection is by inhalation of basidiospore form or small, poorly encapsulated yeasts.
2
Cryptococcus neoformans infection typically happens among immunocompromised patients, and meningoencephalitis is the typical manifestation of cryptococcosis among HIV patients.
3
,
4
In immunocompetent, the infection can be subclinical and a study on postmortem immunocompetent just showed small granulomatous disease in the lung without disseminating the infection.
5
,
6
We describe a case of a patient with COVID‐19 who developed Cryptococcemia while being treated by immunosuppressive treatment.
2 CASE PRESENTATION
A 60‐year‐old man with a history of hypertension, diabetes mellitus, and ischemic heart disease admitted to the intensive care unit (ICU) with confirmed COVID‐19 infection required mechanical ventilation; on the same day of admission, he was pronned for many times due to low PaO2/FiO2 (P/F) ratio. He received three doses of tocilizumab (400 mg/once), (600 mg/once), and (600 mg/once), respectively, due to possible cytokine storm; he received several doses of methylprednisolone as part of the COVID‐19 management and hydrocortisone.
Few days after receiving tocilizumab, his bronchial alveolar lavage was positive for Candida glabrate; he was started on anidulafungin 200 mg q24 hours for 7 days. The patient was sedated and intubated for 22 days, so a tracheostomy was done. He developed acute kidney injury (AKI) after 28 days of ICU admission; hence, hemodialysis was started.
Despite that the patient was on antibiotics, his inflammatory marker is still high. Thus, full septic workups were done, and the patient was having candidemia (Candida parapsilosis) after one month of the admission. For which he was started on anidulafungin 200 mg q24 hours for more than 7 days. Many episodes of gastrointestinal (GI) tract bleeding complicated his course manifested as melena and per rectal bleeding, but all the episodes were managed conservatively by the gastroenterology team. The candidemia persists after 2 weeks of treatment and there was an increase in C‐reactive protein (CRP) level despite that the patient was under antibiotic and antifungal cover. Hence, the ID team recommended giving antifungal (anidulafungin 100 mg) for a total of 14 days to involve an ophthalmologist to rule out fungal ophthalmitis. Still, it was not applicable and to do an echocardiogram to rule out vegetation and it was ruled out by trans‐thoracic echocardiogram.
While the patient was on anidulafungin, his blood culture became positive for Cryptococcus neoformans after 18 days of receiving anidulafungin for previous candida infection, for which he was started on amphotericin (300 mg, q24 hours) and flucytosine (500 mg q12 hours). And there was a recommendation from the ID team to do trans esophageal echo and lumbar puncture to rule out vegetation and brain involvement, respectively, but both tests were not done due to poor prognosis and risk of bleeding because the patient had thrombocytopenia (platelet 21, RR = 150‐400 × 109/L). The Cryptococcemia persist despite the management and he developed sepsis and die within 10 days of the Cryptococcemia.
3 DISCUSSION
Disseminated Cryptococcus neoformans infection is a serious infection that can occur in immunocompromised patients.
7
During the outbreak of COVID‐19 disease, there were many studies about the overwhelming immune response to COVID‐19 infection through the activation of a large number of T lymphocytes and mononuclear macrophages, producing cytokines like interleukin‐6 (IL‐6), which bind to the receptor and cause cytokine storm and severe inflammation in the lung and other tissues. Tocilizumab, as an antihuman IL‐6 receptor monoclonal antibody and immunosuppressant drugs, was recommended by several studies for alleviating the inflammatory response.
8
Jean and colleagues have noted in their study of 52 patients with Cryptococcus neoformans isolated from blood culture; the primary three predisposing for Cryptococcemia are Acquired immunodeficiency syndrome, immunosuppressive therapy, and decompensated liver cirrhosis.
9
And in our case, the Cryptococcus neoformans was isolated from the blood culture. And according to Passerini M et al that Cryptococcus neoformans can affect different organs as meningoencephalitis, which is the most common, followed by pulmonary and cutaneous disease.
10
According to Jean et al that patients with positive blood culture for Cryptococcus neoformans developed sepsis by 81%, including those developed septic shock, the lumbar puncture (LP) was positive in 61.5% of patients with positive blood culture for Cryptococcus neoformans and 84% of those with LP positive showed meningeal involvement, in our case LP was recommended but not done because the patient was critically sick and unstable. Also, it was noted by Jean et al that the fatality within 30 days of Cryptococcemia was 37%.
9
Also, in our case, the patient died within 10 days of Cryptococcemia. Therefore, it is essential to suspect Cryptococcus neoformans infection in an immunocompromised patient and early management, keeping in mind the high morbidity associated with it. Consequently, it is crucial to avoid misdiagnosis and mismanagement, keeping in mind the high morbidity.
4 CONCLUSION
This case highlights the importance of early suspicion of Cryptococcus neoformans infection and other opportunistic infections in immunocompromised patients, putting in mind that patients with Cryptococcaemia have a high risk of mortality within 30 days, which warrants the use of corticosteroid and immunomodulatory drugs in a critically ill patient with COVID‐19. In the current scenario, the use of immunosuppressive therapy should be justified and to be alert for opportunistic infection like Cryptococcus neoformans infection, which can lead to sepsis and mortality.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
AUTHORS' CONTRIBUTIONS
MYK, AAA, SBS, ASM, AJN: involved in data collection, literature search, and manuscript preparation. All authors read and approved the final manuscript.
ETHICAL APPROVAL
The article describes a case report. Therefore, no additional permission from our Ethics Committee was required.
ACKNOWLEDGMENTS
Open Access funding provided by the Qatar National Library. The consent for publication was obtained.
DATA AVAILABILITY STATEMENT
All data generated or analyzed during this study are included in this published article. | Fatal | ReactionOutcome | CC BY-NC-ND | 33598258 | 19,041,516 | 2021-02 |
What was the outcome of reaction 'Gastrointestinal haemorrhage'? | Cryptococcemia in a patient with COVID-19: A case report.
The authors urge clinicians to balance the use of Immunosuppressant drugs and tocilizumab for COVID-19 patients to avoid the development of infections like Cryptococcemia, leading to death within 30 days.
1 BACKGROUND
Cryptococcus neoformans infection is a known cause of meningoencephalitis in immunocompromised patients. However, it is less frequent in immunocompetent individuals. Here, we report a case of a 60‐year‐old COVID‐19 patient with a history of several comorbidities who received tocilizumab and corticosteroids, which lead to Cryptococcemia.
Cryptococcus neoformans are basidiomycetous; encapsulated yeasts are classified into four serotypes according to their capsule.
1
The way of the infection is by inhalation of basidiospore form or small, poorly encapsulated yeasts.
2
Cryptococcus neoformans infection typically happens among immunocompromised patients, and meningoencephalitis is the typical manifestation of cryptococcosis among HIV patients.
3
,
4
In immunocompetent, the infection can be subclinical and a study on postmortem immunocompetent just showed small granulomatous disease in the lung without disseminating the infection.
5
,
6
We describe a case of a patient with COVID‐19 who developed Cryptococcemia while being treated by immunosuppressive treatment.
2 CASE PRESENTATION
A 60‐year‐old man with a history of hypertension, diabetes mellitus, and ischemic heart disease admitted to the intensive care unit (ICU) with confirmed COVID‐19 infection required mechanical ventilation; on the same day of admission, he was pronned for many times due to low PaO2/FiO2 (P/F) ratio. He received three doses of tocilizumab (400 mg/once), (600 mg/once), and (600 mg/once), respectively, due to possible cytokine storm; he received several doses of methylprednisolone as part of the COVID‐19 management and hydrocortisone.
Few days after receiving tocilizumab, his bronchial alveolar lavage was positive for Candida glabrate; he was started on anidulafungin 200 mg q24 hours for 7 days. The patient was sedated and intubated for 22 days, so a tracheostomy was done. He developed acute kidney injury (AKI) after 28 days of ICU admission; hence, hemodialysis was started.
Despite that the patient was on antibiotics, his inflammatory marker is still high. Thus, full septic workups were done, and the patient was having candidemia (Candida parapsilosis) after one month of the admission. For which he was started on anidulafungin 200 mg q24 hours for more than 7 days. Many episodes of gastrointestinal (GI) tract bleeding complicated his course manifested as melena and per rectal bleeding, but all the episodes were managed conservatively by the gastroenterology team. The candidemia persists after 2 weeks of treatment and there was an increase in C‐reactive protein (CRP) level despite that the patient was under antibiotic and antifungal cover. Hence, the ID team recommended giving antifungal (anidulafungin 100 mg) for a total of 14 days to involve an ophthalmologist to rule out fungal ophthalmitis. Still, it was not applicable and to do an echocardiogram to rule out vegetation and it was ruled out by trans‐thoracic echocardiogram.
While the patient was on anidulafungin, his blood culture became positive for Cryptococcus neoformans after 18 days of receiving anidulafungin for previous candida infection, for which he was started on amphotericin (300 mg, q24 hours) and flucytosine (500 mg q12 hours). And there was a recommendation from the ID team to do trans esophageal echo and lumbar puncture to rule out vegetation and brain involvement, respectively, but both tests were not done due to poor prognosis and risk of bleeding because the patient had thrombocytopenia (platelet 21, RR = 150‐400 × 109/L). The Cryptococcemia persist despite the management and he developed sepsis and die within 10 days of the Cryptococcemia.
3 DISCUSSION
Disseminated Cryptococcus neoformans infection is a serious infection that can occur in immunocompromised patients.
7
During the outbreak of COVID‐19 disease, there were many studies about the overwhelming immune response to COVID‐19 infection through the activation of a large number of T lymphocytes and mononuclear macrophages, producing cytokines like interleukin‐6 (IL‐6), which bind to the receptor and cause cytokine storm and severe inflammation in the lung and other tissues. Tocilizumab, as an antihuman IL‐6 receptor monoclonal antibody and immunosuppressant drugs, was recommended by several studies for alleviating the inflammatory response.
8
Jean and colleagues have noted in their study of 52 patients with Cryptococcus neoformans isolated from blood culture; the primary three predisposing for Cryptococcemia are Acquired immunodeficiency syndrome, immunosuppressive therapy, and decompensated liver cirrhosis.
9
And in our case, the Cryptococcus neoformans was isolated from the blood culture. And according to Passerini M et al that Cryptococcus neoformans can affect different organs as meningoencephalitis, which is the most common, followed by pulmonary and cutaneous disease.
10
According to Jean et al that patients with positive blood culture for Cryptococcus neoformans developed sepsis by 81%, including those developed septic shock, the lumbar puncture (LP) was positive in 61.5% of patients with positive blood culture for Cryptococcus neoformans and 84% of those with LP positive showed meningeal involvement, in our case LP was recommended but not done because the patient was critically sick and unstable. Also, it was noted by Jean et al that the fatality within 30 days of Cryptococcemia was 37%.
9
Also, in our case, the patient died within 10 days of Cryptococcemia. Therefore, it is essential to suspect Cryptococcus neoformans infection in an immunocompromised patient and early management, keeping in mind the high morbidity associated with it. Consequently, it is crucial to avoid misdiagnosis and mismanagement, keeping in mind the high morbidity.
4 CONCLUSION
This case highlights the importance of early suspicion of Cryptococcus neoformans infection and other opportunistic infections in immunocompromised patients, putting in mind that patients with Cryptococcaemia have a high risk of mortality within 30 days, which warrants the use of corticosteroid and immunomodulatory drugs in a critically ill patient with COVID‐19. In the current scenario, the use of immunosuppressive therapy should be justified and to be alert for opportunistic infection like Cryptococcus neoformans infection, which can lead to sepsis and mortality.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
AUTHORS' CONTRIBUTIONS
MYK, AAA, SBS, ASM, AJN: involved in data collection, literature search, and manuscript preparation. All authors read and approved the final manuscript.
ETHICAL APPROVAL
The article describes a case report. Therefore, no additional permission from our Ethics Committee was required.
ACKNOWLEDGMENTS
Open Access funding provided by the Qatar National Library. The consent for publication was obtained.
DATA AVAILABILITY STATEMENT
All data generated or analyzed during this study are included in this published article. | Recovered | ReactionOutcome | CC BY-NC-ND | 33598258 | 19,012,839 | 2021-02 |
What was the outcome of reaction 'Sepsis'? | Cryptococcemia in a patient with COVID-19: A case report.
The authors urge clinicians to balance the use of Immunosuppressant drugs and tocilizumab for COVID-19 patients to avoid the development of infections like Cryptococcemia, leading to death within 30 days.
1 BACKGROUND
Cryptococcus neoformans infection is a known cause of meningoencephalitis in immunocompromised patients. However, it is less frequent in immunocompetent individuals. Here, we report a case of a 60‐year‐old COVID‐19 patient with a history of several comorbidities who received tocilizumab and corticosteroids, which lead to Cryptococcemia.
Cryptococcus neoformans are basidiomycetous; encapsulated yeasts are classified into four serotypes according to their capsule.
1
The way of the infection is by inhalation of basidiospore form or small, poorly encapsulated yeasts.
2
Cryptococcus neoformans infection typically happens among immunocompromised patients, and meningoencephalitis is the typical manifestation of cryptococcosis among HIV patients.
3
,
4
In immunocompetent, the infection can be subclinical and a study on postmortem immunocompetent just showed small granulomatous disease in the lung without disseminating the infection.
5
,
6
We describe a case of a patient with COVID‐19 who developed Cryptococcemia while being treated by immunosuppressive treatment.
2 CASE PRESENTATION
A 60‐year‐old man with a history of hypertension, diabetes mellitus, and ischemic heart disease admitted to the intensive care unit (ICU) with confirmed COVID‐19 infection required mechanical ventilation; on the same day of admission, he was pronned for many times due to low PaO2/FiO2 (P/F) ratio. He received three doses of tocilizumab (400 mg/once), (600 mg/once), and (600 mg/once), respectively, due to possible cytokine storm; he received several doses of methylprednisolone as part of the COVID‐19 management and hydrocortisone.
Few days after receiving tocilizumab, his bronchial alveolar lavage was positive for Candida glabrate; he was started on anidulafungin 200 mg q24 hours for 7 days. The patient was sedated and intubated for 22 days, so a tracheostomy was done. He developed acute kidney injury (AKI) after 28 days of ICU admission; hence, hemodialysis was started.
Despite that the patient was on antibiotics, his inflammatory marker is still high. Thus, full septic workups were done, and the patient was having candidemia (Candida parapsilosis) after one month of the admission. For which he was started on anidulafungin 200 mg q24 hours for more than 7 days. Many episodes of gastrointestinal (GI) tract bleeding complicated his course manifested as melena and per rectal bleeding, but all the episodes were managed conservatively by the gastroenterology team. The candidemia persists after 2 weeks of treatment and there was an increase in C‐reactive protein (CRP) level despite that the patient was under antibiotic and antifungal cover. Hence, the ID team recommended giving antifungal (anidulafungin 100 mg) for a total of 14 days to involve an ophthalmologist to rule out fungal ophthalmitis. Still, it was not applicable and to do an echocardiogram to rule out vegetation and it was ruled out by trans‐thoracic echocardiogram.
While the patient was on anidulafungin, his blood culture became positive for Cryptococcus neoformans after 18 days of receiving anidulafungin for previous candida infection, for which he was started on amphotericin (300 mg, q24 hours) and flucytosine (500 mg q12 hours). And there was a recommendation from the ID team to do trans esophageal echo and lumbar puncture to rule out vegetation and brain involvement, respectively, but both tests were not done due to poor prognosis and risk of bleeding because the patient had thrombocytopenia (platelet 21, RR = 150‐400 × 109/L). The Cryptococcemia persist despite the management and he developed sepsis and die within 10 days of the Cryptococcemia.
3 DISCUSSION
Disseminated Cryptococcus neoformans infection is a serious infection that can occur in immunocompromised patients.
7
During the outbreak of COVID‐19 disease, there were many studies about the overwhelming immune response to COVID‐19 infection through the activation of a large number of T lymphocytes and mononuclear macrophages, producing cytokines like interleukin‐6 (IL‐6), which bind to the receptor and cause cytokine storm and severe inflammation in the lung and other tissues. Tocilizumab, as an antihuman IL‐6 receptor monoclonal antibody and immunosuppressant drugs, was recommended by several studies for alleviating the inflammatory response.
8
Jean and colleagues have noted in their study of 52 patients with Cryptococcus neoformans isolated from blood culture; the primary three predisposing for Cryptococcemia are Acquired immunodeficiency syndrome, immunosuppressive therapy, and decompensated liver cirrhosis.
9
And in our case, the Cryptococcus neoformans was isolated from the blood culture. And according to Passerini M et al that Cryptococcus neoformans can affect different organs as meningoencephalitis, which is the most common, followed by pulmonary and cutaneous disease.
10
According to Jean et al that patients with positive blood culture for Cryptococcus neoformans developed sepsis by 81%, including those developed septic shock, the lumbar puncture (LP) was positive in 61.5% of patients with positive blood culture for Cryptococcus neoformans and 84% of those with LP positive showed meningeal involvement, in our case LP was recommended but not done because the patient was critically sick and unstable. Also, it was noted by Jean et al that the fatality within 30 days of Cryptococcemia was 37%.
9
Also, in our case, the patient died within 10 days of Cryptococcemia. Therefore, it is essential to suspect Cryptococcus neoformans infection in an immunocompromised patient and early management, keeping in mind the high morbidity associated with it. Consequently, it is crucial to avoid misdiagnosis and mismanagement, keeping in mind the high morbidity.
4 CONCLUSION
This case highlights the importance of early suspicion of Cryptococcus neoformans infection and other opportunistic infections in immunocompromised patients, putting in mind that patients with Cryptococcaemia have a high risk of mortality within 30 days, which warrants the use of corticosteroid and immunomodulatory drugs in a critically ill patient with COVID‐19. In the current scenario, the use of immunosuppressive therapy should be justified and to be alert for opportunistic infection like Cryptococcus neoformans infection, which can lead to sepsis and mortality.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
AUTHORS' CONTRIBUTIONS
MYK, AAA, SBS, ASM, AJN: involved in data collection, literature search, and manuscript preparation. All authors read and approved the final manuscript.
ETHICAL APPROVAL
The article describes a case report. Therefore, no additional permission from our Ethics Committee was required.
ACKNOWLEDGMENTS
Open Access funding provided by the Qatar National Library. The consent for publication was obtained.
DATA AVAILABILITY STATEMENT
All data generated or analyzed during this study are included in this published article. | Fatal | ReactionOutcome | CC BY-NC-ND | 33598258 | 19,041,516 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ascites'. | Severe tumor lysis syndrome during the induction therapy for the treatment of blastic plasmacytoid dendritic cell neoplasm arising from myelodysplastic/myeloproliferative neoplasms.
BPDCN shows clinically heterogeneous characteristics. And as other hematological malignancies, symptoms of BPDCN suggesting a high tumor burden, such as high white blood cell count or splenomegaly, should be carefully considered to prevent TLS.
1 INTRODUCTION
Blastic plasmacytoid dendritic cell neoplasm is a rare disease with difficulty in diagnosis, and clinical courses of patients with BPDCN vary widely. We report a case of a 63‐year‐old man with BPDCN showing severe tumor lysis syndrome (TLS). BPDCN with high tumor burden should be carefully considered to prevent TLS.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with dismal prognosis. With difficulty in diagnosis, BPDCN was used in the 2008 World Health Organization (WHO) classification for the first time and became a distinct entity in 2016 WHO classification.
1
Recently, the presence of four out of five characteristic markers of BPDCN, namely, CD4, CD56, CD123, CD303, and TCL1, has been shown to aid in the accurate diagnosis of BPDCN.
2
Skin lesions commonly occur in a majority of patients with BPDCN, and blasts of BPDCN are suggested to arise from premalignant hematopoietic precursor clones.
3
Thus, patients with systemic lesions were treated with conventional chemotherapies for acute lymphoblastic leukemia, acute myeloid leukemia, or non‐Hodgkin’s lymphoma, sometimes followed by autologous or allogeneic hematopoietic cell transplantation as a consolidation therapy.
4
However, its clinical and biological heterogeneous characteristics make its clinical management difficult.
5
Herein, we describe the case of a patient who suddenly developed leukemic form of BPDCN accompanied with CALReticulin (CALR) mutation arising from myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN‐RS‐T) without cutaneous lesion, showing severe tumor lysis syndrome (TLS) immediately after the induction therapy.
2 CASE PRESENTATION
A 63‐year‐old man previously diagnosed with MDS/MPN‐RS‐T 6 years before the presentation was referred to our hospital for rapid progression of leukocytosis and anemia. Physical examination and computed tomography revealed splenomegaly and inguinal lymphadenopathy without skin involvement (Figure 1 A, B). He did not have fever and had a performance status of 2 according to the Eastern Cooperative Oncology Group score. Blood examination showed the following abnormalities: white blood cell (WBC) count, 44.8 × 109/L with 88% blasts; hemoglobin, 5.5 g/dL; platelet count, 17.0 × 109/L; and serum lactate dehydrogenase (LDH), 300 IU/L. Genetic analyses of his peripheral blood cells detected type 1 CALR mutation without Janus kinase 2 mutation. Markedly hypercellular marrow occupied by agranular blasts with small cytoplasm and fine chromatin were detected in the bone marrow aspiration (Figure 1C, D), and bone marrow biopsy showed severe myelofibrosis (MF‐3) (Figure 1E). Flow cytometry performed on bone marrow aspirate revealed that blasts expressed CD4, CD7, CD56, and HLA‐DR without other myeloid and lymphoid markers. Similar blasts occupied the inguinal lymph node, which suggested lymph node involvement. Based on these results, the patient was suspected to have aggressive NK cell leukemia (ANKL), acute leukemia with ambiguous lineage, or BPDCN.
FIGURE 1 Computed tomography revealed splenomegaly (A) and inguinal lymphadenopathy (B). Markedly hypercellular marrow was occupied by blasts (C), presenting agranular small cytoplasm and fine chromatin (D). Bone marrow biopsy showed severe fibrosis (MF‐3) (E) (magnification of all images ×400).
Due to rapidly increasing WBC count of 106 × 109/L and worsening malaise, the dose‐reduced SMILE regimen without methotrexate which contained etoposide 70 mg/m2 day1–3, ifosfamide 1050 mg/m2 day 1‐3, dexamethasone 30 mg/body day 1‐3, and L‐asparaginase 4000 U/m2 day 7, 9, 11, 13, 15, 17, and 19 was immediately initiated without accurate diagnosis.
6
More than 3 L/d of intravenous hydration and 60 mg/d of febuxostat were administered as prophylaxis for tumor lysis syndrome (TLS). Then, immunohistochemistry performed on bone marrow specimen demonstrated that blasts were positive for CD123, TCL‐1, and CD303, and thus, he was diagnosed with BPDCN (Figure 2). In addition, blasts were positive for cMyc and Bcl‐2 and negative for TdT, with relatively low Ki67 index (Figure 2). Cytogenetic analysis revealed normal karyotype of blasts. The urine volume after initiating the chemotherapy was 3000 mL/d, and his condition improved that he could eat a meal the next day. However, his urine volume suddenly decreased, and his condition worsened again on the third day. WBC count immediately decreased; uric acid, potassium, and phosphorus concentrations increased; calcium concentration decreased with rapid increase in serum creatinine concentration, suggesting a clinical TLS (Table 1). Despite the intensive treatment such as aggressive hydration with noradrenaline administration to restore circulation and bicarbonate to correct metabolic acidosis, he finally died of circulatory failure. Autopsy revealed massive ascites and alveolar hemorrhage, whereas only a few blasts remained in bone marrow and spleen.
FIGURE 2 Blasts were positive for CD4, CD56, CD123, CD303, TCL‐1, cMyc, and Bcl‐2 and negative for TdT, myeloperoxidase, CD3, and CD8. Positive rate of Ki67 was approximately 30% (magnification of all images ×400).
TABLE 1 Blood tests before and after the induction therapy.
Before treatment Day 2 Day 3
BUN mg/dL 34.2 87.9 123.5
Creatinine mg/dL 1.3 1.6 2.7
UA mg/dL 6.0 5.5 8.5
P mg/dL 3.0 17 22.4
Na mmol/L 137 134 137
K mmol/L 4.7 7.2 6.9
Ca mg/dL 7.6 6 6.5
LDH U/L 395 828 784
WBC 109/L 106 55.7 2.4
Blast % 96 85 76
RBC 1012/L 1.2 1.4 1.1
Hb g/dL 3.7 4.4 3.3
Platelet ×109/L 17.0 15.0 10.0
Abbreviations: BUN, blood urea nitrogen; Hb, hemoglobin; LDH, lactate dehydrogenase; RBC, red blood cell; UA, uric acid; WBC, white blood cell.
John Wiley & Sons, Ltd3 DISCUSSION
In this case report, the patient was diagnosed with BPDCN arising from MDS/MPN‐RS‐T that progressed into clinical TLS immediately after the initiation of chemotherapy. Majority of patients with MDS/MPN‐RS‐T have a SF3B1 mutation.
7
Although SF3B1 mutations were not examined in this case, morphologically apparent dysplasia and the presence of ringed sideroblasts strongly supported the diagnosis of MDS/MPN‐RS‐T. On the other hand, while there is one case report about a patient with MDS/MPN‐RS‐T that was positive for both CALR and SF3B1 gene mutations,
8
BPDCN with CALR mutation has not yet been reported to the best of our knowledge. Therefore, in this case, MDS/MPN‐RS‐T might already have been accompanied with CALR mutation.
TdT negativity was reportedly associated with inferior survival in BPDCN;
9
however, whether the aggressive clinical course observed in this case was typical for TdT‐negative BPDCN remains unknown. Conversely, majority of patients with BPDCN expressing cMyc were reportedly accompanied by 8q24 rearrangement, immunoblastoid morphology, and skin lesions.
10
Although 8q24 rearrangement was not examined in this case, the patient had no skin lesions and his blasts showed classic cytomorphology, which suggested that his clinical features were not typical for MYC‐positive BPDCN.
Previous studies showed that BPDCN with leukemic presentation without skin manifestation rarely occurs and tends to present with cytopenia rather than leukocytosis.
11
However, although the patient had leukemia at diagnosis, it was not accompanied with skin lesions and showed very high WBC count, suggesting it to be a very rare case. Moreover, rapid increase in WBC counts and massive splenomegaly indicated a very high tumor burden and rapid tumor growth. The SMILE regimen was selected because it was effective for ANKL
12
and the etoposide contained in SMILE regimen was also effective for BPDCN.
13
Although occurrence of TLS was cautiously considered in spite of low Ki67 index and enough hydration and febuxostat were provided to the patient for the prevention of TLS, he developed fatal TLS. More rigorous management including the early use of rasburicase and induction of hemodialysis is required.
Although the risk prediction of TLS in BPDCN is unknown because of the rarity and heterogeneity of this disease, the high‐disease burden may indicate the risk of TLS as same as other hematological malignancies, and the evaluation of peripheral blood WBC counts and serum LDH concentration may be useful for risk classification of TLS in BPDCN as in acute leukemia.
14
In conclusion, BPDCN shows clinically heterogeneous characteristics, and patients with clinical symptoms suggesting an aggressive clinical course with high tumor burden, including high WBC count or splenomegaly, should be carefully considered to prevent TLS.
CONFLICT OF INTEREST
There are no conflicts of interest to report.
AUTHOR CONTRIBUTIONS
KS: selected the patient and designed the manuscript. KS, MI, NF, and AK: wrote the manuscript. RF: performed the immunohistochemistry. All the authors: reviewed the paper and agreed with the final version.
ETHICAL APPROVAL
This study was approved by the institutional ethical committee of the Konan Kosei Hospital. Written informed consent was obtained from the family of the patient for publication of this case report.
ACKNOWLEDGMENTS
We acknowledge all of the physicians, nurses, and staff who contributed to the patient care at the Department of Hematology and Oncology in Konan Kosei Hospital. Published with written consent of the patient.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. | ASPARAGINASE, DEXAMETHASONE, ETOPOSIDE, FEBUXOSTAT, IFOSFAMIDE | DrugsGivenReaction | CC BY | 33598264 | 19,587,477 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Severe tumor lysis syndrome during the induction therapy for the treatment of blastic plasmacytoid dendritic cell neoplasm arising from myelodysplastic/myeloproliferative neoplasms.
BPDCN shows clinically heterogeneous characteristics. And as other hematological malignancies, symptoms of BPDCN suggesting a high tumor burden, such as high white blood cell count or splenomegaly, should be carefully considered to prevent TLS.
1 INTRODUCTION
Blastic plasmacytoid dendritic cell neoplasm is a rare disease with difficulty in diagnosis, and clinical courses of patients with BPDCN vary widely. We report a case of a 63‐year‐old man with BPDCN showing severe tumor lysis syndrome (TLS). BPDCN with high tumor burden should be carefully considered to prevent TLS.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with dismal prognosis. With difficulty in diagnosis, BPDCN was used in the 2008 World Health Organization (WHO) classification for the first time and became a distinct entity in 2016 WHO classification.
1
Recently, the presence of four out of five characteristic markers of BPDCN, namely, CD4, CD56, CD123, CD303, and TCL1, has been shown to aid in the accurate diagnosis of BPDCN.
2
Skin lesions commonly occur in a majority of patients with BPDCN, and blasts of BPDCN are suggested to arise from premalignant hematopoietic precursor clones.
3
Thus, patients with systemic lesions were treated with conventional chemotherapies for acute lymphoblastic leukemia, acute myeloid leukemia, or non‐Hodgkin’s lymphoma, sometimes followed by autologous or allogeneic hematopoietic cell transplantation as a consolidation therapy.
4
However, its clinical and biological heterogeneous characteristics make its clinical management difficult.
5
Herein, we describe the case of a patient who suddenly developed leukemic form of BPDCN accompanied with CALReticulin (CALR) mutation arising from myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN‐RS‐T) without cutaneous lesion, showing severe tumor lysis syndrome (TLS) immediately after the induction therapy.
2 CASE PRESENTATION
A 63‐year‐old man previously diagnosed with MDS/MPN‐RS‐T 6 years before the presentation was referred to our hospital for rapid progression of leukocytosis and anemia. Physical examination and computed tomography revealed splenomegaly and inguinal lymphadenopathy without skin involvement (Figure 1 A, B). He did not have fever and had a performance status of 2 according to the Eastern Cooperative Oncology Group score. Blood examination showed the following abnormalities: white blood cell (WBC) count, 44.8 × 109/L with 88% blasts; hemoglobin, 5.5 g/dL; platelet count, 17.0 × 109/L; and serum lactate dehydrogenase (LDH), 300 IU/L. Genetic analyses of his peripheral blood cells detected type 1 CALR mutation without Janus kinase 2 mutation. Markedly hypercellular marrow occupied by agranular blasts with small cytoplasm and fine chromatin were detected in the bone marrow aspiration (Figure 1C, D), and bone marrow biopsy showed severe myelofibrosis (MF‐3) (Figure 1E). Flow cytometry performed on bone marrow aspirate revealed that blasts expressed CD4, CD7, CD56, and HLA‐DR without other myeloid and lymphoid markers. Similar blasts occupied the inguinal lymph node, which suggested lymph node involvement. Based on these results, the patient was suspected to have aggressive NK cell leukemia (ANKL), acute leukemia with ambiguous lineage, or BPDCN.
FIGURE 1 Computed tomography revealed splenomegaly (A) and inguinal lymphadenopathy (B). Markedly hypercellular marrow was occupied by blasts (C), presenting agranular small cytoplasm and fine chromatin (D). Bone marrow biopsy showed severe fibrosis (MF‐3) (E) (magnification of all images ×400).
Due to rapidly increasing WBC count of 106 × 109/L and worsening malaise, the dose‐reduced SMILE regimen without methotrexate which contained etoposide 70 mg/m2 day1–3, ifosfamide 1050 mg/m2 day 1‐3, dexamethasone 30 mg/body day 1‐3, and L‐asparaginase 4000 U/m2 day 7, 9, 11, 13, 15, 17, and 19 was immediately initiated without accurate diagnosis.
6
More than 3 L/d of intravenous hydration and 60 mg/d of febuxostat were administered as prophylaxis for tumor lysis syndrome (TLS). Then, immunohistochemistry performed on bone marrow specimen demonstrated that blasts were positive for CD123, TCL‐1, and CD303, and thus, he was diagnosed with BPDCN (Figure 2). In addition, blasts were positive for cMyc and Bcl‐2 and negative for TdT, with relatively low Ki67 index (Figure 2). Cytogenetic analysis revealed normal karyotype of blasts. The urine volume after initiating the chemotherapy was 3000 mL/d, and his condition improved that he could eat a meal the next day. However, his urine volume suddenly decreased, and his condition worsened again on the third day. WBC count immediately decreased; uric acid, potassium, and phosphorus concentrations increased; calcium concentration decreased with rapid increase in serum creatinine concentration, suggesting a clinical TLS (Table 1). Despite the intensive treatment such as aggressive hydration with noradrenaline administration to restore circulation and bicarbonate to correct metabolic acidosis, he finally died of circulatory failure. Autopsy revealed massive ascites and alveolar hemorrhage, whereas only a few blasts remained in bone marrow and spleen.
FIGURE 2 Blasts were positive for CD4, CD56, CD123, CD303, TCL‐1, cMyc, and Bcl‐2 and negative for TdT, myeloperoxidase, CD3, and CD8. Positive rate of Ki67 was approximately 30% (magnification of all images ×400).
TABLE 1 Blood tests before and after the induction therapy.
Before treatment Day 2 Day 3
BUN mg/dL 34.2 87.9 123.5
Creatinine mg/dL 1.3 1.6 2.7
UA mg/dL 6.0 5.5 8.5
P mg/dL 3.0 17 22.4
Na mmol/L 137 134 137
K mmol/L 4.7 7.2 6.9
Ca mg/dL 7.6 6 6.5
LDH U/L 395 828 784
WBC 109/L 106 55.7 2.4
Blast % 96 85 76
RBC 1012/L 1.2 1.4 1.1
Hb g/dL 3.7 4.4 3.3
Platelet ×109/L 17.0 15.0 10.0
Abbreviations: BUN, blood urea nitrogen; Hb, hemoglobin; LDH, lactate dehydrogenase; RBC, red blood cell; UA, uric acid; WBC, white blood cell.
John Wiley & Sons, Ltd3 DISCUSSION
In this case report, the patient was diagnosed with BPDCN arising from MDS/MPN‐RS‐T that progressed into clinical TLS immediately after the initiation of chemotherapy. Majority of patients with MDS/MPN‐RS‐T have a SF3B1 mutation.
7
Although SF3B1 mutations were not examined in this case, morphologically apparent dysplasia and the presence of ringed sideroblasts strongly supported the diagnosis of MDS/MPN‐RS‐T. On the other hand, while there is one case report about a patient with MDS/MPN‐RS‐T that was positive for both CALR and SF3B1 gene mutations,
8
BPDCN with CALR mutation has not yet been reported to the best of our knowledge. Therefore, in this case, MDS/MPN‐RS‐T might already have been accompanied with CALR mutation.
TdT negativity was reportedly associated with inferior survival in BPDCN;
9
however, whether the aggressive clinical course observed in this case was typical for TdT‐negative BPDCN remains unknown. Conversely, majority of patients with BPDCN expressing cMyc were reportedly accompanied by 8q24 rearrangement, immunoblastoid morphology, and skin lesions.
10
Although 8q24 rearrangement was not examined in this case, the patient had no skin lesions and his blasts showed classic cytomorphology, which suggested that his clinical features were not typical for MYC‐positive BPDCN.
Previous studies showed that BPDCN with leukemic presentation without skin manifestation rarely occurs and tends to present with cytopenia rather than leukocytosis.
11
However, although the patient had leukemia at diagnosis, it was not accompanied with skin lesions and showed very high WBC count, suggesting it to be a very rare case. Moreover, rapid increase in WBC counts and massive splenomegaly indicated a very high tumor burden and rapid tumor growth. The SMILE regimen was selected because it was effective for ANKL
12
and the etoposide contained in SMILE regimen was also effective for BPDCN.
13
Although occurrence of TLS was cautiously considered in spite of low Ki67 index and enough hydration and febuxostat were provided to the patient for the prevention of TLS, he developed fatal TLS. More rigorous management including the early use of rasburicase and induction of hemodialysis is required.
Although the risk prediction of TLS in BPDCN is unknown because of the rarity and heterogeneity of this disease, the high‐disease burden may indicate the risk of TLS as same as other hematological malignancies, and the evaluation of peripheral blood WBC counts and serum LDH concentration may be useful for risk classification of TLS in BPDCN as in acute leukemia.
14
In conclusion, BPDCN shows clinically heterogeneous characteristics, and patients with clinical symptoms suggesting an aggressive clinical course with high tumor burden, including high WBC count or splenomegaly, should be carefully considered to prevent TLS.
CONFLICT OF INTEREST
There are no conflicts of interest to report.
AUTHOR CONTRIBUTIONS
KS: selected the patient and designed the manuscript. KS, MI, NF, and AK: wrote the manuscript. RF: performed the immunohistochemistry. All the authors: reviewed the paper and agreed with the final version.
ETHICAL APPROVAL
This study was approved by the institutional ethical committee of the Konan Kosei Hospital. Written informed consent was obtained from the family of the patient for publication of this case report.
ACKNOWLEDGMENTS
We acknowledge all of the physicians, nurses, and staff who contributed to the patient care at the Department of Hematology and Oncology in Konan Kosei Hospital. Published with written consent of the patient.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. | ASPARAGINASE, DEXAMETHASONE, ETOPOSIDE, IFOSFAMIDE | DrugsGivenReaction | CC BY | 33598264 | 19,029,947 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pulmonary alveolar haemorrhage'. | Severe tumor lysis syndrome during the induction therapy for the treatment of blastic plasmacytoid dendritic cell neoplasm arising from myelodysplastic/myeloproliferative neoplasms.
BPDCN shows clinically heterogeneous characteristics. And as other hematological malignancies, symptoms of BPDCN suggesting a high tumor burden, such as high white blood cell count or splenomegaly, should be carefully considered to prevent TLS.
1 INTRODUCTION
Blastic plasmacytoid dendritic cell neoplasm is a rare disease with difficulty in diagnosis, and clinical courses of patients with BPDCN vary widely. We report a case of a 63‐year‐old man with BPDCN showing severe tumor lysis syndrome (TLS). BPDCN with high tumor burden should be carefully considered to prevent TLS.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with dismal prognosis. With difficulty in diagnosis, BPDCN was used in the 2008 World Health Organization (WHO) classification for the first time and became a distinct entity in 2016 WHO classification.
1
Recently, the presence of four out of five characteristic markers of BPDCN, namely, CD4, CD56, CD123, CD303, and TCL1, has been shown to aid in the accurate diagnosis of BPDCN.
2
Skin lesions commonly occur in a majority of patients with BPDCN, and blasts of BPDCN are suggested to arise from premalignant hematopoietic precursor clones.
3
Thus, patients with systemic lesions were treated with conventional chemotherapies for acute lymphoblastic leukemia, acute myeloid leukemia, or non‐Hodgkin’s lymphoma, sometimes followed by autologous or allogeneic hematopoietic cell transplantation as a consolidation therapy.
4
However, its clinical and biological heterogeneous characteristics make its clinical management difficult.
5
Herein, we describe the case of a patient who suddenly developed leukemic form of BPDCN accompanied with CALReticulin (CALR) mutation arising from myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN‐RS‐T) without cutaneous lesion, showing severe tumor lysis syndrome (TLS) immediately after the induction therapy.
2 CASE PRESENTATION
A 63‐year‐old man previously diagnosed with MDS/MPN‐RS‐T 6 years before the presentation was referred to our hospital for rapid progression of leukocytosis and anemia. Physical examination and computed tomography revealed splenomegaly and inguinal lymphadenopathy without skin involvement (Figure 1 A, B). He did not have fever and had a performance status of 2 according to the Eastern Cooperative Oncology Group score. Blood examination showed the following abnormalities: white blood cell (WBC) count, 44.8 × 109/L with 88% blasts; hemoglobin, 5.5 g/dL; platelet count, 17.0 × 109/L; and serum lactate dehydrogenase (LDH), 300 IU/L. Genetic analyses of his peripheral blood cells detected type 1 CALR mutation without Janus kinase 2 mutation. Markedly hypercellular marrow occupied by agranular blasts with small cytoplasm and fine chromatin were detected in the bone marrow aspiration (Figure 1C, D), and bone marrow biopsy showed severe myelofibrosis (MF‐3) (Figure 1E). Flow cytometry performed on bone marrow aspirate revealed that blasts expressed CD4, CD7, CD56, and HLA‐DR without other myeloid and lymphoid markers. Similar blasts occupied the inguinal lymph node, which suggested lymph node involvement. Based on these results, the patient was suspected to have aggressive NK cell leukemia (ANKL), acute leukemia with ambiguous lineage, or BPDCN.
FIGURE 1 Computed tomography revealed splenomegaly (A) and inguinal lymphadenopathy (B). Markedly hypercellular marrow was occupied by blasts (C), presenting agranular small cytoplasm and fine chromatin (D). Bone marrow biopsy showed severe fibrosis (MF‐3) (E) (magnification of all images ×400).
Due to rapidly increasing WBC count of 106 × 109/L and worsening malaise, the dose‐reduced SMILE regimen without methotrexate which contained etoposide 70 mg/m2 day1–3, ifosfamide 1050 mg/m2 day 1‐3, dexamethasone 30 mg/body day 1‐3, and L‐asparaginase 4000 U/m2 day 7, 9, 11, 13, 15, 17, and 19 was immediately initiated without accurate diagnosis.
6
More than 3 L/d of intravenous hydration and 60 mg/d of febuxostat were administered as prophylaxis for tumor lysis syndrome (TLS). Then, immunohistochemistry performed on bone marrow specimen demonstrated that blasts were positive for CD123, TCL‐1, and CD303, and thus, he was diagnosed with BPDCN (Figure 2). In addition, blasts were positive for cMyc and Bcl‐2 and negative for TdT, with relatively low Ki67 index (Figure 2). Cytogenetic analysis revealed normal karyotype of blasts. The urine volume after initiating the chemotherapy was 3000 mL/d, and his condition improved that he could eat a meal the next day. However, his urine volume suddenly decreased, and his condition worsened again on the third day. WBC count immediately decreased; uric acid, potassium, and phosphorus concentrations increased; calcium concentration decreased with rapid increase in serum creatinine concentration, suggesting a clinical TLS (Table 1). Despite the intensive treatment such as aggressive hydration with noradrenaline administration to restore circulation and bicarbonate to correct metabolic acidosis, he finally died of circulatory failure. Autopsy revealed massive ascites and alveolar hemorrhage, whereas only a few blasts remained in bone marrow and spleen.
FIGURE 2 Blasts were positive for CD4, CD56, CD123, CD303, TCL‐1, cMyc, and Bcl‐2 and negative for TdT, myeloperoxidase, CD3, and CD8. Positive rate of Ki67 was approximately 30% (magnification of all images ×400).
TABLE 1 Blood tests before and after the induction therapy.
Before treatment Day 2 Day 3
BUN mg/dL 34.2 87.9 123.5
Creatinine mg/dL 1.3 1.6 2.7
UA mg/dL 6.0 5.5 8.5
P mg/dL 3.0 17 22.4
Na mmol/L 137 134 137
K mmol/L 4.7 7.2 6.9
Ca mg/dL 7.6 6 6.5
LDH U/L 395 828 784
WBC 109/L 106 55.7 2.4
Blast % 96 85 76
RBC 1012/L 1.2 1.4 1.1
Hb g/dL 3.7 4.4 3.3
Platelet ×109/L 17.0 15.0 10.0
Abbreviations: BUN, blood urea nitrogen; Hb, hemoglobin; LDH, lactate dehydrogenase; RBC, red blood cell; UA, uric acid; WBC, white blood cell.
John Wiley & Sons, Ltd3 DISCUSSION
In this case report, the patient was diagnosed with BPDCN arising from MDS/MPN‐RS‐T that progressed into clinical TLS immediately after the initiation of chemotherapy. Majority of patients with MDS/MPN‐RS‐T have a SF3B1 mutation.
7
Although SF3B1 mutations were not examined in this case, morphologically apparent dysplasia and the presence of ringed sideroblasts strongly supported the diagnosis of MDS/MPN‐RS‐T. On the other hand, while there is one case report about a patient with MDS/MPN‐RS‐T that was positive for both CALR and SF3B1 gene mutations,
8
BPDCN with CALR mutation has not yet been reported to the best of our knowledge. Therefore, in this case, MDS/MPN‐RS‐T might already have been accompanied with CALR mutation.
TdT negativity was reportedly associated with inferior survival in BPDCN;
9
however, whether the aggressive clinical course observed in this case was typical for TdT‐negative BPDCN remains unknown. Conversely, majority of patients with BPDCN expressing cMyc were reportedly accompanied by 8q24 rearrangement, immunoblastoid morphology, and skin lesions.
10
Although 8q24 rearrangement was not examined in this case, the patient had no skin lesions and his blasts showed classic cytomorphology, which suggested that his clinical features were not typical for MYC‐positive BPDCN.
Previous studies showed that BPDCN with leukemic presentation without skin manifestation rarely occurs and tends to present with cytopenia rather than leukocytosis.
11
However, although the patient had leukemia at diagnosis, it was not accompanied with skin lesions and showed very high WBC count, suggesting it to be a very rare case. Moreover, rapid increase in WBC counts and massive splenomegaly indicated a very high tumor burden and rapid tumor growth. The SMILE regimen was selected because it was effective for ANKL
12
and the etoposide contained in SMILE regimen was also effective for BPDCN.
13
Although occurrence of TLS was cautiously considered in spite of low Ki67 index and enough hydration and febuxostat were provided to the patient for the prevention of TLS, he developed fatal TLS. More rigorous management including the early use of rasburicase and induction of hemodialysis is required.
Although the risk prediction of TLS in BPDCN is unknown because of the rarity and heterogeneity of this disease, the high‐disease burden may indicate the risk of TLS as same as other hematological malignancies, and the evaluation of peripheral blood WBC counts and serum LDH concentration may be useful for risk classification of TLS in BPDCN as in acute leukemia.
14
In conclusion, BPDCN shows clinically heterogeneous characteristics, and patients with clinical symptoms suggesting an aggressive clinical course with high tumor burden, including high WBC count or splenomegaly, should be carefully considered to prevent TLS.
CONFLICT OF INTEREST
There are no conflicts of interest to report.
AUTHOR CONTRIBUTIONS
KS: selected the patient and designed the manuscript. KS, MI, NF, and AK: wrote the manuscript. RF: performed the immunohistochemistry. All the authors: reviewed the paper and agreed with the final version.
ETHICAL APPROVAL
This study was approved by the institutional ethical committee of the Konan Kosei Hospital. Written informed consent was obtained from the family of the patient for publication of this case report.
ACKNOWLEDGMENTS
We acknowledge all of the physicians, nurses, and staff who contributed to the patient care at the Department of Hematology and Oncology in Konan Kosei Hospital. Published with written consent of the patient.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. | ASPARAGINASE, DEXAMETHASONE, ETOPOSIDE, FEBUXOSTAT, IFOSFAMIDE | DrugsGivenReaction | CC BY | 33598264 | 19,587,477 | 2021-02 |
What was the outcome of reaction 'Ascites'? | Severe tumor lysis syndrome during the induction therapy for the treatment of blastic plasmacytoid dendritic cell neoplasm arising from myelodysplastic/myeloproliferative neoplasms.
BPDCN shows clinically heterogeneous characteristics. And as other hematological malignancies, symptoms of BPDCN suggesting a high tumor burden, such as high white blood cell count or splenomegaly, should be carefully considered to prevent TLS.
1 INTRODUCTION
Blastic plasmacytoid dendritic cell neoplasm is a rare disease with difficulty in diagnosis, and clinical courses of patients with BPDCN vary widely. We report a case of a 63‐year‐old man with BPDCN showing severe tumor lysis syndrome (TLS). BPDCN with high tumor burden should be carefully considered to prevent TLS.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with dismal prognosis. With difficulty in diagnosis, BPDCN was used in the 2008 World Health Organization (WHO) classification for the first time and became a distinct entity in 2016 WHO classification.
1
Recently, the presence of four out of five characteristic markers of BPDCN, namely, CD4, CD56, CD123, CD303, and TCL1, has been shown to aid in the accurate diagnosis of BPDCN.
2
Skin lesions commonly occur in a majority of patients with BPDCN, and blasts of BPDCN are suggested to arise from premalignant hematopoietic precursor clones.
3
Thus, patients with systemic lesions were treated with conventional chemotherapies for acute lymphoblastic leukemia, acute myeloid leukemia, or non‐Hodgkin’s lymphoma, sometimes followed by autologous or allogeneic hematopoietic cell transplantation as a consolidation therapy.
4
However, its clinical and biological heterogeneous characteristics make its clinical management difficult.
5
Herein, we describe the case of a patient who suddenly developed leukemic form of BPDCN accompanied with CALReticulin (CALR) mutation arising from myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN‐RS‐T) without cutaneous lesion, showing severe tumor lysis syndrome (TLS) immediately after the induction therapy.
2 CASE PRESENTATION
A 63‐year‐old man previously diagnosed with MDS/MPN‐RS‐T 6 years before the presentation was referred to our hospital for rapid progression of leukocytosis and anemia. Physical examination and computed tomography revealed splenomegaly and inguinal lymphadenopathy without skin involvement (Figure 1 A, B). He did not have fever and had a performance status of 2 according to the Eastern Cooperative Oncology Group score. Blood examination showed the following abnormalities: white blood cell (WBC) count, 44.8 × 109/L with 88% blasts; hemoglobin, 5.5 g/dL; platelet count, 17.0 × 109/L; and serum lactate dehydrogenase (LDH), 300 IU/L. Genetic analyses of his peripheral blood cells detected type 1 CALR mutation without Janus kinase 2 mutation. Markedly hypercellular marrow occupied by agranular blasts with small cytoplasm and fine chromatin were detected in the bone marrow aspiration (Figure 1C, D), and bone marrow biopsy showed severe myelofibrosis (MF‐3) (Figure 1E). Flow cytometry performed on bone marrow aspirate revealed that blasts expressed CD4, CD7, CD56, and HLA‐DR without other myeloid and lymphoid markers. Similar blasts occupied the inguinal lymph node, which suggested lymph node involvement. Based on these results, the patient was suspected to have aggressive NK cell leukemia (ANKL), acute leukemia with ambiguous lineage, or BPDCN.
FIGURE 1 Computed tomography revealed splenomegaly (A) and inguinal lymphadenopathy (B). Markedly hypercellular marrow was occupied by blasts (C), presenting agranular small cytoplasm and fine chromatin (D). Bone marrow biopsy showed severe fibrosis (MF‐3) (E) (magnification of all images ×400).
Due to rapidly increasing WBC count of 106 × 109/L and worsening malaise, the dose‐reduced SMILE regimen without methotrexate which contained etoposide 70 mg/m2 day1–3, ifosfamide 1050 mg/m2 day 1‐3, dexamethasone 30 mg/body day 1‐3, and L‐asparaginase 4000 U/m2 day 7, 9, 11, 13, 15, 17, and 19 was immediately initiated without accurate diagnosis.
6
More than 3 L/d of intravenous hydration and 60 mg/d of febuxostat were administered as prophylaxis for tumor lysis syndrome (TLS). Then, immunohistochemistry performed on bone marrow specimen demonstrated that blasts were positive for CD123, TCL‐1, and CD303, and thus, he was diagnosed with BPDCN (Figure 2). In addition, blasts were positive for cMyc and Bcl‐2 and negative for TdT, with relatively low Ki67 index (Figure 2). Cytogenetic analysis revealed normal karyotype of blasts. The urine volume after initiating the chemotherapy was 3000 mL/d, and his condition improved that he could eat a meal the next day. However, his urine volume suddenly decreased, and his condition worsened again on the third day. WBC count immediately decreased; uric acid, potassium, and phosphorus concentrations increased; calcium concentration decreased with rapid increase in serum creatinine concentration, suggesting a clinical TLS (Table 1). Despite the intensive treatment such as aggressive hydration with noradrenaline administration to restore circulation and bicarbonate to correct metabolic acidosis, he finally died of circulatory failure. Autopsy revealed massive ascites and alveolar hemorrhage, whereas only a few blasts remained in bone marrow and spleen.
FIGURE 2 Blasts were positive for CD4, CD56, CD123, CD303, TCL‐1, cMyc, and Bcl‐2 and negative for TdT, myeloperoxidase, CD3, and CD8. Positive rate of Ki67 was approximately 30% (magnification of all images ×400).
TABLE 1 Blood tests before and after the induction therapy.
Before treatment Day 2 Day 3
BUN mg/dL 34.2 87.9 123.5
Creatinine mg/dL 1.3 1.6 2.7
UA mg/dL 6.0 5.5 8.5
P mg/dL 3.0 17 22.4
Na mmol/L 137 134 137
K mmol/L 4.7 7.2 6.9
Ca mg/dL 7.6 6 6.5
LDH U/L 395 828 784
WBC 109/L 106 55.7 2.4
Blast % 96 85 76
RBC 1012/L 1.2 1.4 1.1
Hb g/dL 3.7 4.4 3.3
Platelet ×109/L 17.0 15.0 10.0
Abbreviations: BUN, blood urea nitrogen; Hb, hemoglobin; LDH, lactate dehydrogenase; RBC, red blood cell; UA, uric acid; WBC, white blood cell.
John Wiley & Sons, Ltd3 DISCUSSION
In this case report, the patient was diagnosed with BPDCN arising from MDS/MPN‐RS‐T that progressed into clinical TLS immediately after the initiation of chemotherapy. Majority of patients with MDS/MPN‐RS‐T have a SF3B1 mutation.
7
Although SF3B1 mutations were not examined in this case, morphologically apparent dysplasia and the presence of ringed sideroblasts strongly supported the diagnosis of MDS/MPN‐RS‐T. On the other hand, while there is one case report about a patient with MDS/MPN‐RS‐T that was positive for both CALR and SF3B1 gene mutations,
8
BPDCN with CALR mutation has not yet been reported to the best of our knowledge. Therefore, in this case, MDS/MPN‐RS‐T might already have been accompanied with CALR mutation.
TdT negativity was reportedly associated with inferior survival in BPDCN;
9
however, whether the aggressive clinical course observed in this case was typical for TdT‐negative BPDCN remains unknown. Conversely, majority of patients with BPDCN expressing cMyc were reportedly accompanied by 8q24 rearrangement, immunoblastoid morphology, and skin lesions.
10
Although 8q24 rearrangement was not examined in this case, the patient had no skin lesions and his blasts showed classic cytomorphology, which suggested that his clinical features were not typical for MYC‐positive BPDCN.
Previous studies showed that BPDCN with leukemic presentation without skin manifestation rarely occurs and tends to present with cytopenia rather than leukocytosis.
11
However, although the patient had leukemia at diagnosis, it was not accompanied with skin lesions and showed very high WBC count, suggesting it to be a very rare case. Moreover, rapid increase in WBC counts and massive splenomegaly indicated a very high tumor burden and rapid tumor growth. The SMILE regimen was selected because it was effective for ANKL
12
and the etoposide contained in SMILE regimen was also effective for BPDCN.
13
Although occurrence of TLS was cautiously considered in spite of low Ki67 index and enough hydration and febuxostat were provided to the patient for the prevention of TLS, he developed fatal TLS. More rigorous management including the early use of rasburicase and induction of hemodialysis is required.
Although the risk prediction of TLS in BPDCN is unknown because of the rarity and heterogeneity of this disease, the high‐disease burden may indicate the risk of TLS as same as other hematological malignancies, and the evaluation of peripheral blood WBC counts and serum LDH concentration may be useful for risk classification of TLS in BPDCN as in acute leukemia.
14
In conclusion, BPDCN shows clinically heterogeneous characteristics, and patients with clinical symptoms suggesting an aggressive clinical course with high tumor burden, including high WBC count or splenomegaly, should be carefully considered to prevent TLS.
CONFLICT OF INTEREST
There are no conflicts of interest to report.
AUTHOR CONTRIBUTIONS
KS: selected the patient and designed the manuscript. KS, MI, NF, and AK: wrote the manuscript. RF: performed the immunohistochemistry. All the authors: reviewed the paper and agreed with the final version.
ETHICAL APPROVAL
This study was approved by the institutional ethical committee of the Konan Kosei Hospital. Written informed consent was obtained from the family of the patient for publication of this case report.
ACKNOWLEDGMENTS
We acknowledge all of the physicians, nurses, and staff who contributed to the patient care at the Department of Hematology and Oncology in Konan Kosei Hospital. Published with written consent of the patient.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. | Fatal | ReactionOutcome | CC BY | 33598264 | 19,587,477 | 2021-02 |
What was the outcome of reaction 'Circulatory collapse'? | Severe tumor lysis syndrome during the induction therapy for the treatment of blastic plasmacytoid dendritic cell neoplasm arising from myelodysplastic/myeloproliferative neoplasms.
BPDCN shows clinically heterogeneous characteristics. And as other hematological malignancies, symptoms of BPDCN suggesting a high tumor burden, such as high white blood cell count or splenomegaly, should be carefully considered to prevent TLS.
1 INTRODUCTION
Blastic plasmacytoid dendritic cell neoplasm is a rare disease with difficulty in diagnosis, and clinical courses of patients with BPDCN vary widely. We report a case of a 63‐year‐old man with BPDCN showing severe tumor lysis syndrome (TLS). BPDCN with high tumor burden should be carefully considered to prevent TLS.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with dismal prognosis. With difficulty in diagnosis, BPDCN was used in the 2008 World Health Organization (WHO) classification for the first time and became a distinct entity in 2016 WHO classification.
1
Recently, the presence of four out of five characteristic markers of BPDCN, namely, CD4, CD56, CD123, CD303, and TCL1, has been shown to aid in the accurate diagnosis of BPDCN.
2
Skin lesions commonly occur in a majority of patients with BPDCN, and blasts of BPDCN are suggested to arise from premalignant hematopoietic precursor clones.
3
Thus, patients with systemic lesions were treated with conventional chemotherapies for acute lymphoblastic leukemia, acute myeloid leukemia, or non‐Hodgkin’s lymphoma, sometimes followed by autologous or allogeneic hematopoietic cell transplantation as a consolidation therapy.
4
However, its clinical and biological heterogeneous characteristics make its clinical management difficult.
5
Herein, we describe the case of a patient who suddenly developed leukemic form of BPDCN accompanied with CALReticulin (CALR) mutation arising from myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN‐RS‐T) without cutaneous lesion, showing severe tumor lysis syndrome (TLS) immediately after the induction therapy.
2 CASE PRESENTATION
A 63‐year‐old man previously diagnosed with MDS/MPN‐RS‐T 6 years before the presentation was referred to our hospital for rapid progression of leukocytosis and anemia. Physical examination and computed tomography revealed splenomegaly and inguinal lymphadenopathy without skin involvement (Figure 1 A, B). He did not have fever and had a performance status of 2 according to the Eastern Cooperative Oncology Group score. Blood examination showed the following abnormalities: white blood cell (WBC) count, 44.8 × 109/L with 88% blasts; hemoglobin, 5.5 g/dL; platelet count, 17.0 × 109/L; and serum lactate dehydrogenase (LDH), 300 IU/L. Genetic analyses of his peripheral blood cells detected type 1 CALR mutation without Janus kinase 2 mutation. Markedly hypercellular marrow occupied by agranular blasts with small cytoplasm and fine chromatin were detected in the bone marrow aspiration (Figure 1C, D), and bone marrow biopsy showed severe myelofibrosis (MF‐3) (Figure 1E). Flow cytometry performed on bone marrow aspirate revealed that blasts expressed CD4, CD7, CD56, and HLA‐DR without other myeloid and lymphoid markers. Similar blasts occupied the inguinal lymph node, which suggested lymph node involvement. Based on these results, the patient was suspected to have aggressive NK cell leukemia (ANKL), acute leukemia with ambiguous lineage, or BPDCN.
FIGURE 1 Computed tomography revealed splenomegaly (A) and inguinal lymphadenopathy (B). Markedly hypercellular marrow was occupied by blasts (C), presenting agranular small cytoplasm and fine chromatin (D). Bone marrow biopsy showed severe fibrosis (MF‐3) (E) (magnification of all images ×400).
Due to rapidly increasing WBC count of 106 × 109/L and worsening malaise, the dose‐reduced SMILE regimen without methotrexate which contained etoposide 70 mg/m2 day1–3, ifosfamide 1050 mg/m2 day 1‐3, dexamethasone 30 mg/body day 1‐3, and L‐asparaginase 4000 U/m2 day 7, 9, 11, 13, 15, 17, and 19 was immediately initiated without accurate diagnosis.
6
More than 3 L/d of intravenous hydration and 60 mg/d of febuxostat were administered as prophylaxis for tumor lysis syndrome (TLS). Then, immunohistochemistry performed on bone marrow specimen demonstrated that blasts were positive for CD123, TCL‐1, and CD303, and thus, he was diagnosed with BPDCN (Figure 2). In addition, blasts were positive for cMyc and Bcl‐2 and negative for TdT, with relatively low Ki67 index (Figure 2). Cytogenetic analysis revealed normal karyotype of blasts. The urine volume after initiating the chemotherapy was 3000 mL/d, and his condition improved that he could eat a meal the next day. However, his urine volume suddenly decreased, and his condition worsened again on the third day. WBC count immediately decreased; uric acid, potassium, and phosphorus concentrations increased; calcium concentration decreased with rapid increase in serum creatinine concentration, suggesting a clinical TLS (Table 1). Despite the intensive treatment such as aggressive hydration with noradrenaline administration to restore circulation and bicarbonate to correct metabolic acidosis, he finally died of circulatory failure. Autopsy revealed massive ascites and alveolar hemorrhage, whereas only a few blasts remained in bone marrow and spleen.
FIGURE 2 Blasts were positive for CD4, CD56, CD123, CD303, TCL‐1, cMyc, and Bcl‐2 and negative for TdT, myeloperoxidase, CD3, and CD8. Positive rate of Ki67 was approximately 30% (magnification of all images ×400).
TABLE 1 Blood tests before and after the induction therapy.
Before treatment Day 2 Day 3
BUN mg/dL 34.2 87.9 123.5
Creatinine mg/dL 1.3 1.6 2.7
UA mg/dL 6.0 5.5 8.5
P mg/dL 3.0 17 22.4
Na mmol/L 137 134 137
K mmol/L 4.7 7.2 6.9
Ca mg/dL 7.6 6 6.5
LDH U/L 395 828 784
WBC 109/L 106 55.7 2.4
Blast % 96 85 76
RBC 1012/L 1.2 1.4 1.1
Hb g/dL 3.7 4.4 3.3
Platelet ×109/L 17.0 15.0 10.0
Abbreviations: BUN, blood urea nitrogen; Hb, hemoglobin; LDH, lactate dehydrogenase; RBC, red blood cell; UA, uric acid; WBC, white blood cell.
John Wiley & Sons, Ltd3 DISCUSSION
In this case report, the patient was diagnosed with BPDCN arising from MDS/MPN‐RS‐T that progressed into clinical TLS immediately after the initiation of chemotherapy. Majority of patients with MDS/MPN‐RS‐T have a SF3B1 mutation.
7
Although SF3B1 mutations were not examined in this case, morphologically apparent dysplasia and the presence of ringed sideroblasts strongly supported the diagnosis of MDS/MPN‐RS‐T. On the other hand, while there is one case report about a patient with MDS/MPN‐RS‐T that was positive for both CALR and SF3B1 gene mutations,
8
BPDCN with CALR mutation has not yet been reported to the best of our knowledge. Therefore, in this case, MDS/MPN‐RS‐T might already have been accompanied with CALR mutation.
TdT negativity was reportedly associated with inferior survival in BPDCN;
9
however, whether the aggressive clinical course observed in this case was typical for TdT‐negative BPDCN remains unknown. Conversely, majority of patients with BPDCN expressing cMyc were reportedly accompanied by 8q24 rearrangement, immunoblastoid morphology, and skin lesions.
10
Although 8q24 rearrangement was not examined in this case, the patient had no skin lesions and his blasts showed classic cytomorphology, which suggested that his clinical features were not typical for MYC‐positive BPDCN.
Previous studies showed that BPDCN with leukemic presentation without skin manifestation rarely occurs and tends to present with cytopenia rather than leukocytosis.
11
However, although the patient had leukemia at diagnosis, it was not accompanied with skin lesions and showed very high WBC count, suggesting it to be a very rare case. Moreover, rapid increase in WBC counts and massive splenomegaly indicated a very high tumor burden and rapid tumor growth. The SMILE regimen was selected because it was effective for ANKL
12
and the etoposide contained in SMILE regimen was also effective for BPDCN.
13
Although occurrence of TLS was cautiously considered in spite of low Ki67 index and enough hydration and febuxostat were provided to the patient for the prevention of TLS, he developed fatal TLS. More rigorous management including the early use of rasburicase and induction of hemodialysis is required.
Although the risk prediction of TLS in BPDCN is unknown because of the rarity and heterogeneity of this disease, the high‐disease burden may indicate the risk of TLS as same as other hematological malignancies, and the evaluation of peripheral blood WBC counts and serum LDH concentration may be useful for risk classification of TLS in BPDCN as in acute leukemia.
14
In conclusion, BPDCN shows clinically heterogeneous characteristics, and patients with clinical symptoms suggesting an aggressive clinical course with high tumor burden, including high WBC count or splenomegaly, should be carefully considered to prevent TLS.
CONFLICT OF INTEREST
There are no conflicts of interest to report.
AUTHOR CONTRIBUTIONS
KS: selected the patient and designed the manuscript. KS, MI, NF, and AK: wrote the manuscript. RF: performed the immunohistochemistry. All the authors: reviewed the paper and agreed with the final version.
ETHICAL APPROVAL
This study was approved by the institutional ethical committee of the Konan Kosei Hospital. Written informed consent was obtained from the family of the patient for publication of this case report.
ACKNOWLEDGMENTS
We acknowledge all of the physicians, nurses, and staff who contributed to the patient care at the Department of Hematology and Oncology in Konan Kosei Hospital. Published with written consent of the patient.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. | Fatal | ReactionOutcome | CC BY | 33598264 | 19,587,477 | 2021-02 |
What was the outcome of reaction 'Drug ineffective'? | Severe tumor lysis syndrome during the induction therapy for the treatment of blastic plasmacytoid dendritic cell neoplasm arising from myelodysplastic/myeloproliferative neoplasms.
BPDCN shows clinically heterogeneous characteristics. And as other hematological malignancies, symptoms of BPDCN suggesting a high tumor burden, such as high white blood cell count or splenomegaly, should be carefully considered to prevent TLS.
1 INTRODUCTION
Blastic plasmacytoid dendritic cell neoplasm is a rare disease with difficulty in diagnosis, and clinical courses of patients with BPDCN vary widely. We report a case of a 63‐year‐old man with BPDCN showing severe tumor lysis syndrome (TLS). BPDCN with high tumor burden should be carefully considered to prevent TLS.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with dismal prognosis. With difficulty in diagnosis, BPDCN was used in the 2008 World Health Organization (WHO) classification for the first time and became a distinct entity in 2016 WHO classification.
1
Recently, the presence of four out of five characteristic markers of BPDCN, namely, CD4, CD56, CD123, CD303, and TCL1, has been shown to aid in the accurate diagnosis of BPDCN.
2
Skin lesions commonly occur in a majority of patients with BPDCN, and blasts of BPDCN are suggested to arise from premalignant hematopoietic precursor clones.
3
Thus, patients with systemic lesions were treated with conventional chemotherapies for acute lymphoblastic leukemia, acute myeloid leukemia, or non‐Hodgkin’s lymphoma, sometimes followed by autologous or allogeneic hematopoietic cell transplantation as a consolidation therapy.
4
However, its clinical and biological heterogeneous characteristics make its clinical management difficult.
5
Herein, we describe the case of a patient who suddenly developed leukemic form of BPDCN accompanied with CALReticulin (CALR) mutation arising from myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN‐RS‐T) without cutaneous lesion, showing severe tumor lysis syndrome (TLS) immediately after the induction therapy.
2 CASE PRESENTATION
A 63‐year‐old man previously diagnosed with MDS/MPN‐RS‐T 6 years before the presentation was referred to our hospital for rapid progression of leukocytosis and anemia. Physical examination and computed tomography revealed splenomegaly and inguinal lymphadenopathy without skin involvement (Figure 1 A, B). He did not have fever and had a performance status of 2 according to the Eastern Cooperative Oncology Group score. Blood examination showed the following abnormalities: white blood cell (WBC) count, 44.8 × 109/L with 88% blasts; hemoglobin, 5.5 g/dL; platelet count, 17.0 × 109/L; and serum lactate dehydrogenase (LDH), 300 IU/L. Genetic analyses of his peripheral blood cells detected type 1 CALR mutation without Janus kinase 2 mutation. Markedly hypercellular marrow occupied by agranular blasts with small cytoplasm and fine chromatin were detected in the bone marrow aspiration (Figure 1C, D), and bone marrow biopsy showed severe myelofibrosis (MF‐3) (Figure 1E). Flow cytometry performed on bone marrow aspirate revealed that blasts expressed CD4, CD7, CD56, and HLA‐DR without other myeloid and lymphoid markers. Similar blasts occupied the inguinal lymph node, which suggested lymph node involvement. Based on these results, the patient was suspected to have aggressive NK cell leukemia (ANKL), acute leukemia with ambiguous lineage, or BPDCN.
FIGURE 1 Computed tomography revealed splenomegaly (A) and inguinal lymphadenopathy (B). Markedly hypercellular marrow was occupied by blasts (C), presenting agranular small cytoplasm and fine chromatin (D). Bone marrow biopsy showed severe fibrosis (MF‐3) (E) (magnification of all images ×400).
Due to rapidly increasing WBC count of 106 × 109/L and worsening malaise, the dose‐reduced SMILE regimen without methotrexate which contained etoposide 70 mg/m2 day1–3, ifosfamide 1050 mg/m2 day 1‐3, dexamethasone 30 mg/body day 1‐3, and L‐asparaginase 4000 U/m2 day 7, 9, 11, 13, 15, 17, and 19 was immediately initiated without accurate diagnosis.
6
More than 3 L/d of intravenous hydration and 60 mg/d of febuxostat were administered as prophylaxis for tumor lysis syndrome (TLS). Then, immunohistochemistry performed on bone marrow specimen demonstrated that blasts were positive for CD123, TCL‐1, and CD303, and thus, he was diagnosed with BPDCN (Figure 2). In addition, blasts were positive for cMyc and Bcl‐2 and negative for TdT, with relatively low Ki67 index (Figure 2). Cytogenetic analysis revealed normal karyotype of blasts. The urine volume after initiating the chemotherapy was 3000 mL/d, and his condition improved that he could eat a meal the next day. However, his urine volume suddenly decreased, and his condition worsened again on the third day. WBC count immediately decreased; uric acid, potassium, and phosphorus concentrations increased; calcium concentration decreased with rapid increase in serum creatinine concentration, suggesting a clinical TLS (Table 1). Despite the intensive treatment such as aggressive hydration with noradrenaline administration to restore circulation and bicarbonate to correct metabolic acidosis, he finally died of circulatory failure. Autopsy revealed massive ascites and alveolar hemorrhage, whereas only a few blasts remained in bone marrow and spleen.
FIGURE 2 Blasts were positive for CD4, CD56, CD123, CD303, TCL‐1, cMyc, and Bcl‐2 and negative for TdT, myeloperoxidase, CD3, and CD8. Positive rate of Ki67 was approximately 30% (magnification of all images ×400).
TABLE 1 Blood tests before and after the induction therapy.
Before treatment Day 2 Day 3
BUN mg/dL 34.2 87.9 123.5
Creatinine mg/dL 1.3 1.6 2.7
UA mg/dL 6.0 5.5 8.5
P mg/dL 3.0 17 22.4
Na mmol/L 137 134 137
K mmol/L 4.7 7.2 6.9
Ca mg/dL 7.6 6 6.5
LDH U/L 395 828 784
WBC 109/L 106 55.7 2.4
Blast % 96 85 76
RBC 1012/L 1.2 1.4 1.1
Hb g/dL 3.7 4.4 3.3
Platelet ×109/L 17.0 15.0 10.0
Abbreviations: BUN, blood urea nitrogen; Hb, hemoglobin; LDH, lactate dehydrogenase; RBC, red blood cell; UA, uric acid; WBC, white blood cell.
John Wiley & Sons, Ltd3 DISCUSSION
In this case report, the patient was diagnosed with BPDCN arising from MDS/MPN‐RS‐T that progressed into clinical TLS immediately after the initiation of chemotherapy. Majority of patients with MDS/MPN‐RS‐T have a SF3B1 mutation.
7
Although SF3B1 mutations were not examined in this case, morphologically apparent dysplasia and the presence of ringed sideroblasts strongly supported the diagnosis of MDS/MPN‐RS‐T. On the other hand, while there is one case report about a patient with MDS/MPN‐RS‐T that was positive for both CALR and SF3B1 gene mutations,
8
BPDCN with CALR mutation has not yet been reported to the best of our knowledge. Therefore, in this case, MDS/MPN‐RS‐T might already have been accompanied with CALR mutation.
TdT negativity was reportedly associated with inferior survival in BPDCN;
9
however, whether the aggressive clinical course observed in this case was typical for TdT‐negative BPDCN remains unknown. Conversely, majority of patients with BPDCN expressing cMyc were reportedly accompanied by 8q24 rearrangement, immunoblastoid morphology, and skin lesions.
10
Although 8q24 rearrangement was not examined in this case, the patient had no skin lesions and his blasts showed classic cytomorphology, which suggested that his clinical features were not typical for MYC‐positive BPDCN.
Previous studies showed that BPDCN with leukemic presentation without skin manifestation rarely occurs and tends to present with cytopenia rather than leukocytosis.
11
However, although the patient had leukemia at diagnosis, it was not accompanied with skin lesions and showed very high WBC count, suggesting it to be a very rare case. Moreover, rapid increase in WBC counts and massive splenomegaly indicated a very high tumor burden and rapid tumor growth. The SMILE regimen was selected because it was effective for ANKL
12
and the etoposide contained in SMILE regimen was also effective for BPDCN.
13
Although occurrence of TLS was cautiously considered in spite of low Ki67 index and enough hydration and febuxostat were provided to the patient for the prevention of TLS, he developed fatal TLS. More rigorous management including the early use of rasburicase and induction of hemodialysis is required.
Although the risk prediction of TLS in BPDCN is unknown because of the rarity and heterogeneity of this disease, the high‐disease burden may indicate the risk of TLS as same as other hematological malignancies, and the evaluation of peripheral blood WBC counts and serum LDH concentration may be useful for risk classification of TLS in BPDCN as in acute leukemia.
14
In conclusion, BPDCN shows clinically heterogeneous characteristics, and patients with clinical symptoms suggesting an aggressive clinical course with high tumor burden, including high WBC count or splenomegaly, should be carefully considered to prevent TLS.
CONFLICT OF INTEREST
There are no conflicts of interest to report.
AUTHOR CONTRIBUTIONS
KS: selected the patient and designed the manuscript. KS, MI, NF, and AK: wrote the manuscript. RF: performed the immunohistochemistry. All the authors: reviewed the paper and agreed with the final version.
ETHICAL APPROVAL
This study was approved by the institutional ethical committee of the Konan Kosei Hospital. Written informed consent was obtained from the family of the patient for publication of this case report.
ACKNOWLEDGMENTS
We acknowledge all of the physicians, nurses, and staff who contributed to the patient care at the Department of Hematology and Oncology in Konan Kosei Hospital. Published with written consent of the patient.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. | Fatal | ReactionOutcome | CC BY | 33598264 | 19,076,406 | 2021-02 |
What was the outcome of reaction 'Metabolic acidosis'? | Severe tumor lysis syndrome during the induction therapy for the treatment of blastic plasmacytoid dendritic cell neoplasm arising from myelodysplastic/myeloproliferative neoplasms.
BPDCN shows clinically heterogeneous characteristics. And as other hematological malignancies, symptoms of BPDCN suggesting a high tumor burden, such as high white blood cell count or splenomegaly, should be carefully considered to prevent TLS.
1 INTRODUCTION
Blastic plasmacytoid dendritic cell neoplasm is a rare disease with difficulty in diagnosis, and clinical courses of patients with BPDCN vary widely. We report a case of a 63‐year‐old man with BPDCN showing severe tumor lysis syndrome (TLS). BPDCN with high tumor burden should be carefully considered to prevent TLS.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with dismal prognosis. With difficulty in diagnosis, BPDCN was used in the 2008 World Health Organization (WHO) classification for the first time and became a distinct entity in 2016 WHO classification.
1
Recently, the presence of four out of five characteristic markers of BPDCN, namely, CD4, CD56, CD123, CD303, and TCL1, has been shown to aid in the accurate diagnosis of BPDCN.
2
Skin lesions commonly occur in a majority of patients with BPDCN, and blasts of BPDCN are suggested to arise from premalignant hematopoietic precursor clones.
3
Thus, patients with systemic lesions were treated with conventional chemotherapies for acute lymphoblastic leukemia, acute myeloid leukemia, or non‐Hodgkin’s lymphoma, sometimes followed by autologous or allogeneic hematopoietic cell transplantation as a consolidation therapy.
4
However, its clinical and biological heterogeneous characteristics make its clinical management difficult.
5
Herein, we describe the case of a patient who suddenly developed leukemic form of BPDCN accompanied with CALReticulin (CALR) mutation arising from myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN‐RS‐T) without cutaneous lesion, showing severe tumor lysis syndrome (TLS) immediately after the induction therapy.
2 CASE PRESENTATION
A 63‐year‐old man previously diagnosed with MDS/MPN‐RS‐T 6 years before the presentation was referred to our hospital for rapid progression of leukocytosis and anemia. Physical examination and computed tomography revealed splenomegaly and inguinal lymphadenopathy without skin involvement (Figure 1 A, B). He did not have fever and had a performance status of 2 according to the Eastern Cooperative Oncology Group score. Blood examination showed the following abnormalities: white blood cell (WBC) count, 44.8 × 109/L with 88% blasts; hemoglobin, 5.5 g/dL; platelet count, 17.0 × 109/L; and serum lactate dehydrogenase (LDH), 300 IU/L. Genetic analyses of his peripheral blood cells detected type 1 CALR mutation without Janus kinase 2 mutation. Markedly hypercellular marrow occupied by agranular blasts with small cytoplasm and fine chromatin were detected in the bone marrow aspiration (Figure 1C, D), and bone marrow biopsy showed severe myelofibrosis (MF‐3) (Figure 1E). Flow cytometry performed on bone marrow aspirate revealed that blasts expressed CD4, CD7, CD56, and HLA‐DR without other myeloid and lymphoid markers. Similar blasts occupied the inguinal lymph node, which suggested lymph node involvement. Based on these results, the patient was suspected to have aggressive NK cell leukemia (ANKL), acute leukemia with ambiguous lineage, or BPDCN.
FIGURE 1 Computed tomography revealed splenomegaly (A) and inguinal lymphadenopathy (B). Markedly hypercellular marrow was occupied by blasts (C), presenting agranular small cytoplasm and fine chromatin (D). Bone marrow biopsy showed severe fibrosis (MF‐3) (E) (magnification of all images ×400).
Due to rapidly increasing WBC count of 106 × 109/L and worsening malaise, the dose‐reduced SMILE regimen without methotrexate which contained etoposide 70 mg/m2 day1–3, ifosfamide 1050 mg/m2 day 1‐3, dexamethasone 30 mg/body day 1‐3, and L‐asparaginase 4000 U/m2 day 7, 9, 11, 13, 15, 17, and 19 was immediately initiated without accurate diagnosis.
6
More than 3 L/d of intravenous hydration and 60 mg/d of febuxostat were administered as prophylaxis for tumor lysis syndrome (TLS). Then, immunohistochemistry performed on bone marrow specimen demonstrated that blasts were positive for CD123, TCL‐1, and CD303, and thus, he was diagnosed with BPDCN (Figure 2). In addition, blasts were positive for cMyc and Bcl‐2 and negative for TdT, with relatively low Ki67 index (Figure 2). Cytogenetic analysis revealed normal karyotype of blasts. The urine volume after initiating the chemotherapy was 3000 mL/d, and his condition improved that he could eat a meal the next day. However, his urine volume suddenly decreased, and his condition worsened again on the third day. WBC count immediately decreased; uric acid, potassium, and phosphorus concentrations increased; calcium concentration decreased with rapid increase in serum creatinine concentration, suggesting a clinical TLS (Table 1). Despite the intensive treatment such as aggressive hydration with noradrenaline administration to restore circulation and bicarbonate to correct metabolic acidosis, he finally died of circulatory failure. Autopsy revealed massive ascites and alveolar hemorrhage, whereas only a few blasts remained in bone marrow and spleen.
FIGURE 2 Blasts were positive for CD4, CD56, CD123, CD303, TCL‐1, cMyc, and Bcl‐2 and negative for TdT, myeloperoxidase, CD3, and CD8. Positive rate of Ki67 was approximately 30% (magnification of all images ×400).
TABLE 1 Blood tests before and after the induction therapy.
Before treatment Day 2 Day 3
BUN mg/dL 34.2 87.9 123.5
Creatinine mg/dL 1.3 1.6 2.7
UA mg/dL 6.0 5.5 8.5
P mg/dL 3.0 17 22.4
Na mmol/L 137 134 137
K mmol/L 4.7 7.2 6.9
Ca mg/dL 7.6 6 6.5
LDH U/L 395 828 784
WBC 109/L 106 55.7 2.4
Blast % 96 85 76
RBC 1012/L 1.2 1.4 1.1
Hb g/dL 3.7 4.4 3.3
Platelet ×109/L 17.0 15.0 10.0
Abbreviations: BUN, blood urea nitrogen; Hb, hemoglobin; LDH, lactate dehydrogenase; RBC, red blood cell; UA, uric acid; WBC, white blood cell.
John Wiley & Sons, Ltd3 DISCUSSION
In this case report, the patient was diagnosed with BPDCN arising from MDS/MPN‐RS‐T that progressed into clinical TLS immediately after the initiation of chemotherapy. Majority of patients with MDS/MPN‐RS‐T have a SF3B1 mutation.
7
Although SF3B1 mutations were not examined in this case, morphologically apparent dysplasia and the presence of ringed sideroblasts strongly supported the diagnosis of MDS/MPN‐RS‐T. On the other hand, while there is one case report about a patient with MDS/MPN‐RS‐T that was positive for both CALR and SF3B1 gene mutations,
8
BPDCN with CALR mutation has not yet been reported to the best of our knowledge. Therefore, in this case, MDS/MPN‐RS‐T might already have been accompanied with CALR mutation.
TdT negativity was reportedly associated with inferior survival in BPDCN;
9
however, whether the aggressive clinical course observed in this case was typical for TdT‐negative BPDCN remains unknown. Conversely, majority of patients with BPDCN expressing cMyc were reportedly accompanied by 8q24 rearrangement, immunoblastoid morphology, and skin lesions.
10
Although 8q24 rearrangement was not examined in this case, the patient had no skin lesions and his blasts showed classic cytomorphology, which suggested that his clinical features were not typical for MYC‐positive BPDCN.
Previous studies showed that BPDCN with leukemic presentation without skin manifestation rarely occurs and tends to present with cytopenia rather than leukocytosis.
11
However, although the patient had leukemia at diagnosis, it was not accompanied with skin lesions and showed very high WBC count, suggesting it to be a very rare case. Moreover, rapid increase in WBC counts and massive splenomegaly indicated a very high tumor burden and rapid tumor growth. The SMILE regimen was selected because it was effective for ANKL
12
and the etoposide contained in SMILE regimen was also effective for BPDCN.
13
Although occurrence of TLS was cautiously considered in spite of low Ki67 index and enough hydration and febuxostat were provided to the patient for the prevention of TLS, he developed fatal TLS. More rigorous management including the early use of rasburicase and induction of hemodialysis is required.
Although the risk prediction of TLS in BPDCN is unknown because of the rarity and heterogeneity of this disease, the high‐disease burden may indicate the risk of TLS as same as other hematological malignancies, and the evaluation of peripheral blood WBC counts and serum LDH concentration may be useful for risk classification of TLS in BPDCN as in acute leukemia.
14
In conclusion, BPDCN shows clinically heterogeneous characteristics, and patients with clinical symptoms suggesting an aggressive clinical course with high tumor burden, including high WBC count or splenomegaly, should be carefully considered to prevent TLS.
CONFLICT OF INTEREST
There are no conflicts of interest to report.
AUTHOR CONTRIBUTIONS
KS: selected the patient and designed the manuscript. KS, MI, NF, and AK: wrote the manuscript. RF: performed the immunohistochemistry. All the authors: reviewed the paper and agreed with the final version.
ETHICAL APPROVAL
This study was approved by the institutional ethical committee of the Konan Kosei Hospital. Written informed consent was obtained from the family of the patient for publication of this case report.
ACKNOWLEDGMENTS
We acknowledge all of the physicians, nurses, and staff who contributed to the patient care at the Department of Hematology and Oncology in Konan Kosei Hospital. Published with written consent of the patient.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. | Fatal | ReactionOutcome | CC BY | 33598264 | 19,587,477 | 2021-02 |
What was the outcome of reaction 'Pulmonary alveolar haemorrhage'? | Severe tumor lysis syndrome during the induction therapy for the treatment of blastic plasmacytoid dendritic cell neoplasm arising from myelodysplastic/myeloproliferative neoplasms.
BPDCN shows clinically heterogeneous characteristics. And as other hematological malignancies, symptoms of BPDCN suggesting a high tumor burden, such as high white blood cell count or splenomegaly, should be carefully considered to prevent TLS.
1 INTRODUCTION
Blastic plasmacytoid dendritic cell neoplasm is a rare disease with difficulty in diagnosis, and clinical courses of patients with BPDCN vary widely. We report a case of a 63‐year‐old man with BPDCN showing severe tumor lysis syndrome (TLS). BPDCN with high tumor burden should be carefully considered to prevent TLS.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with dismal prognosis. With difficulty in diagnosis, BPDCN was used in the 2008 World Health Organization (WHO) classification for the first time and became a distinct entity in 2016 WHO classification.
1
Recently, the presence of four out of five characteristic markers of BPDCN, namely, CD4, CD56, CD123, CD303, and TCL1, has been shown to aid in the accurate diagnosis of BPDCN.
2
Skin lesions commonly occur in a majority of patients with BPDCN, and blasts of BPDCN are suggested to arise from premalignant hematopoietic precursor clones.
3
Thus, patients with systemic lesions were treated with conventional chemotherapies for acute lymphoblastic leukemia, acute myeloid leukemia, or non‐Hodgkin’s lymphoma, sometimes followed by autologous or allogeneic hematopoietic cell transplantation as a consolidation therapy.
4
However, its clinical and biological heterogeneous characteristics make its clinical management difficult.
5
Herein, we describe the case of a patient who suddenly developed leukemic form of BPDCN accompanied with CALReticulin (CALR) mutation arising from myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN‐RS‐T) without cutaneous lesion, showing severe tumor lysis syndrome (TLS) immediately after the induction therapy.
2 CASE PRESENTATION
A 63‐year‐old man previously diagnosed with MDS/MPN‐RS‐T 6 years before the presentation was referred to our hospital for rapid progression of leukocytosis and anemia. Physical examination and computed tomography revealed splenomegaly and inguinal lymphadenopathy without skin involvement (Figure 1 A, B). He did not have fever and had a performance status of 2 according to the Eastern Cooperative Oncology Group score. Blood examination showed the following abnormalities: white blood cell (WBC) count, 44.8 × 109/L with 88% blasts; hemoglobin, 5.5 g/dL; platelet count, 17.0 × 109/L; and serum lactate dehydrogenase (LDH), 300 IU/L. Genetic analyses of his peripheral blood cells detected type 1 CALR mutation without Janus kinase 2 mutation. Markedly hypercellular marrow occupied by agranular blasts with small cytoplasm and fine chromatin were detected in the bone marrow aspiration (Figure 1C, D), and bone marrow biopsy showed severe myelofibrosis (MF‐3) (Figure 1E). Flow cytometry performed on bone marrow aspirate revealed that blasts expressed CD4, CD7, CD56, and HLA‐DR without other myeloid and lymphoid markers. Similar blasts occupied the inguinal lymph node, which suggested lymph node involvement. Based on these results, the patient was suspected to have aggressive NK cell leukemia (ANKL), acute leukemia with ambiguous lineage, or BPDCN.
FIGURE 1 Computed tomography revealed splenomegaly (A) and inguinal lymphadenopathy (B). Markedly hypercellular marrow was occupied by blasts (C), presenting agranular small cytoplasm and fine chromatin (D). Bone marrow biopsy showed severe fibrosis (MF‐3) (E) (magnification of all images ×400).
Due to rapidly increasing WBC count of 106 × 109/L and worsening malaise, the dose‐reduced SMILE regimen without methotrexate which contained etoposide 70 mg/m2 day1–3, ifosfamide 1050 mg/m2 day 1‐3, dexamethasone 30 mg/body day 1‐3, and L‐asparaginase 4000 U/m2 day 7, 9, 11, 13, 15, 17, and 19 was immediately initiated without accurate diagnosis.
6
More than 3 L/d of intravenous hydration and 60 mg/d of febuxostat were administered as prophylaxis for tumor lysis syndrome (TLS). Then, immunohistochemistry performed on bone marrow specimen demonstrated that blasts were positive for CD123, TCL‐1, and CD303, and thus, he was diagnosed with BPDCN (Figure 2). In addition, blasts were positive for cMyc and Bcl‐2 and negative for TdT, with relatively low Ki67 index (Figure 2). Cytogenetic analysis revealed normal karyotype of blasts. The urine volume after initiating the chemotherapy was 3000 mL/d, and his condition improved that he could eat a meal the next day. However, his urine volume suddenly decreased, and his condition worsened again on the third day. WBC count immediately decreased; uric acid, potassium, and phosphorus concentrations increased; calcium concentration decreased with rapid increase in serum creatinine concentration, suggesting a clinical TLS (Table 1). Despite the intensive treatment such as aggressive hydration with noradrenaline administration to restore circulation and bicarbonate to correct metabolic acidosis, he finally died of circulatory failure. Autopsy revealed massive ascites and alveolar hemorrhage, whereas only a few blasts remained in bone marrow and spleen.
FIGURE 2 Blasts were positive for CD4, CD56, CD123, CD303, TCL‐1, cMyc, and Bcl‐2 and negative for TdT, myeloperoxidase, CD3, and CD8. Positive rate of Ki67 was approximately 30% (magnification of all images ×400).
TABLE 1 Blood tests before and after the induction therapy.
Before treatment Day 2 Day 3
BUN mg/dL 34.2 87.9 123.5
Creatinine mg/dL 1.3 1.6 2.7
UA mg/dL 6.0 5.5 8.5
P mg/dL 3.0 17 22.4
Na mmol/L 137 134 137
K mmol/L 4.7 7.2 6.9
Ca mg/dL 7.6 6 6.5
LDH U/L 395 828 784
WBC 109/L 106 55.7 2.4
Blast % 96 85 76
RBC 1012/L 1.2 1.4 1.1
Hb g/dL 3.7 4.4 3.3
Platelet ×109/L 17.0 15.0 10.0
Abbreviations: BUN, blood urea nitrogen; Hb, hemoglobin; LDH, lactate dehydrogenase; RBC, red blood cell; UA, uric acid; WBC, white blood cell.
John Wiley & Sons, Ltd3 DISCUSSION
In this case report, the patient was diagnosed with BPDCN arising from MDS/MPN‐RS‐T that progressed into clinical TLS immediately after the initiation of chemotherapy. Majority of patients with MDS/MPN‐RS‐T have a SF3B1 mutation.
7
Although SF3B1 mutations were not examined in this case, morphologically apparent dysplasia and the presence of ringed sideroblasts strongly supported the diagnosis of MDS/MPN‐RS‐T. On the other hand, while there is one case report about a patient with MDS/MPN‐RS‐T that was positive for both CALR and SF3B1 gene mutations,
8
BPDCN with CALR mutation has not yet been reported to the best of our knowledge. Therefore, in this case, MDS/MPN‐RS‐T might already have been accompanied with CALR mutation.
TdT negativity was reportedly associated with inferior survival in BPDCN;
9
however, whether the aggressive clinical course observed in this case was typical for TdT‐negative BPDCN remains unknown. Conversely, majority of patients with BPDCN expressing cMyc were reportedly accompanied by 8q24 rearrangement, immunoblastoid morphology, and skin lesions.
10
Although 8q24 rearrangement was not examined in this case, the patient had no skin lesions and his blasts showed classic cytomorphology, which suggested that his clinical features were not typical for MYC‐positive BPDCN.
Previous studies showed that BPDCN with leukemic presentation without skin manifestation rarely occurs and tends to present with cytopenia rather than leukocytosis.
11
However, although the patient had leukemia at diagnosis, it was not accompanied with skin lesions and showed very high WBC count, suggesting it to be a very rare case. Moreover, rapid increase in WBC counts and massive splenomegaly indicated a very high tumor burden and rapid tumor growth. The SMILE regimen was selected because it was effective for ANKL
12
and the etoposide contained in SMILE regimen was also effective for BPDCN.
13
Although occurrence of TLS was cautiously considered in spite of low Ki67 index and enough hydration and febuxostat were provided to the patient for the prevention of TLS, he developed fatal TLS. More rigorous management including the early use of rasburicase and induction of hemodialysis is required.
Although the risk prediction of TLS in BPDCN is unknown because of the rarity and heterogeneity of this disease, the high‐disease burden may indicate the risk of TLS as same as other hematological malignancies, and the evaluation of peripheral blood WBC counts and serum LDH concentration may be useful for risk classification of TLS in BPDCN as in acute leukemia.
14
In conclusion, BPDCN shows clinically heterogeneous characteristics, and patients with clinical symptoms suggesting an aggressive clinical course with high tumor burden, including high WBC count or splenomegaly, should be carefully considered to prevent TLS.
CONFLICT OF INTEREST
There are no conflicts of interest to report.
AUTHOR CONTRIBUTIONS
KS: selected the patient and designed the manuscript. KS, MI, NF, and AK: wrote the manuscript. RF: performed the immunohistochemistry. All the authors: reviewed the paper and agreed with the final version.
ETHICAL APPROVAL
This study was approved by the institutional ethical committee of the Konan Kosei Hospital. Written informed consent was obtained from the family of the patient for publication of this case report.
ACKNOWLEDGMENTS
We acknowledge all of the physicians, nurses, and staff who contributed to the patient care at the Department of Hematology and Oncology in Konan Kosei Hospital. Published with written consent of the patient.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. | Fatal | ReactionOutcome | CC BY | 33598264 | 19,587,477 | 2021-02 |
What was the outcome of reaction 'Tumour lysis syndrome'? | Severe tumor lysis syndrome during the induction therapy for the treatment of blastic plasmacytoid dendritic cell neoplasm arising from myelodysplastic/myeloproliferative neoplasms.
BPDCN shows clinically heterogeneous characteristics. And as other hematological malignancies, symptoms of BPDCN suggesting a high tumor burden, such as high white blood cell count or splenomegaly, should be carefully considered to prevent TLS.
1 INTRODUCTION
Blastic plasmacytoid dendritic cell neoplasm is a rare disease with difficulty in diagnosis, and clinical courses of patients with BPDCN vary widely. We report a case of a 63‐year‐old man with BPDCN showing severe tumor lysis syndrome (TLS). BPDCN with high tumor burden should be carefully considered to prevent TLS.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with dismal prognosis. With difficulty in diagnosis, BPDCN was used in the 2008 World Health Organization (WHO) classification for the first time and became a distinct entity in 2016 WHO classification.
1
Recently, the presence of four out of five characteristic markers of BPDCN, namely, CD4, CD56, CD123, CD303, and TCL1, has been shown to aid in the accurate diagnosis of BPDCN.
2
Skin lesions commonly occur in a majority of patients with BPDCN, and blasts of BPDCN are suggested to arise from premalignant hematopoietic precursor clones.
3
Thus, patients with systemic lesions were treated with conventional chemotherapies for acute lymphoblastic leukemia, acute myeloid leukemia, or non‐Hodgkin’s lymphoma, sometimes followed by autologous or allogeneic hematopoietic cell transplantation as a consolidation therapy.
4
However, its clinical and biological heterogeneous characteristics make its clinical management difficult.
5
Herein, we describe the case of a patient who suddenly developed leukemic form of BPDCN accompanied with CALReticulin (CALR) mutation arising from myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN‐RS‐T) without cutaneous lesion, showing severe tumor lysis syndrome (TLS) immediately after the induction therapy.
2 CASE PRESENTATION
A 63‐year‐old man previously diagnosed with MDS/MPN‐RS‐T 6 years before the presentation was referred to our hospital for rapid progression of leukocytosis and anemia. Physical examination and computed tomography revealed splenomegaly and inguinal lymphadenopathy without skin involvement (Figure 1 A, B). He did not have fever and had a performance status of 2 according to the Eastern Cooperative Oncology Group score. Blood examination showed the following abnormalities: white blood cell (WBC) count, 44.8 × 109/L with 88% blasts; hemoglobin, 5.5 g/dL; platelet count, 17.0 × 109/L; and serum lactate dehydrogenase (LDH), 300 IU/L. Genetic analyses of his peripheral blood cells detected type 1 CALR mutation without Janus kinase 2 mutation. Markedly hypercellular marrow occupied by agranular blasts with small cytoplasm and fine chromatin were detected in the bone marrow aspiration (Figure 1C, D), and bone marrow biopsy showed severe myelofibrosis (MF‐3) (Figure 1E). Flow cytometry performed on bone marrow aspirate revealed that blasts expressed CD4, CD7, CD56, and HLA‐DR without other myeloid and lymphoid markers. Similar blasts occupied the inguinal lymph node, which suggested lymph node involvement. Based on these results, the patient was suspected to have aggressive NK cell leukemia (ANKL), acute leukemia with ambiguous lineage, or BPDCN.
FIGURE 1 Computed tomography revealed splenomegaly (A) and inguinal lymphadenopathy (B). Markedly hypercellular marrow was occupied by blasts (C), presenting agranular small cytoplasm and fine chromatin (D). Bone marrow biopsy showed severe fibrosis (MF‐3) (E) (magnification of all images ×400).
Due to rapidly increasing WBC count of 106 × 109/L and worsening malaise, the dose‐reduced SMILE regimen without methotrexate which contained etoposide 70 mg/m2 day1–3, ifosfamide 1050 mg/m2 day 1‐3, dexamethasone 30 mg/body day 1‐3, and L‐asparaginase 4000 U/m2 day 7, 9, 11, 13, 15, 17, and 19 was immediately initiated without accurate diagnosis.
6
More than 3 L/d of intravenous hydration and 60 mg/d of febuxostat were administered as prophylaxis for tumor lysis syndrome (TLS). Then, immunohistochemistry performed on bone marrow specimen demonstrated that blasts were positive for CD123, TCL‐1, and CD303, and thus, he was diagnosed with BPDCN (Figure 2). In addition, blasts were positive for cMyc and Bcl‐2 and negative for TdT, with relatively low Ki67 index (Figure 2). Cytogenetic analysis revealed normal karyotype of blasts. The urine volume after initiating the chemotherapy was 3000 mL/d, and his condition improved that he could eat a meal the next day. However, his urine volume suddenly decreased, and his condition worsened again on the third day. WBC count immediately decreased; uric acid, potassium, and phosphorus concentrations increased; calcium concentration decreased with rapid increase in serum creatinine concentration, suggesting a clinical TLS (Table 1). Despite the intensive treatment such as aggressive hydration with noradrenaline administration to restore circulation and bicarbonate to correct metabolic acidosis, he finally died of circulatory failure. Autopsy revealed massive ascites and alveolar hemorrhage, whereas only a few blasts remained in bone marrow and spleen.
FIGURE 2 Blasts were positive for CD4, CD56, CD123, CD303, TCL‐1, cMyc, and Bcl‐2 and negative for TdT, myeloperoxidase, CD3, and CD8. Positive rate of Ki67 was approximately 30% (magnification of all images ×400).
TABLE 1 Blood tests before and after the induction therapy.
Before treatment Day 2 Day 3
BUN mg/dL 34.2 87.9 123.5
Creatinine mg/dL 1.3 1.6 2.7
UA mg/dL 6.0 5.5 8.5
P mg/dL 3.0 17 22.4
Na mmol/L 137 134 137
K mmol/L 4.7 7.2 6.9
Ca mg/dL 7.6 6 6.5
LDH U/L 395 828 784
WBC 109/L 106 55.7 2.4
Blast % 96 85 76
RBC 1012/L 1.2 1.4 1.1
Hb g/dL 3.7 4.4 3.3
Platelet ×109/L 17.0 15.0 10.0
Abbreviations: BUN, blood urea nitrogen; Hb, hemoglobin; LDH, lactate dehydrogenase; RBC, red blood cell; UA, uric acid; WBC, white blood cell.
John Wiley & Sons, Ltd3 DISCUSSION
In this case report, the patient was diagnosed with BPDCN arising from MDS/MPN‐RS‐T that progressed into clinical TLS immediately after the initiation of chemotherapy. Majority of patients with MDS/MPN‐RS‐T have a SF3B1 mutation.
7
Although SF3B1 mutations were not examined in this case, morphologically apparent dysplasia and the presence of ringed sideroblasts strongly supported the diagnosis of MDS/MPN‐RS‐T. On the other hand, while there is one case report about a patient with MDS/MPN‐RS‐T that was positive for both CALR and SF3B1 gene mutations,
8
BPDCN with CALR mutation has not yet been reported to the best of our knowledge. Therefore, in this case, MDS/MPN‐RS‐T might already have been accompanied with CALR mutation.
TdT negativity was reportedly associated with inferior survival in BPDCN;
9
however, whether the aggressive clinical course observed in this case was typical for TdT‐negative BPDCN remains unknown. Conversely, majority of patients with BPDCN expressing cMyc were reportedly accompanied by 8q24 rearrangement, immunoblastoid morphology, and skin lesions.
10
Although 8q24 rearrangement was not examined in this case, the patient had no skin lesions and his blasts showed classic cytomorphology, which suggested that his clinical features were not typical for MYC‐positive BPDCN.
Previous studies showed that BPDCN with leukemic presentation without skin manifestation rarely occurs and tends to present with cytopenia rather than leukocytosis.
11
However, although the patient had leukemia at diagnosis, it was not accompanied with skin lesions and showed very high WBC count, suggesting it to be a very rare case. Moreover, rapid increase in WBC counts and massive splenomegaly indicated a very high tumor burden and rapid tumor growth. The SMILE regimen was selected because it was effective for ANKL
12
and the etoposide contained in SMILE regimen was also effective for BPDCN.
13
Although occurrence of TLS was cautiously considered in spite of low Ki67 index and enough hydration and febuxostat were provided to the patient for the prevention of TLS, he developed fatal TLS. More rigorous management including the early use of rasburicase and induction of hemodialysis is required.
Although the risk prediction of TLS in BPDCN is unknown because of the rarity and heterogeneity of this disease, the high‐disease burden may indicate the risk of TLS as same as other hematological malignancies, and the evaluation of peripheral blood WBC counts and serum LDH concentration may be useful for risk classification of TLS in BPDCN as in acute leukemia.
14
In conclusion, BPDCN shows clinically heterogeneous characteristics, and patients with clinical symptoms suggesting an aggressive clinical course with high tumor burden, including high WBC count or splenomegaly, should be carefully considered to prevent TLS.
CONFLICT OF INTEREST
There are no conflicts of interest to report.
AUTHOR CONTRIBUTIONS
KS: selected the patient and designed the manuscript. KS, MI, NF, and AK: wrote the manuscript. RF: performed the immunohistochemistry. All the authors: reviewed the paper and agreed with the final version.
ETHICAL APPROVAL
This study was approved by the institutional ethical committee of the Konan Kosei Hospital. Written informed consent was obtained from the family of the patient for publication of this case report.
ACKNOWLEDGMENTS
We acknowledge all of the physicians, nurses, and staff who contributed to the patient care at the Department of Hematology and Oncology in Konan Kosei Hospital. Published with written consent of the patient.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. | Fatal | ReactionOutcome | CC BY | 33598264 | 19,587,477 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug resistance'. | Treatment of genital herpes using olive leaf extract.
Genital herpes is one of the sexually transmitted diseases that is reported with a greater incidence of primary and secondary recurrence. In this study, olive leaf extract was used for its antiviral properties to treat the infection. The randomized-clinical trials using such a therapeutic approach are required in this field.
1 INTRODUCTION
Genital herpes is one of the most commonly reported sexually transmitted infections (STI) that is associated with a greater incidence of recurrence and does not respond to conventional treatments. Type I and II viruses are involved in the pathogenesis of the disease where it affects lips, face, and genitals.
1
The infection begins with irritation and itching followed by pain up to 24 hours, after which the virus widespread to sensory nerves.
2
Due to the weakening of the immune system, the virus in the sensory nerves returns to the surface of the skin to cause reinfection. Factors that can worsen the infection include stress, fatigue, cold wind, burn, loss of immunity, infection, fever, and cold, to name few.
3
The symptoms usually last 4‐7 days after the first contact with the virus carrying virus or virus‐containing secretions.
4
The most common symptom of the disease is the appearance of small blisters in the genital area that when puncture, produce painful ulcers. Some people may find only red or prominent lesions, and some are likely to be presented with painful urination.
5
In women, vaginal vesiculate secretions may also be observed. Urination, with clear watery secretions from the urethra, is often a known complication of the infection. Ulceration usually occurs 4‐7 days after the first infection, and the symptoms are similar to that of cold, such as fever, sore throat, and lumbago swelling.
6
Conventional treatment for herpes includes antiviral drugs, which inhibit the replication of viral RNA.
4
These drugs include acyclovir, ganciclovir, valaciclovir, and penciclovir. The overuse of drugs has led to drug resistance.
7
On the other hand, they are not cost‐effective, owing to the long course of treatment.
8
Currently, two herbal remedies, Melissa and Myrtoplex, are used in Iran.
9
Herbal medicine is currently under investigation for its effectiveness in the treatment of the herpes virus. Studies have indicated that plants and derived compounds can be used to treat herpes viruses.
10
,
11
Olive extracts are reported to be effective against various pathological conditions. Polyphenolic compounds, including oleuropein (OLE) and hydroxytyrosol (HT), are active ingredients in olive leave extracts. In this report, we present a case of acyclovir‐resistant herpes that was reported to our center, due to the severity of the symptoms. Olive leaf extract ointment led to the patient recovery in 48 hours.
2 OLIVE LEAF EXTRACTION METHOD
Olive leaves were collected in Mid‐November and dried at ambient room temperature, and the powdered extract was stored in dark until further usage. The powder was dissolved in 100 mL of extraction solvent that was made of 80% ethanol at 60°C. The mixture was filtered using Whatman filter paper NO: 1. The extract was evaporated at room temperature under vacuum conditions. The leaves were obtained at the best possible time of the year, which had the highest amount of active ingredients; washed, dried, and hydroalcoholic extract was extracted. The extract analysis using the HPLC showed that the active ingredient, oleuropein, was 0.475 mg/g of the total extract. The ointment was prepared in 2% and was provided to the patient.
3 CASE REPORT
The patient was a married 19‐year‐old woman with multiple mucocutaneous, round polycyclic lesions in the perineal region, dysuria and had severe burning sensations and pain, especially during defecation and her vulva was inflamed with swollen and tender inguinal lymph node. She reported that the appearance of the lesion started a week before her referral. Her husband (only sexual partner) did not have any such lesions, and she did not have any travel history for past 6 months. She visited her gynecologist for pap test 4 months ago. No other body part had lesions or rashes. The patient was healthy otherwise and did not have any medical or surgical history. The patient was referred to Asali Women's Hospital. During this period, the patient underwent multiple visits to general practitioners and general surgery specialists with a primary diagnosis of anal fissure. Her blood chemistry did not show any abnormality in exception to increased white blood cell counts: 15 000/mm3. During her referral to dermatologist, she was diagnosed with herpes infection from lesion biopsy, PCR test, and serologic tests for herpes glycoprotein (ELISA) and was treated with acyclovir ointment. At this time, her husband was not tested positive for the infection. Nonetheless, the patient did not respond to the treatment and was known to be a case of acyclovir‐resistant herpes infection. She was thereby, treated with the localized application of topical olive leaf extract, twice a day, owing to the lesion biopsy reports. The response to this treatment was evaluated on day 3 and 6, and 2 weeks after treatment. Following 3 days of the treatment, the pain and wounds completely disappeared whereas the lesions of the perineal and rectal areas were completely recovered on day 6, and after 2 weeks of follow‐up, no relapse was observed (Figure 1).
FIGURE 1 A, Indicates a first‐day lesion before treatment. B, indicates a third‐day post‐treatment lesion. C, indicates a lesion on day 6 after treatment. D, indicates a lesion 2 wk after treatment
Written consent of the patient was obtained from the patient for this study.
4 DISCUSSION
Herpes infection is one of the most common STI, worldwide. Acyclovir ointment and creams are usually used for the treatment of the infection. However, cases of acyclovir resistance and related agents have been reported widely, as a result of thymidine kinase deficiency. Hence, alternative drugs are used for the treatment. Some researchers, in addition to direct antiviral effects, seek to boost the immune system against these viruses. Recently, Olea Europrae plant with antibacterial, antifungal, and antiviral effects has been reported for immune‐boosting effects to treat HSV infection.
12
,
13
Similarly, imiquimod, as an immune‐modifier, is also used for the purpose.
14
In vivo studies have shown the efficacy of olive leaves extract against HSV‐1.
15
The application of olive leaf extract is also indicated for the treatment of HSV.
16
In a patent, it has been pointed out that the olive leaf extract in six patients with herpes genitalis eliminated lesions in three of them after 48 hours and in a patient after 72 hours. The remaining two patients showed 66% improvement.
17
Oleuropein is one of the active phenolic compounds in olive leaves that is known for the treatment of cancer, microbes, viruses, and hyperlipidemia. It is effective against rotavirus, hepatitis, parvovirus, influenza virus, herpes, and human immunodeficiency viruses. Furthermore, anti‐inflammatory and analgesic effects are also reported.
18
In this case, we have reported the treatment of herpes simplex virus infection using olive leaf extract in an acyclovir‐resistant patient. It was seen that the ointment with the 2% of the extract can control itching, bleeding, and pain. It was also effective against the lesions, similar to acyclovir. These outcomes are likely to direct cost‐effective methods for treating herpes using herbal medicine with low‐to‐no adverse effects. Therefore, further clinical studies are recommended in the area.
5 CONCLUSION
Olive leaf extracts are the potential antiviral compounds that can be used to treat genital herpes.
CONFLICT OF INTEREST
The authors deny any conflict of interest in any terms or by any means during the study.
AUTHOR CONTRIBUTIONS
Dr NL: conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript. Dr NK: designed the data collection instruments, collected data, carried out the initial analyses, and reviewed and revised the manuscript. Dr YK: coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content.
ETHICAL APPROVAL
All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
CONSENT FOR PUBLICATION
Not applicable.
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. | ACYCLOVIR | DrugsGivenReaction | CC BY-NC-ND | 33598284 | 18,955,420 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pathogen resistance'. | Treatment of genital herpes using olive leaf extract.
Genital herpes is one of the sexually transmitted diseases that is reported with a greater incidence of primary and secondary recurrence. In this study, olive leaf extract was used for its antiviral properties to treat the infection. The randomized-clinical trials using such a therapeutic approach are required in this field.
1 INTRODUCTION
Genital herpes is one of the most commonly reported sexually transmitted infections (STI) that is associated with a greater incidence of recurrence and does not respond to conventional treatments. Type I and II viruses are involved in the pathogenesis of the disease where it affects lips, face, and genitals.
1
The infection begins with irritation and itching followed by pain up to 24 hours, after which the virus widespread to sensory nerves.
2
Due to the weakening of the immune system, the virus in the sensory nerves returns to the surface of the skin to cause reinfection. Factors that can worsen the infection include stress, fatigue, cold wind, burn, loss of immunity, infection, fever, and cold, to name few.
3
The symptoms usually last 4‐7 days after the first contact with the virus carrying virus or virus‐containing secretions.
4
The most common symptom of the disease is the appearance of small blisters in the genital area that when puncture, produce painful ulcers. Some people may find only red or prominent lesions, and some are likely to be presented with painful urination.
5
In women, vaginal vesiculate secretions may also be observed. Urination, with clear watery secretions from the urethra, is often a known complication of the infection. Ulceration usually occurs 4‐7 days after the first infection, and the symptoms are similar to that of cold, such as fever, sore throat, and lumbago swelling.
6
Conventional treatment for herpes includes antiviral drugs, which inhibit the replication of viral RNA.
4
These drugs include acyclovir, ganciclovir, valaciclovir, and penciclovir. The overuse of drugs has led to drug resistance.
7
On the other hand, they are not cost‐effective, owing to the long course of treatment.
8
Currently, two herbal remedies, Melissa and Myrtoplex, are used in Iran.
9
Herbal medicine is currently under investigation for its effectiveness in the treatment of the herpes virus. Studies have indicated that plants and derived compounds can be used to treat herpes viruses.
10
,
11
Olive extracts are reported to be effective against various pathological conditions. Polyphenolic compounds, including oleuropein (OLE) and hydroxytyrosol (HT), are active ingredients in olive leave extracts. In this report, we present a case of acyclovir‐resistant herpes that was reported to our center, due to the severity of the symptoms. Olive leaf extract ointment led to the patient recovery in 48 hours.
2 OLIVE LEAF EXTRACTION METHOD
Olive leaves were collected in Mid‐November and dried at ambient room temperature, and the powdered extract was stored in dark until further usage. The powder was dissolved in 100 mL of extraction solvent that was made of 80% ethanol at 60°C. The mixture was filtered using Whatman filter paper NO: 1. The extract was evaporated at room temperature under vacuum conditions. The leaves were obtained at the best possible time of the year, which had the highest amount of active ingredients; washed, dried, and hydroalcoholic extract was extracted. The extract analysis using the HPLC showed that the active ingredient, oleuropein, was 0.475 mg/g of the total extract. The ointment was prepared in 2% and was provided to the patient.
3 CASE REPORT
The patient was a married 19‐year‐old woman with multiple mucocutaneous, round polycyclic lesions in the perineal region, dysuria and had severe burning sensations and pain, especially during defecation and her vulva was inflamed with swollen and tender inguinal lymph node. She reported that the appearance of the lesion started a week before her referral. Her husband (only sexual partner) did not have any such lesions, and she did not have any travel history for past 6 months. She visited her gynecologist for pap test 4 months ago. No other body part had lesions or rashes. The patient was healthy otherwise and did not have any medical or surgical history. The patient was referred to Asali Women's Hospital. During this period, the patient underwent multiple visits to general practitioners and general surgery specialists with a primary diagnosis of anal fissure. Her blood chemistry did not show any abnormality in exception to increased white blood cell counts: 15 000/mm3. During her referral to dermatologist, she was diagnosed with herpes infection from lesion biopsy, PCR test, and serologic tests for herpes glycoprotein (ELISA) and was treated with acyclovir ointment. At this time, her husband was not tested positive for the infection. Nonetheless, the patient did not respond to the treatment and was known to be a case of acyclovir‐resistant herpes infection. She was thereby, treated with the localized application of topical olive leaf extract, twice a day, owing to the lesion biopsy reports. The response to this treatment was evaluated on day 3 and 6, and 2 weeks after treatment. Following 3 days of the treatment, the pain and wounds completely disappeared whereas the lesions of the perineal and rectal areas were completely recovered on day 6, and after 2 weeks of follow‐up, no relapse was observed (Figure 1).
FIGURE 1 A, Indicates a first‐day lesion before treatment. B, indicates a third‐day post‐treatment lesion. C, indicates a lesion on day 6 after treatment. D, indicates a lesion 2 wk after treatment
Written consent of the patient was obtained from the patient for this study.
4 DISCUSSION
Herpes infection is one of the most common STI, worldwide. Acyclovir ointment and creams are usually used for the treatment of the infection. However, cases of acyclovir resistance and related agents have been reported widely, as a result of thymidine kinase deficiency. Hence, alternative drugs are used for the treatment. Some researchers, in addition to direct antiviral effects, seek to boost the immune system against these viruses. Recently, Olea Europrae plant with antibacterial, antifungal, and antiviral effects has been reported for immune‐boosting effects to treat HSV infection.
12
,
13
Similarly, imiquimod, as an immune‐modifier, is also used for the purpose.
14
In vivo studies have shown the efficacy of olive leaves extract against HSV‐1.
15
The application of olive leaf extract is also indicated for the treatment of HSV.
16
In a patent, it has been pointed out that the olive leaf extract in six patients with herpes genitalis eliminated lesions in three of them after 48 hours and in a patient after 72 hours. The remaining two patients showed 66% improvement.
17
Oleuropein is one of the active phenolic compounds in olive leaves that is known for the treatment of cancer, microbes, viruses, and hyperlipidemia. It is effective against rotavirus, hepatitis, parvovirus, influenza virus, herpes, and human immunodeficiency viruses. Furthermore, anti‐inflammatory and analgesic effects are also reported.
18
In this case, we have reported the treatment of herpes simplex virus infection using olive leaf extract in an acyclovir‐resistant patient. It was seen that the ointment with the 2% of the extract can control itching, bleeding, and pain. It was also effective against the lesions, similar to acyclovir. These outcomes are likely to direct cost‐effective methods for treating herpes using herbal medicine with low‐to‐no adverse effects. Therefore, further clinical studies are recommended in the area.
5 CONCLUSION
Olive leaf extracts are the potential antiviral compounds that can be used to treat genital herpes.
CONFLICT OF INTEREST
The authors deny any conflict of interest in any terms or by any means during the study.
AUTHOR CONTRIBUTIONS
Dr NL: conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript. Dr NK: designed the data collection instruments, collected data, carried out the initial analyses, and reviewed and revised the manuscript. Dr YK: coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content.
ETHICAL APPROVAL
All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
CONSENT FOR PUBLICATION
Not applicable.
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. | ACYCLOVIR | DrugsGivenReaction | CC BY-NC-ND | 33598284 | 18,955,420 | 2021-02 |
What was the outcome of reaction 'Drug resistance'? | Treatment of genital herpes using olive leaf extract.
Genital herpes is one of the sexually transmitted diseases that is reported with a greater incidence of primary and secondary recurrence. In this study, olive leaf extract was used for its antiviral properties to treat the infection. The randomized-clinical trials using such a therapeutic approach are required in this field.
1 INTRODUCTION
Genital herpes is one of the most commonly reported sexually transmitted infections (STI) that is associated with a greater incidence of recurrence and does not respond to conventional treatments. Type I and II viruses are involved in the pathogenesis of the disease where it affects lips, face, and genitals.
1
The infection begins with irritation and itching followed by pain up to 24 hours, after which the virus widespread to sensory nerves.
2
Due to the weakening of the immune system, the virus in the sensory nerves returns to the surface of the skin to cause reinfection. Factors that can worsen the infection include stress, fatigue, cold wind, burn, loss of immunity, infection, fever, and cold, to name few.
3
The symptoms usually last 4‐7 days after the first contact with the virus carrying virus or virus‐containing secretions.
4
The most common symptom of the disease is the appearance of small blisters in the genital area that when puncture, produce painful ulcers. Some people may find only red or prominent lesions, and some are likely to be presented with painful urination.
5
In women, vaginal vesiculate secretions may also be observed. Urination, with clear watery secretions from the urethra, is often a known complication of the infection. Ulceration usually occurs 4‐7 days after the first infection, and the symptoms are similar to that of cold, such as fever, sore throat, and lumbago swelling.
6
Conventional treatment for herpes includes antiviral drugs, which inhibit the replication of viral RNA.
4
These drugs include acyclovir, ganciclovir, valaciclovir, and penciclovir. The overuse of drugs has led to drug resistance.
7
On the other hand, they are not cost‐effective, owing to the long course of treatment.
8
Currently, two herbal remedies, Melissa and Myrtoplex, are used in Iran.
9
Herbal medicine is currently under investigation for its effectiveness in the treatment of the herpes virus. Studies have indicated that plants and derived compounds can be used to treat herpes viruses.
10
,
11
Olive extracts are reported to be effective against various pathological conditions. Polyphenolic compounds, including oleuropein (OLE) and hydroxytyrosol (HT), are active ingredients in olive leave extracts. In this report, we present a case of acyclovir‐resistant herpes that was reported to our center, due to the severity of the symptoms. Olive leaf extract ointment led to the patient recovery in 48 hours.
2 OLIVE LEAF EXTRACTION METHOD
Olive leaves were collected in Mid‐November and dried at ambient room temperature, and the powdered extract was stored in dark until further usage. The powder was dissolved in 100 mL of extraction solvent that was made of 80% ethanol at 60°C. The mixture was filtered using Whatman filter paper NO: 1. The extract was evaporated at room temperature under vacuum conditions. The leaves were obtained at the best possible time of the year, which had the highest amount of active ingredients; washed, dried, and hydroalcoholic extract was extracted. The extract analysis using the HPLC showed that the active ingredient, oleuropein, was 0.475 mg/g of the total extract. The ointment was prepared in 2% and was provided to the patient.
3 CASE REPORT
The patient was a married 19‐year‐old woman with multiple mucocutaneous, round polycyclic lesions in the perineal region, dysuria and had severe burning sensations and pain, especially during defecation and her vulva was inflamed with swollen and tender inguinal lymph node. She reported that the appearance of the lesion started a week before her referral. Her husband (only sexual partner) did not have any such lesions, and she did not have any travel history for past 6 months. She visited her gynecologist for pap test 4 months ago. No other body part had lesions or rashes. The patient was healthy otherwise and did not have any medical or surgical history. The patient was referred to Asali Women's Hospital. During this period, the patient underwent multiple visits to general practitioners and general surgery specialists with a primary diagnosis of anal fissure. Her blood chemistry did not show any abnormality in exception to increased white blood cell counts: 15 000/mm3. During her referral to dermatologist, she was diagnosed with herpes infection from lesion biopsy, PCR test, and serologic tests for herpes glycoprotein (ELISA) and was treated with acyclovir ointment. At this time, her husband was not tested positive for the infection. Nonetheless, the patient did not respond to the treatment and was known to be a case of acyclovir‐resistant herpes infection. She was thereby, treated with the localized application of topical olive leaf extract, twice a day, owing to the lesion biopsy reports. The response to this treatment was evaluated on day 3 and 6, and 2 weeks after treatment. Following 3 days of the treatment, the pain and wounds completely disappeared whereas the lesions of the perineal and rectal areas were completely recovered on day 6, and after 2 weeks of follow‐up, no relapse was observed (Figure 1).
FIGURE 1 A, Indicates a first‐day lesion before treatment. B, indicates a third‐day post‐treatment lesion. C, indicates a lesion on day 6 after treatment. D, indicates a lesion 2 wk after treatment
Written consent of the patient was obtained from the patient for this study.
4 DISCUSSION
Herpes infection is one of the most common STI, worldwide. Acyclovir ointment and creams are usually used for the treatment of the infection. However, cases of acyclovir resistance and related agents have been reported widely, as a result of thymidine kinase deficiency. Hence, alternative drugs are used for the treatment. Some researchers, in addition to direct antiviral effects, seek to boost the immune system against these viruses. Recently, Olea Europrae plant with antibacterial, antifungal, and antiviral effects has been reported for immune‐boosting effects to treat HSV infection.
12
,
13
Similarly, imiquimod, as an immune‐modifier, is also used for the purpose.
14
In vivo studies have shown the efficacy of olive leaves extract against HSV‐1.
15
The application of olive leaf extract is also indicated for the treatment of HSV.
16
In a patent, it has been pointed out that the olive leaf extract in six patients with herpes genitalis eliminated lesions in three of them after 48 hours and in a patient after 72 hours. The remaining two patients showed 66% improvement.
17
Oleuropein is one of the active phenolic compounds in olive leaves that is known for the treatment of cancer, microbes, viruses, and hyperlipidemia. It is effective against rotavirus, hepatitis, parvovirus, influenza virus, herpes, and human immunodeficiency viruses. Furthermore, anti‐inflammatory and analgesic effects are also reported.
18
In this case, we have reported the treatment of herpes simplex virus infection using olive leaf extract in an acyclovir‐resistant patient. It was seen that the ointment with the 2% of the extract can control itching, bleeding, and pain. It was also effective against the lesions, similar to acyclovir. These outcomes are likely to direct cost‐effective methods for treating herpes using herbal medicine with low‐to‐no adverse effects. Therefore, further clinical studies are recommended in the area.
5 CONCLUSION
Olive leaf extracts are the potential antiviral compounds that can be used to treat genital herpes.
CONFLICT OF INTEREST
The authors deny any conflict of interest in any terms or by any means during the study.
AUTHOR CONTRIBUTIONS
Dr NL: conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript. Dr NK: designed the data collection instruments, collected data, carried out the initial analyses, and reviewed and revised the manuscript. Dr YK: coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content.
ETHICAL APPROVAL
All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
CONSENT FOR PUBLICATION
Not applicable.
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. | Recovered | ReactionOutcome | CC BY-NC-ND | 33598284 | 18,955,420 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypoxia'. | Everolimus induced organizing pneumonia in a patient with tuberous sclerosis complex.
Organizing pneumonia is characterized by a distinct histologic pattern in the lung interstitium and presents clinically as hypoxemia, fever, cough, and dyspnea that is not attributable to concurrent infection. Typical etiologies of this condition include inflammatory disease, malignancy, toxic inhalation, and an array of medications including the mTOR inhibitor everolimus. In this report, we describe the case of a female with tuberous sclerosis complex on everolimus therapy for renal angiomyolipomas who presented to the hospital with persistent cough, dyspnea, and fevers and bilateral lower lobe opacities on chest X-ray despite multiple courses of antibiotic therapy. Bronchoscopy was performed with transbronchial biopsies, and results demonstrated a lymphocytic predominance and pathologic findings of intraluminal plugs composed of fibroblasts and myofibroblasts consistent with organizing pneumonia. Everolimus therapy was discontinued and patient completed a steroid course with resolution of symptoms. To our knowledge, this is the first published case of organizing pneumonia secondary to everolimus in a patient with tuberous sclerosis complex.
1 Introduction
Everolimus is a an orally available mammalian target of rapamycin (mTOR) inhibitor that belongs to the group of proliferation signal inhibitors, which also includes sirolimus and temsirolimus. These compounds have antiproliferative and antifibrotic properties [9]. Because of these properties they are typically used in the treatment of various malignancies and in patients with solid organ transplantation [8]. Both everolimus and sirolimus are known to induce pulmonary toxicity, such as interstitial pneumonia and organizing pneumonia [5].
Organizing pneumonia due to everolimus is an uncommon presentation of drug-induced interstitial lung disease that compromises the distal bronchioles, respiratory bronchioles and alveoli, specifically the alveolar wall. This condition is defined histopathologically by intra-alveolar buds of granulation tissue, consisting of intermixed myofibroblasts and connective tissue [11]. High resolution computed tomography often reveals patchy air-space consolidation, ground-glass opacities, small nodular opacities, and bronchial wall thickening with dilation [12].
In this case, we present a case of a female with tuberous sclerosis complex with symptomatic renal angiomyolipomas that developed organizing pneumonia secondary to everolimus.
2 Case report
46-year-old female with history of tuberous sclerosis complex with renal angiomyolipomas (Fig. 1) and stage II CKD that presented with one month of cough, dyspnea, and intermittent fevers. She was admitted one week prior for community-acquired pneumonia having already received a 10-day course of amoxicillin/clavulanate without improvement. During the second admission, the patient was treated with doxycycline and Azithromycin, transitioned to cefdinir at discharge.Fig. 1 Tomography of the abdomen.
Bilateral lobular kidneys with multiple fat-containing lesions consistent with renal angiomyolipomas commonly seen in tuberous sclerosis complex.
Fig. 1
Everolimus was started ten years prior to admission due to enlarging renal angiomyolipomas and patient had previously been stable on this therapy. On presentation, the patient was afebrile, tachypneic, and hypoxemic requiring 4 L nasal cannula to maintain oxygen saturation above 90%. Physical exam was notable for diminished bilateral lower breath sounds without wheezes. Laboratory studies included a white blood cell count of 10,300, platelets 608,000, C-reactive protein of 13.1 mg/dL, and procalcitonin of 0.53 mg/dL. Urinary streptococcal and legionella antigens were negative. Chest X-ray (Fig. 2) showed bilateral lower lobe airspace disease. CT Chest (Fig. 3a, Fig. 3b) showed bilateral multifocal pulmonary infiltrates and ground-glass opacities (GGO) predominantly perihilar and lower lobe in location on the right, with extensive involvement of the left upper and lower lung zones. She received fluid resuscitation along with IV vancomycin and cefepime. Her hypoxemia failed to improve with appropriate antibiotics and bronchoscopy was performed. Bronchoalveolar lavage of the right middle lobe, endobronchial biopsies of the right upper lobe, and transbronchial biopsies of the right lower lobe were performed. Bronchoalveolar lavage showed 678,000 WBC with 26% lymphocytes, 12% neutrophils, and 60% macrophages. Cultures from all the different specimens did not show any organisms. Transbronchial biopsies (Fig. 4a, Fig. 4b) demonstrated “patchy intraluminal plugs composed of fibroblasts and myofibroblasts embedded in loose connective tissue with mild chronic interstitial pneumonia” consistent with organizing pneumonia. Given these findings on transbronchial biopsies, a combined decision between pulmonary and urology was made to stop everolimus. She was started on oral prednisone at 0.75 mg/kg of ideal body weight and antibiotics were discontinued. The patient was discharged home on 2 L of oxygen and steroids. She was seen in Pulmonary clinic one month later and her hypoxemia has resolved. The patient was symptomatically back to baseline. Follow-up CT chest (Fig. 5) one month later showed improvement of the bilateral infiltrates. Chest x-ray Chest tomography one month later.CT Chest on month later shows interval improvement in the right lower lobe consolidations but more extensive ground glass in the left lower lobe with occasional subpleural cysts.(Fig. 6) two month after initiation of therapy showed resolution of the infiltrates. Steroids were weaned over the course of several months and the patient returned to her baseline functional status.Fig. 2 Initial chest X-ray.
AP View chest x-ray showing bibasilar centrally located infiltrates, more prominent on the left.
Fig. 2Fig. 3a Initial chest tomography.
CT Chest demonstrating bilateral airspace disease with varying distributions. The consolidations are more bronchocentric in the right middle lobe with diffuse consolidation with some intervening ground glass in the right lower lobe. Infiltrates in the left lower lobe are more peripheral and subpleural in distribution.
Fig. 3aFig. 3b Initial chest tomography.
Coronal image of CT Chest showing both central and peripheral consolidations with surrounding ground glass infiltrates.
Fig. 3bFig. 4a Pathology.
Fig. 4aFig. 4b Pathology.
Pathology description
Microscopically, the biopsy demonstrates patchy intraluminal plugs composed of fibroblasts and myofibrobalsts embedded in loose connective tissue with mild chronic interstitial pneumonia.
Special stains were performed for microorganisms; which were negative.
Fig. 4bFig. 5 Chest tomography one month later.
CT Chest on month later shows interval improvement in the right lower lobe consolidations but more extensive ground glass in the left lower lobe with occasional subpleural cysts.
Fig. 5Fig. 6 Chest X-Ray two months after initiation of treatment with steroids.
Chest x-ray 2 months after treatment with corticosteroids. Bilateral lower zone infiltrates have nearly completely resolved.
Fig. 6
3 Discussion
Organizing pneumonia is an uncommon subtype of interstitial lung disease. Organizing pneumonia can be classified as secondary due to medications or connective tissue disease or cryptogenic without an obvious etiology. Patients usually present with several weeks of constitutional symptoms and can mimic community-acquired pneumonia with fleeting pulmonary infiltrates. Not uncommonly, patients receive multiple rounds of antibiotics for bacterial pneumonias. Oral corticosteroids are the backbone treatment for organizing pneumonia, but other immunosuppressive medications have been used along with macrolides [13,14]. Here, we present a case of biopsy-proved everolimus-induced organizing pneumonia in a patient with tuberous sclerosis.
The benefit of use of Everolimus in tuberous sclerosis patients for the treatment of renal cell angiomyolipomas was first widely recognized with the publication of the EXIST-2 trial in 2013 [1], the first randomized, placebo-controlled, phase 3 study to assess everolimus efficacy and safety in patients with TS-associated renal angiomyolipoma. There have been numerous case reports and clinical trials documenting noninfectious pneumonitis and organizing pneumonia as a side effect of everolimus in use for treatment of a variety of conditions including renal cell carcinoma [2,5], Waldenstrom Macroglobulinemia [3], renal transplant [4,6], and insulinoma [10]. However, our study is one of few to document biopsy-proven organizing pneumonia as a side effect of everolimus in a tuberous sclerosis patient. One case report published in 2015 documented similar findings in a patient with concurrent pulmonary lymphangioleiomyomatosis and stage 3 CKD, proposing these comorbidities as a potential increased risk for everolimus-induced pulmonary toxicity [8]. Our patient similarly demonstrated stage 2 CKD at time if onset but had no underlying pulmonary disease. Additionally, a unique feature of our patient's presentation was the fact that everolimus had been initiated 10 years prior. In the aforementioned case study, patient symptoms occurred 6 months after initiation of the medications. Clinical trials have documented median time of onset as 108 days [2], 5.7 months [3], 162 days [6], and case reports range from 4 weeks [7] to 15 months [5]. However, we were unable to determine another potential trigger of patient's presentation with an extensive negative infectious workup and no improvement on antimicrobial therapy. Our patient did demonstrate marked improvement however with discontinuation of everolimus and initiation of steroids. We therefore recommend that, when developing a differential diagnosis for organizing pneumonia, providers seriously consider the administration of everolimus as a potential cause, regardless of treatment timeline.
4 Conclusion
Everolimus is a mTOR inhibitor used in the treatment of both renal cell carcinoma and tuberous sclerosis. Rarely, it can cause organizing pneumonia which can be treated with discontinuation of the medication and oral corticosteroids.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | EVEROLIMUS | DrugsGivenReaction | CC BY-NC-ND | 33598397 | 19,548,885 | 2021 |
What was the dosage of drug 'AMOXICILLIN\CLAVULANATE POTASSIUM'? | Everolimus induced organizing pneumonia in a patient with tuberous sclerosis complex.
Organizing pneumonia is characterized by a distinct histologic pattern in the lung interstitium and presents clinically as hypoxemia, fever, cough, and dyspnea that is not attributable to concurrent infection. Typical etiologies of this condition include inflammatory disease, malignancy, toxic inhalation, and an array of medications including the mTOR inhibitor everolimus. In this report, we describe the case of a female with tuberous sclerosis complex on everolimus therapy for renal angiomyolipomas who presented to the hospital with persistent cough, dyspnea, and fevers and bilateral lower lobe opacities on chest X-ray despite multiple courses of antibiotic therapy. Bronchoscopy was performed with transbronchial biopsies, and results demonstrated a lymphocytic predominance and pathologic findings of intraluminal plugs composed of fibroblasts and myofibroblasts consistent with organizing pneumonia. Everolimus therapy was discontinued and patient completed a steroid course with resolution of symptoms. To our knowledge, this is the first published case of organizing pneumonia secondary to everolimus in a patient with tuberous sclerosis complex.
1 Introduction
Everolimus is a an orally available mammalian target of rapamycin (mTOR) inhibitor that belongs to the group of proliferation signal inhibitors, which also includes sirolimus and temsirolimus. These compounds have antiproliferative and antifibrotic properties [9]. Because of these properties they are typically used in the treatment of various malignancies and in patients with solid organ transplantation [8]. Both everolimus and sirolimus are known to induce pulmonary toxicity, such as interstitial pneumonia and organizing pneumonia [5].
Organizing pneumonia due to everolimus is an uncommon presentation of drug-induced interstitial lung disease that compromises the distal bronchioles, respiratory bronchioles and alveoli, specifically the alveolar wall. This condition is defined histopathologically by intra-alveolar buds of granulation tissue, consisting of intermixed myofibroblasts and connective tissue [11]. High resolution computed tomography often reveals patchy air-space consolidation, ground-glass opacities, small nodular opacities, and bronchial wall thickening with dilation [12].
In this case, we present a case of a female with tuberous sclerosis complex with symptomatic renal angiomyolipomas that developed organizing pneumonia secondary to everolimus.
2 Case report
46-year-old female with history of tuberous sclerosis complex with renal angiomyolipomas (Fig. 1) and stage II CKD that presented with one month of cough, dyspnea, and intermittent fevers. She was admitted one week prior for community-acquired pneumonia having already received a 10-day course of amoxicillin/clavulanate without improvement. During the second admission, the patient was treated with doxycycline and Azithromycin, transitioned to cefdinir at discharge.Fig. 1 Tomography of the abdomen.
Bilateral lobular kidneys with multiple fat-containing lesions consistent with renal angiomyolipomas commonly seen in tuberous sclerosis complex.
Fig. 1
Everolimus was started ten years prior to admission due to enlarging renal angiomyolipomas and patient had previously been stable on this therapy. On presentation, the patient was afebrile, tachypneic, and hypoxemic requiring 4 L nasal cannula to maintain oxygen saturation above 90%. Physical exam was notable for diminished bilateral lower breath sounds without wheezes. Laboratory studies included a white blood cell count of 10,300, platelets 608,000, C-reactive protein of 13.1 mg/dL, and procalcitonin of 0.53 mg/dL. Urinary streptococcal and legionella antigens were negative. Chest X-ray (Fig. 2) showed bilateral lower lobe airspace disease. CT Chest (Fig. 3a, Fig. 3b) showed bilateral multifocal pulmonary infiltrates and ground-glass opacities (GGO) predominantly perihilar and lower lobe in location on the right, with extensive involvement of the left upper and lower lung zones. She received fluid resuscitation along with IV vancomycin and cefepime. Her hypoxemia failed to improve with appropriate antibiotics and bronchoscopy was performed. Bronchoalveolar lavage of the right middle lobe, endobronchial biopsies of the right upper lobe, and transbronchial biopsies of the right lower lobe were performed. Bronchoalveolar lavage showed 678,000 WBC with 26% lymphocytes, 12% neutrophils, and 60% macrophages. Cultures from all the different specimens did not show any organisms. Transbronchial biopsies (Fig. 4a, Fig. 4b) demonstrated “patchy intraluminal plugs composed of fibroblasts and myofibroblasts embedded in loose connective tissue with mild chronic interstitial pneumonia” consistent with organizing pneumonia. Given these findings on transbronchial biopsies, a combined decision between pulmonary and urology was made to stop everolimus. She was started on oral prednisone at 0.75 mg/kg of ideal body weight and antibiotics were discontinued. The patient was discharged home on 2 L of oxygen and steroids. She was seen in Pulmonary clinic one month later and her hypoxemia has resolved. The patient was symptomatically back to baseline. Follow-up CT chest (Fig. 5) one month later showed improvement of the bilateral infiltrates. Chest x-ray Chest tomography one month later.CT Chest on month later shows interval improvement in the right lower lobe consolidations but more extensive ground glass in the left lower lobe with occasional subpleural cysts.(Fig. 6) two month after initiation of therapy showed resolution of the infiltrates. Steroids were weaned over the course of several months and the patient returned to her baseline functional status.Fig. 2 Initial chest X-ray.
AP View chest x-ray showing bibasilar centrally located infiltrates, more prominent on the left.
Fig. 2Fig. 3a Initial chest tomography.
CT Chest demonstrating bilateral airspace disease with varying distributions. The consolidations are more bronchocentric in the right middle lobe with diffuse consolidation with some intervening ground glass in the right lower lobe. Infiltrates in the left lower lobe are more peripheral and subpleural in distribution.
Fig. 3aFig. 3b Initial chest tomography.
Coronal image of CT Chest showing both central and peripheral consolidations with surrounding ground glass infiltrates.
Fig. 3bFig. 4a Pathology.
Fig. 4aFig. 4b Pathology.
Pathology description
Microscopically, the biopsy demonstrates patchy intraluminal plugs composed of fibroblasts and myofibrobalsts embedded in loose connective tissue with mild chronic interstitial pneumonia.
Special stains were performed for microorganisms; which were negative.
Fig. 4bFig. 5 Chest tomography one month later.
CT Chest on month later shows interval improvement in the right lower lobe consolidations but more extensive ground glass in the left lower lobe with occasional subpleural cysts.
Fig. 5Fig. 6 Chest X-Ray two months after initiation of treatment with steroids.
Chest x-ray 2 months after treatment with corticosteroids. Bilateral lower zone infiltrates have nearly completely resolved.
Fig. 6
3 Discussion
Organizing pneumonia is an uncommon subtype of interstitial lung disease. Organizing pneumonia can be classified as secondary due to medications or connective tissue disease or cryptogenic without an obvious etiology. Patients usually present with several weeks of constitutional symptoms and can mimic community-acquired pneumonia with fleeting pulmonary infiltrates. Not uncommonly, patients receive multiple rounds of antibiotics for bacterial pneumonias. Oral corticosteroids are the backbone treatment for organizing pneumonia, but other immunosuppressive medications have been used along with macrolides [13,14]. Here, we present a case of biopsy-proved everolimus-induced organizing pneumonia in a patient with tuberous sclerosis.
The benefit of use of Everolimus in tuberous sclerosis patients for the treatment of renal cell angiomyolipomas was first widely recognized with the publication of the EXIST-2 trial in 2013 [1], the first randomized, placebo-controlled, phase 3 study to assess everolimus efficacy and safety in patients with TS-associated renal angiomyolipoma. There have been numerous case reports and clinical trials documenting noninfectious pneumonitis and organizing pneumonia as a side effect of everolimus in use for treatment of a variety of conditions including renal cell carcinoma [2,5], Waldenstrom Macroglobulinemia [3], renal transplant [4,6], and insulinoma [10]. However, our study is one of few to document biopsy-proven organizing pneumonia as a side effect of everolimus in a tuberous sclerosis patient. One case report published in 2015 documented similar findings in a patient with concurrent pulmonary lymphangioleiomyomatosis and stage 3 CKD, proposing these comorbidities as a potential increased risk for everolimus-induced pulmonary toxicity [8]. Our patient similarly demonstrated stage 2 CKD at time if onset but had no underlying pulmonary disease. Additionally, a unique feature of our patient's presentation was the fact that everolimus had been initiated 10 years prior. In the aforementioned case study, patient symptoms occurred 6 months after initiation of the medications. Clinical trials have documented median time of onset as 108 days [2], 5.7 months [3], 162 days [6], and case reports range from 4 weeks [7] to 15 months [5]. However, we were unable to determine another potential trigger of patient's presentation with an extensive negative infectious workup and no improvement on antimicrobial therapy. Our patient did demonstrate marked improvement however with discontinuation of everolimus and initiation of steroids. We therefore recommend that, when developing a differential diagnosis for organizing pneumonia, providers seriously consider the administration of everolimus as a potential cause, regardless of treatment timeline.
4 Conclusion
Everolimus is a mTOR inhibitor used in the treatment of both renal cell carcinoma and tuberous sclerosis. Rarely, it can cause organizing pneumonia which can be treated with discontinuation of the medication and oral corticosteroids.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33598397 | 19,015,144 | 2021 |
What was the dosage of drug 'AZITHROMYCIN ANHYDROUS'? | Everolimus induced organizing pneumonia in a patient with tuberous sclerosis complex.
Organizing pneumonia is characterized by a distinct histologic pattern in the lung interstitium and presents clinically as hypoxemia, fever, cough, and dyspnea that is not attributable to concurrent infection. Typical etiologies of this condition include inflammatory disease, malignancy, toxic inhalation, and an array of medications including the mTOR inhibitor everolimus. In this report, we describe the case of a female with tuberous sclerosis complex on everolimus therapy for renal angiomyolipomas who presented to the hospital with persistent cough, dyspnea, and fevers and bilateral lower lobe opacities on chest X-ray despite multiple courses of antibiotic therapy. Bronchoscopy was performed with transbronchial biopsies, and results demonstrated a lymphocytic predominance and pathologic findings of intraluminal plugs composed of fibroblasts and myofibroblasts consistent with organizing pneumonia. Everolimus therapy was discontinued and patient completed a steroid course with resolution of symptoms. To our knowledge, this is the first published case of organizing pneumonia secondary to everolimus in a patient with tuberous sclerosis complex.
1 Introduction
Everolimus is a an orally available mammalian target of rapamycin (mTOR) inhibitor that belongs to the group of proliferation signal inhibitors, which also includes sirolimus and temsirolimus. These compounds have antiproliferative and antifibrotic properties [9]. Because of these properties they are typically used in the treatment of various malignancies and in patients with solid organ transplantation [8]. Both everolimus and sirolimus are known to induce pulmonary toxicity, such as interstitial pneumonia and organizing pneumonia [5].
Organizing pneumonia due to everolimus is an uncommon presentation of drug-induced interstitial lung disease that compromises the distal bronchioles, respiratory bronchioles and alveoli, specifically the alveolar wall. This condition is defined histopathologically by intra-alveolar buds of granulation tissue, consisting of intermixed myofibroblasts and connective tissue [11]. High resolution computed tomography often reveals patchy air-space consolidation, ground-glass opacities, small nodular opacities, and bronchial wall thickening with dilation [12].
In this case, we present a case of a female with tuberous sclerosis complex with symptomatic renal angiomyolipomas that developed organizing pneumonia secondary to everolimus.
2 Case report
46-year-old female with history of tuberous sclerosis complex with renal angiomyolipomas (Fig. 1) and stage II CKD that presented with one month of cough, dyspnea, and intermittent fevers. She was admitted one week prior for community-acquired pneumonia having already received a 10-day course of amoxicillin/clavulanate without improvement. During the second admission, the patient was treated with doxycycline and Azithromycin, transitioned to cefdinir at discharge.Fig. 1 Tomography of the abdomen.
Bilateral lobular kidneys with multiple fat-containing lesions consistent with renal angiomyolipomas commonly seen in tuberous sclerosis complex.
Fig. 1
Everolimus was started ten years prior to admission due to enlarging renal angiomyolipomas and patient had previously been stable on this therapy. On presentation, the patient was afebrile, tachypneic, and hypoxemic requiring 4 L nasal cannula to maintain oxygen saturation above 90%. Physical exam was notable for diminished bilateral lower breath sounds without wheezes. Laboratory studies included a white blood cell count of 10,300, platelets 608,000, C-reactive protein of 13.1 mg/dL, and procalcitonin of 0.53 mg/dL. Urinary streptococcal and legionella antigens were negative. Chest X-ray (Fig. 2) showed bilateral lower lobe airspace disease. CT Chest (Fig. 3a, Fig. 3b) showed bilateral multifocal pulmonary infiltrates and ground-glass opacities (GGO) predominantly perihilar and lower lobe in location on the right, with extensive involvement of the left upper and lower lung zones. She received fluid resuscitation along with IV vancomycin and cefepime. Her hypoxemia failed to improve with appropriate antibiotics and bronchoscopy was performed. Bronchoalveolar lavage of the right middle lobe, endobronchial biopsies of the right upper lobe, and transbronchial biopsies of the right lower lobe were performed. Bronchoalveolar lavage showed 678,000 WBC with 26% lymphocytes, 12% neutrophils, and 60% macrophages. Cultures from all the different specimens did not show any organisms. Transbronchial biopsies (Fig. 4a, Fig. 4b) demonstrated “patchy intraluminal plugs composed of fibroblasts and myofibroblasts embedded in loose connective tissue with mild chronic interstitial pneumonia” consistent with organizing pneumonia. Given these findings on transbronchial biopsies, a combined decision between pulmonary and urology was made to stop everolimus. She was started on oral prednisone at 0.75 mg/kg of ideal body weight and antibiotics were discontinued. The patient was discharged home on 2 L of oxygen and steroids. She was seen in Pulmonary clinic one month later and her hypoxemia has resolved. The patient was symptomatically back to baseline. Follow-up CT chest (Fig. 5) one month later showed improvement of the bilateral infiltrates. Chest x-ray Chest tomography one month later.CT Chest on month later shows interval improvement in the right lower lobe consolidations but more extensive ground glass in the left lower lobe with occasional subpleural cysts.(Fig. 6) two month after initiation of therapy showed resolution of the infiltrates. Steroids were weaned over the course of several months and the patient returned to her baseline functional status.Fig. 2 Initial chest X-ray.
AP View chest x-ray showing bibasilar centrally located infiltrates, more prominent on the left.
Fig. 2Fig. 3a Initial chest tomography.
CT Chest demonstrating bilateral airspace disease with varying distributions. The consolidations are more bronchocentric in the right middle lobe with diffuse consolidation with some intervening ground glass in the right lower lobe. Infiltrates in the left lower lobe are more peripheral and subpleural in distribution.
Fig. 3aFig. 3b Initial chest tomography.
Coronal image of CT Chest showing both central and peripheral consolidations with surrounding ground glass infiltrates.
Fig. 3bFig. 4a Pathology.
Fig. 4aFig. 4b Pathology.
Pathology description
Microscopically, the biopsy demonstrates patchy intraluminal plugs composed of fibroblasts and myofibrobalsts embedded in loose connective tissue with mild chronic interstitial pneumonia.
Special stains were performed for microorganisms; which were negative.
Fig. 4bFig. 5 Chest tomography one month later.
CT Chest on month later shows interval improvement in the right lower lobe consolidations but more extensive ground glass in the left lower lobe with occasional subpleural cysts.
Fig. 5Fig. 6 Chest X-Ray two months after initiation of treatment with steroids.
Chest x-ray 2 months after treatment with corticosteroids. Bilateral lower zone infiltrates have nearly completely resolved.
Fig. 6
3 Discussion
Organizing pneumonia is an uncommon subtype of interstitial lung disease. Organizing pneumonia can be classified as secondary due to medications or connective tissue disease or cryptogenic without an obvious etiology. Patients usually present with several weeks of constitutional symptoms and can mimic community-acquired pneumonia with fleeting pulmonary infiltrates. Not uncommonly, patients receive multiple rounds of antibiotics for bacterial pneumonias. Oral corticosteroids are the backbone treatment for organizing pneumonia, but other immunosuppressive medications have been used along with macrolides [13,14]. Here, we present a case of biopsy-proved everolimus-induced organizing pneumonia in a patient with tuberous sclerosis.
The benefit of use of Everolimus in tuberous sclerosis patients for the treatment of renal cell angiomyolipomas was first widely recognized with the publication of the EXIST-2 trial in 2013 [1], the first randomized, placebo-controlled, phase 3 study to assess everolimus efficacy and safety in patients with TS-associated renal angiomyolipoma. There have been numerous case reports and clinical trials documenting noninfectious pneumonitis and organizing pneumonia as a side effect of everolimus in use for treatment of a variety of conditions including renal cell carcinoma [2,5], Waldenstrom Macroglobulinemia [3], renal transplant [4,6], and insulinoma [10]. However, our study is one of few to document biopsy-proven organizing pneumonia as a side effect of everolimus in a tuberous sclerosis patient. One case report published in 2015 documented similar findings in a patient with concurrent pulmonary lymphangioleiomyomatosis and stage 3 CKD, proposing these comorbidities as a potential increased risk for everolimus-induced pulmonary toxicity [8]. Our patient similarly demonstrated stage 2 CKD at time if onset but had no underlying pulmonary disease. Additionally, a unique feature of our patient's presentation was the fact that everolimus had been initiated 10 years prior. In the aforementioned case study, patient symptoms occurred 6 months after initiation of the medications. Clinical trials have documented median time of onset as 108 days [2], 5.7 months [3], 162 days [6], and case reports range from 4 weeks [7] to 15 months [5]. However, we were unable to determine another potential trigger of patient's presentation with an extensive negative infectious workup and no improvement on antimicrobial therapy. Our patient did demonstrate marked improvement however with discontinuation of everolimus and initiation of steroids. We therefore recommend that, when developing a differential diagnosis for organizing pneumonia, providers seriously consider the administration of everolimus as a potential cause, regardless of treatment timeline.
4 Conclusion
Everolimus is a mTOR inhibitor used in the treatment of both renal cell carcinoma and tuberous sclerosis. Rarely, it can cause organizing pneumonia which can be treated with discontinuation of the medication and oral corticosteroids.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33598397 | 19,015,144 | 2021 |
What was the dosage of drug 'DOXYCYCLINE'? | Everolimus induced organizing pneumonia in a patient with tuberous sclerosis complex.
Organizing pneumonia is characterized by a distinct histologic pattern in the lung interstitium and presents clinically as hypoxemia, fever, cough, and dyspnea that is not attributable to concurrent infection. Typical etiologies of this condition include inflammatory disease, malignancy, toxic inhalation, and an array of medications including the mTOR inhibitor everolimus. In this report, we describe the case of a female with tuberous sclerosis complex on everolimus therapy for renal angiomyolipomas who presented to the hospital with persistent cough, dyspnea, and fevers and bilateral lower lobe opacities on chest X-ray despite multiple courses of antibiotic therapy. Bronchoscopy was performed with transbronchial biopsies, and results demonstrated a lymphocytic predominance and pathologic findings of intraluminal plugs composed of fibroblasts and myofibroblasts consistent with organizing pneumonia. Everolimus therapy was discontinued and patient completed a steroid course with resolution of symptoms. To our knowledge, this is the first published case of organizing pneumonia secondary to everolimus in a patient with tuberous sclerosis complex.
1 Introduction
Everolimus is a an orally available mammalian target of rapamycin (mTOR) inhibitor that belongs to the group of proliferation signal inhibitors, which also includes sirolimus and temsirolimus. These compounds have antiproliferative and antifibrotic properties [9]. Because of these properties they are typically used in the treatment of various malignancies and in patients with solid organ transplantation [8]. Both everolimus and sirolimus are known to induce pulmonary toxicity, such as interstitial pneumonia and organizing pneumonia [5].
Organizing pneumonia due to everolimus is an uncommon presentation of drug-induced interstitial lung disease that compromises the distal bronchioles, respiratory bronchioles and alveoli, specifically the alveolar wall. This condition is defined histopathologically by intra-alveolar buds of granulation tissue, consisting of intermixed myofibroblasts and connective tissue [11]. High resolution computed tomography often reveals patchy air-space consolidation, ground-glass opacities, small nodular opacities, and bronchial wall thickening with dilation [12].
In this case, we present a case of a female with tuberous sclerosis complex with symptomatic renal angiomyolipomas that developed organizing pneumonia secondary to everolimus.
2 Case report
46-year-old female with history of tuberous sclerosis complex with renal angiomyolipomas (Fig. 1) and stage II CKD that presented with one month of cough, dyspnea, and intermittent fevers. She was admitted one week prior for community-acquired pneumonia having already received a 10-day course of amoxicillin/clavulanate without improvement. During the second admission, the patient was treated with doxycycline and Azithromycin, transitioned to cefdinir at discharge.Fig. 1 Tomography of the abdomen.
Bilateral lobular kidneys with multiple fat-containing lesions consistent with renal angiomyolipomas commonly seen in tuberous sclerosis complex.
Fig. 1
Everolimus was started ten years prior to admission due to enlarging renal angiomyolipomas and patient had previously been stable on this therapy. On presentation, the patient was afebrile, tachypneic, and hypoxemic requiring 4 L nasal cannula to maintain oxygen saturation above 90%. Physical exam was notable for diminished bilateral lower breath sounds without wheezes. Laboratory studies included a white blood cell count of 10,300, platelets 608,000, C-reactive protein of 13.1 mg/dL, and procalcitonin of 0.53 mg/dL. Urinary streptococcal and legionella antigens were negative. Chest X-ray (Fig. 2) showed bilateral lower lobe airspace disease. CT Chest (Fig. 3a, Fig. 3b) showed bilateral multifocal pulmonary infiltrates and ground-glass opacities (GGO) predominantly perihilar and lower lobe in location on the right, with extensive involvement of the left upper and lower lung zones. She received fluid resuscitation along with IV vancomycin and cefepime. Her hypoxemia failed to improve with appropriate antibiotics and bronchoscopy was performed. Bronchoalveolar lavage of the right middle lobe, endobronchial biopsies of the right upper lobe, and transbronchial biopsies of the right lower lobe were performed. Bronchoalveolar lavage showed 678,000 WBC with 26% lymphocytes, 12% neutrophils, and 60% macrophages. Cultures from all the different specimens did not show any organisms. Transbronchial biopsies (Fig. 4a, Fig. 4b) demonstrated “patchy intraluminal plugs composed of fibroblasts and myofibroblasts embedded in loose connective tissue with mild chronic interstitial pneumonia” consistent with organizing pneumonia. Given these findings on transbronchial biopsies, a combined decision between pulmonary and urology was made to stop everolimus. She was started on oral prednisone at 0.75 mg/kg of ideal body weight and antibiotics were discontinued. The patient was discharged home on 2 L of oxygen and steroids. She was seen in Pulmonary clinic one month later and her hypoxemia has resolved. The patient was symptomatically back to baseline. Follow-up CT chest (Fig. 5) one month later showed improvement of the bilateral infiltrates. Chest x-ray Chest tomography one month later.CT Chest on month later shows interval improvement in the right lower lobe consolidations but more extensive ground glass in the left lower lobe with occasional subpleural cysts.(Fig. 6) two month after initiation of therapy showed resolution of the infiltrates. Steroids were weaned over the course of several months and the patient returned to her baseline functional status.Fig. 2 Initial chest X-ray.
AP View chest x-ray showing bibasilar centrally located infiltrates, more prominent on the left.
Fig. 2Fig. 3a Initial chest tomography.
CT Chest demonstrating bilateral airspace disease with varying distributions. The consolidations are more bronchocentric in the right middle lobe with diffuse consolidation with some intervening ground glass in the right lower lobe. Infiltrates in the left lower lobe are more peripheral and subpleural in distribution.
Fig. 3aFig. 3b Initial chest tomography.
Coronal image of CT Chest showing both central and peripheral consolidations with surrounding ground glass infiltrates.
Fig. 3bFig. 4a Pathology.
Fig. 4aFig. 4b Pathology.
Pathology description
Microscopically, the biopsy demonstrates patchy intraluminal plugs composed of fibroblasts and myofibrobalsts embedded in loose connective tissue with mild chronic interstitial pneumonia.
Special stains were performed for microorganisms; which were negative.
Fig. 4bFig. 5 Chest tomography one month later.
CT Chest on month later shows interval improvement in the right lower lobe consolidations but more extensive ground glass in the left lower lobe with occasional subpleural cysts.
Fig. 5Fig. 6 Chest X-Ray two months after initiation of treatment with steroids.
Chest x-ray 2 months after treatment with corticosteroids. Bilateral lower zone infiltrates have nearly completely resolved.
Fig. 6
3 Discussion
Organizing pneumonia is an uncommon subtype of interstitial lung disease. Organizing pneumonia can be classified as secondary due to medications or connective tissue disease or cryptogenic without an obvious etiology. Patients usually present with several weeks of constitutional symptoms and can mimic community-acquired pneumonia with fleeting pulmonary infiltrates. Not uncommonly, patients receive multiple rounds of antibiotics for bacterial pneumonias. Oral corticosteroids are the backbone treatment for organizing pneumonia, but other immunosuppressive medications have been used along with macrolides [13,14]. Here, we present a case of biopsy-proved everolimus-induced organizing pneumonia in a patient with tuberous sclerosis.
The benefit of use of Everolimus in tuberous sclerosis patients for the treatment of renal cell angiomyolipomas was first widely recognized with the publication of the EXIST-2 trial in 2013 [1], the first randomized, placebo-controlled, phase 3 study to assess everolimus efficacy and safety in patients with TS-associated renal angiomyolipoma. There have been numerous case reports and clinical trials documenting noninfectious pneumonitis and organizing pneumonia as a side effect of everolimus in use for treatment of a variety of conditions including renal cell carcinoma [2,5], Waldenstrom Macroglobulinemia [3], renal transplant [4,6], and insulinoma [10]. However, our study is one of few to document biopsy-proven organizing pneumonia as a side effect of everolimus in a tuberous sclerosis patient. One case report published in 2015 documented similar findings in a patient with concurrent pulmonary lymphangioleiomyomatosis and stage 3 CKD, proposing these comorbidities as a potential increased risk for everolimus-induced pulmonary toxicity [8]. Our patient similarly demonstrated stage 2 CKD at time if onset but had no underlying pulmonary disease. Additionally, a unique feature of our patient's presentation was the fact that everolimus had been initiated 10 years prior. In the aforementioned case study, patient symptoms occurred 6 months after initiation of the medications. Clinical trials have documented median time of onset as 108 days [2], 5.7 months [3], 162 days [6], and case reports range from 4 weeks [7] to 15 months [5]. However, we were unable to determine another potential trigger of patient's presentation with an extensive negative infectious workup and no improvement on antimicrobial therapy. Our patient did demonstrate marked improvement however with discontinuation of everolimus and initiation of steroids. We therefore recommend that, when developing a differential diagnosis for organizing pneumonia, providers seriously consider the administration of everolimus as a potential cause, regardless of treatment timeline.
4 Conclusion
Everolimus is a mTOR inhibitor used in the treatment of both renal cell carcinoma and tuberous sclerosis. Rarely, it can cause organizing pneumonia which can be treated with discontinuation of the medication and oral corticosteroids.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33598397 | 19,015,144 | 2021 |
What was the outcome of reaction 'Hypoxia'? | Everolimus induced organizing pneumonia in a patient with tuberous sclerosis complex.
Organizing pneumonia is characterized by a distinct histologic pattern in the lung interstitium and presents clinically as hypoxemia, fever, cough, and dyspnea that is not attributable to concurrent infection. Typical etiologies of this condition include inflammatory disease, malignancy, toxic inhalation, and an array of medications including the mTOR inhibitor everolimus. In this report, we describe the case of a female with tuberous sclerosis complex on everolimus therapy for renal angiomyolipomas who presented to the hospital with persistent cough, dyspnea, and fevers and bilateral lower lobe opacities on chest X-ray despite multiple courses of antibiotic therapy. Bronchoscopy was performed with transbronchial biopsies, and results demonstrated a lymphocytic predominance and pathologic findings of intraluminal plugs composed of fibroblasts and myofibroblasts consistent with organizing pneumonia. Everolimus therapy was discontinued and patient completed a steroid course with resolution of symptoms. To our knowledge, this is the first published case of organizing pneumonia secondary to everolimus in a patient with tuberous sclerosis complex.
1 Introduction
Everolimus is a an orally available mammalian target of rapamycin (mTOR) inhibitor that belongs to the group of proliferation signal inhibitors, which also includes sirolimus and temsirolimus. These compounds have antiproliferative and antifibrotic properties [9]. Because of these properties they are typically used in the treatment of various malignancies and in patients with solid organ transplantation [8]. Both everolimus and sirolimus are known to induce pulmonary toxicity, such as interstitial pneumonia and organizing pneumonia [5].
Organizing pneumonia due to everolimus is an uncommon presentation of drug-induced interstitial lung disease that compromises the distal bronchioles, respiratory bronchioles and alveoli, specifically the alveolar wall. This condition is defined histopathologically by intra-alveolar buds of granulation tissue, consisting of intermixed myofibroblasts and connective tissue [11]. High resolution computed tomography often reveals patchy air-space consolidation, ground-glass opacities, small nodular opacities, and bronchial wall thickening with dilation [12].
In this case, we present a case of a female with tuberous sclerosis complex with symptomatic renal angiomyolipomas that developed organizing pneumonia secondary to everolimus.
2 Case report
46-year-old female with history of tuberous sclerosis complex with renal angiomyolipomas (Fig. 1) and stage II CKD that presented with one month of cough, dyspnea, and intermittent fevers. She was admitted one week prior for community-acquired pneumonia having already received a 10-day course of amoxicillin/clavulanate without improvement. During the second admission, the patient was treated with doxycycline and Azithromycin, transitioned to cefdinir at discharge.Fig. 1 Tomography of the abdomen.
Bilateral lobular kidneys with multiple fat-containing lesions consistent with renal angiomyolipomas commonly seen in tuberous sclerosis complex.
Fig. 1
Everolimus was started ten years prior to admission due to enlarging renal angiomyolipomas and patient had previously been stable on this therapy. On presentation, the patient was afebrile, tachypneic, and hypoxemic requiring 4 L nasal cannula to maintain oxygen saturation above 90%. Physical exam was notable for diminished bilateral lower breath sounds without wheezes. Laboratory studies included a white blood cell count of 10,300, platelets 608,000, C-reactive protein of 13.1 mg/dL, and procalcitonin of 0.53 mg/dL. Urinary streptococcal and legionella antigens were negative. Chest X-ray (Fig. 2) showed bilateral lower lobe airspace disease. CT Chest (Fig. 3a, Fig. 3b) showed bilateral multifocal pulmonary infiltrates and ground-glass opacities (GGO) predominantly perihilar and lower lobe in location on the right, with extensive involvement of the left upper and lower lung zones. She received fluid resuscitation along with IV vancomycin and cefepime. Her hypoxemia failed to improve with appropriate antibiotics and bronchoscopy was performed. Bronchoalveolar lavage of the right middle lobe, endobronchial biopsies of the right upper lobe, and transbronchial biopsies of the right lower lobe were performed. Bronchoalveolar lavage showed 678,000 WBC with 26% lymphocytes, 12% neutrophils, and 60% macrophages. Cultures from all the different specimens did not show any organisms. Transbronchial biopsies (Fig. 4a, Fig. 4b) demonstrated “patchy intraluminal plugs composed of fibroblasts and myofibroblasts embedded in loose connective tissue with mild chronic interstitial pneumonia” consistent with organizing pneumonia. Given these findings on transbronchial biopsies, a combined decision between pulmonary and urology was made to stop everolimus. She was started on oral prednisone at 0.75 mg/kg of ideal body weight and antibiotics were discontinued. The patient was discharged home on 2 L of oxygen and steroids. She was seen in Pulmonary clinic one month later and her hypoxemia has resolved. The patient was symptomatically back to baseline. Follow-up CT chest (Fig. 5) one month later showed improvement of the bilateral infiltrates. Chest x-ray Chest tomography one month later.CT Chest on month later shows interval improvement in the right lower lobe consolidations but more extensive ground glass in the left lower lobe with occasional subpleural cysts.(Fig. 6) two month after initiation of therapy showed resolution of the infiltrates. Steroids were weaned over the course of several months and the patient returned to her baseline functional status.Fig. 2 Initial chest X-ray.
AP View chest x-ray showing bibasilar centrally located infiltrates, more prominent on the left.
Fig. 2Fig. 3a Initial chest tomography.
CT Chest demonstrating bilateral airspace disease with varying distributions. The consolidations are more bronchocentric in the right middle lobe with diffuse consolidation with some intervening ground glass in the right lower lobe. Infiltrates in the left lower lobe are more peripheral and subpleural in distribution.
Fig. 3aFig. 3b Initial chest tomography.
Coronal image of CT Chest showing both central and peripheral consolidations with surrounding ground glass infiltrates.
Fig. 3bFig. 4a Pathology.
Fig. 4aFig. 4b Pathology.
Pathology description
Microscopically, the biopsy demonstrates patchy intraluminal plugs composed of fibroblasts and myofibrobalsts embedded in loose connective tissue with mild chronic interstitial pneumonia.
Special stains were performed for microorganisms; which were negative.
Fig. 4bFig. 5 Chest tomography one month later.
CT Chest on month later shows interval improvement in the right lower lobe consolidations but more extensive ground glass in the left lower lobe with occasional subpleural cysts.
Fig. 5Fig. 6 Chest X-Ray two months after initiation of treatment with steroids.
Chest x-ray 2 months after treatment with corticosteroids. Bilateral lower zone infiltrates have nearly completely resolved.
Fig. 6
3 Discussion
Organizing pneumonia is an uncommon subtype of interstitial lung disease. Organizing pneumonia can be classified as secondary due to medications or connective tissue disease or cryptogenic without an obvious etiology. Patients usually present with several weeks of constitutional symptoms and can mimic community-acquired pneumonia with fleeting pulmonary infiltrates. Not uncommonly, patients receive multiple rounds of antibiotics for bacterial pneumonias. Oral corticosteroids are the backbone treatment for organizing pneumonia, but other immunosuppressive medications have been used along with macrolides [13,14]. Here, we present a case of biopsy-proved everolimus-induced organizing pneumonia in a patient with tuberous sclerosis.
The benefit of use of Everolimus in tuberous sclerosis patients for the treatment of renal cell angiomyolipomas was first widely recognized with the publication of the EXIST-2 trial in 2013 [1], the first randomized, placebo-controlled, phase 3 study to assess everolimus efficacy and safety in patients with TS-associated renal angiomyolipoma. There have been numerous case reports and clinical trials documenting noninfectious pneumonitis and organizing pneumonia as a side effect of everolimus in use for treatment of a variety of conditions including renal cell carcinoma [2,5], Waldenstrom Macroglobulinemia [3], renal transplant [4,6], and insulinoma [10]. However, our study is one of few to document biopsy-proven organizing pneumonia as a side effect of everolimus in a tuberous sclerosis patient. One case report published in 2015 documented similar findings in a patient with concurrent pulmonary lymphangioleiomyomatosis and stage 3 CKD, proposing these comorbidities as a potential increased risk for everolimus-induced pulmonary toxicity [8]. Our patient similarly demonstrated stage 2 CKD at time if onset but had no underlying pulmonary disease. Additionally, a unique feature of our patient's presentation was the fact that everolimus had been initiated 10 years prior. In the aforementioned case study, patient symptoms occurred 6 months after initiation of the medications. Clinical trials have documented median time of onset as 108 days [2], 5.7 months [3], 162 days [6], and case reports range from 4 weeks [7] to 15 months [5]. However, we were unable to determine another potential trigger of patient's presentation with an extensive negative infectious workup and no improvement on antimicrobial therapy. Our patient did demonstrate marked improvement however with discontinuation of everolimus and initiation of steroids. We therefore recommend that, when developing a differential diagnosis for organizing pneumonia, providers seriously consider the administration of everolimus as a potential cause, regardless of treatment timeline.
4 Conclusion
Everolimus is a mTOR inhibitor used in the treatment of both renal cell carcinoma and tuberous sclerosis. Rarely, it can cause organizing pneumonia which can be treated with discontinuation of the medication and oral corticosteroids.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | Recovered | ReactionOutcome | CC BY-NC-ND | 33598397 | 19,548,885 | 2021 |
What was the outcome of reaction 'Organising pneumonia'? | Everolimus induced organizing pneumonia in a patient with tuberous sclerosis complex.
Organizing pneumonia is characterized by a distinct histologic pattern in the lung interstitium and presents clinically as hypoxemia, fever, cough, and dyspnea that is not attributable to concurrent infection. Typical etiologies of this condition include inflammatory disease, malignancy, toxic inhalation, and an array of medications including the mTOR inhibitor everolimus. In this report, we describe the case of a female with tuberous sclerosis complex on everolimus therapy for renal angiomyolipomas who presented to the hospital with persistent cough, dyspnea, and fevers and bilateral lower lobe opacities on chest X-ray despite multiple courses of antibiotic therapy. Bronchoscopy was performed with transbronchial biopsies, and results demonstrated a lymphocytic predominance and pathologic findings of intraluminal plugs composed of fibroblasts and myofibroblasts consistent with organizing pneumonia. Everolimus therapy was discontinued and patient completed a steroid course with resolution of symptoms. To our knowledge, this is the first published case of organizing pneumonia secondary to everolimus in a patient with tuberous sclerosis complex.
1 Introduction
Everolimus is a an orally available mammalian target of rapamycin (mTOR) inhibitor that belongs to the group of proliferation signal inhibitors, which also includes sirolimus and temsirolimus. These compounds have antiproliferative and antifibrotic properties [9]. Because of these properties they are typically used in the treatment of various malignancies and in patients with solid organ transplantation [8]. Both everolimus and sirolimus are known to induce pulmonary toxicity, such as interstitial pneumonia and organizing pneumonia [5].
Organizing pneumonia due to everolimus is an uncommon presentation of drug-induced interstitial lung disease that compromises the distal bronchioles, respiratory bronchioles and alveoli, specifically the alveolar wall. This condition is defined histopathologically by intra-alveolar buds of granulation tissue, consisting of intermixed myofibroblasts and connective tissue [11]. High resolution computed tomography often reveals patchy air-space consolidation, ground-glass opacities, small nodular opacities, and bronchial wall thickening with dilation [12].
In this case, we present a case of a female with tuberous sclerosis complex with symptomatic renal angiomyolipomas that developed organizing pneumonia secondary to everolimus.
2 Case report
46-year-old female with history of tuberous sclerosis complex with renal angiomyolipomas (Fig. 1) and stage II CKD that presented with one month of cough, dyspnea, and intermittent fevers. She was admitted one week prior for community-acquired pneumonia having already received a 10-day course of amoxicillin/clavulanate without improvement. During the second admission, the patient was treated with doxycycline and Azithromycin, transitioned to cefdinir at discharge.Fig. 1 Tomography of the abdomen.
Bilateral lobular kidneys with multiple fat-containing lesions consistent with renal angiomyolipomas commonly seen in tuberous sclerosis complex.
Fig. 1
Everolimus was started ten years prior to admission due to enlarging renal angiomyolipomas and patient had previously been stable on this therapy. On presentation, the patient was afebrile, tachypneic, and hypoxemic requiring 4 L nasal cannula to maintain oxygen saturation above 90%. Physical exam was notable for diminished bilateral lower breath sounds without wheezes. Laboratory studies included a white blood cell count of 10,300, platelets 608,000, C-reactive protein of 13.1 mg/dL, and procalcitonin of 0.53 mg/dL. Urinary streptococcal and legionella antigens were negative. Chest X-ray (Fig. 2) showed bilateral lower lobe airspace disease. CT Chest (Fig. 3a, Fig. 3b) showed bilateral multifocal pulmonary infiltrates and ground-glass opacities (GGO) predominantly perihilar and lower lobe in location on the right, with extensive involvement of the left upper and lower lung zones. She received fluid resuscitation along with IV vancomycin and cefepime. Her hypoxemia failed to improve with appropriate antibiotics and bronchoscopy was performed. Bronchoalveolar lavage of the right middle lobe, endobronchial biopsies of the right upper lobe, and transbronchial biopsies of the right lower lobe were performed. Bronchoalveolar lavage showed 678,000 WBC with 26% lymphocytes, 12% neutrophils, and 60% macrophages. Cultures from all the different specimens did not show any organisms. Transbronchial biopsies (Fig. 4a, Fig. 4b) demonstrated “patchy intraluminal plugs composed of fibroblasts and myofibroblasts embedded in loose connective tissue with mild chronic interstitial pneumonia” consistent with organizing pneumonia. Given these findings on transbronchial biopsies, a combined decision between pulmonary and urology was made to stop everolimus. She was started on oral prednisone at 0.75 mg/kg of ideal body weight and antibiotics were discontinued. The patient was discharged home on 2 L of oxygen and steroids. She was seen in Pulmonary clinic one month later and her hypoxemia has resolved. The patient was symptomatically back to baseline. Follow-up CT chest (Fig. 5) one month later showed improvement of the bilateral infiltrates. Chest x-ray Chest tomography one month later.CT Chest on month later shows interval improvement in the right lower lobe consolidations but more extensive ground glass in the left lower lobe with occasional subpleural cysts.(Fig. 6) two month after initiation of therapy showed resolution of the infiltrates. Steroids were weaned over the course of several months and the patient returned to her baseline functional status.Fig. 2 Initial chest X-ray.
AP View chest x-ray showing bibasilar centrally located infiltrates, more prominent on the left.
Fig. 2Fig. 3a Initial chest tomography.
CT Chest demonstrating bilateral airspace disease with varying distributions. The consolidations are more bronchocentric in the right middle lobe with diffuse consolidation with some intervening ground glass in the right lower lobe. Infiltrates in the left lower lobe are more peripheral and subpleural in distribution.
Fig. 3aFig. 3b Initial chest tomography.
Coronal image of CT Chest showing both central and peripheral consolidations with surrounding ground glass infiltrates.
Fig. 3bFig. 4a Pathology.
Fig. 4aFig. 4b Pathology.
Pathology description
Microscopically, the biopsy demonstrates patchy intraluminal plugs composed of fibroblasts and myofibrobalsts embedded in loose connective tissue with mild chronic interstitial pneumonia.
Special stains were performed for microorganisms; which were negative.
Fig. 4bFig. 5 Chest tomography one month later.
CT Chest on month later shows interval improvement in the right lower lobe consolidations but more extensive ground glass in the left lower lobe with occasional subpleural cysts.
Fig. 5Fig. 6 Chest X-Ray two months after initiation of treatment with steroids.
Chest x-ray 2 months after treatment with corticosteroids. Bilateral lower zone infiltrates have nearly completely resolved.
Fig. 6
3 Discussion
Organizing pneumonia is an uncommon subtype of interstitial lung disease. Organizing pneumonia can be classified as secondary due to medications or connective tissue disease or cryptogenic without an obvious etiology. Patients usually present with several weeks of constitutional symptoms and can mimic community-acquired pneumonia with fleeting pulmonary infiltrates. Not uncommonly, patients receive multiple rounds of antibiotics for bacterial pneumonias. Oral corticosteroids are the backbone treatment for organizing pneumonia, but other immunosuppressive medications have been used along with macrolides [13,14]. Here, we present a case of biopsy-proved everolimus-induced organizing pneumonia in a patient with tuberous sclerosis.
The benefit of use of Everolimus in tuberous sclerosis patients for the treatment of renal cell angiomyolipomas was first widely recognized with the publication of the EXIST-2 trial in 2013 [1], the first randomized, placebo-controlled, phase 3 study to assess everolimus efficacy and safety in patients with TS-associated renal angiomyolipoma. There have been numerous case reports and clinical trials documenting noninfectious pneumonitis and organizing pneumonia as a side effect of everolimus in use for treatment of a variety of conditions including renal cell carcinoma [2,5], Waldenstrom Macroglobulinemia [3], renal transplant [4,6], and insulinoma [10]. However, our study is one of few to document biopsy-proven organizing pneumonia as a side effect of everolimus in a tuberous sclerosis patient. One case report published in 2015 documented similar findings in a patient with concurrent pulmonary lymphangioleiomyomatosis and stage 3 CKD, proposing these comorbidities as a potential increased risk for everolimus-induced pulmonary toxicity [8]. Our patient similarly demonstrated stage 2 CKD at time if onset but had no underlying pulmonary disease. Additionally, a unique feature of our patient's presentation was the fact that everolimus had been initiated 10 years prior. In the aforementioned case study, patient symptoms occurred 6 months after initiation of the medications. Clinical trials have documented median time of onset as 108 days [2], 5.7 months [3], 162 days [6], and case reports range from 4 weeks [7] to 15 months [5]. However, we were unable to determine another potential trigger of patient's presentation with an extensive negative infectious workup and no improvement on antimicrobial therapy. Our patient did demonstrate marked improvement however with discontinuation of everolimus and initiation of steroids. We therefore recommend that, when developing a differential diagnosis for organizing pneumonia, providers seriously consider the administration of everolimus as a potential cause, regardless of treatment timeline.
4 Conclusion
Everolimus is a mTOR inhibitor used in the treatment of both renal cell carcinoma and tuberous sclerosis. Rarely, it can cause organizing pneumonia which can be treated with discontinuation of the medication and oral corticosteroids.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | Recovered | ReactionOutcome | CC BY-NC-ND | 33598397 | 19,015,144 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Secondary organizing pneumonia after coronavirus disease 2019: Two cases.
Coronavirus disease 2019 (COVID-19) has been reported to induce persistent symptoms even after an acute phase. However, the pathophysiology and treatment of this condition have been unclear. We report two patients who recovered from COVID-19, but presented persistent respiratory symptoms. Their respiratory conditions deteriorated, and computed tomography showed remaining ground glass opacities and consolidations. The pathological findings of transbronchial lung biopsy corresponded to organizing pneumonia. We diagnosed them with secondary organizing pneumonia after COVID-19. Subsequently, we administered systemic corticosteroids. Their symptoms, oxygenations, radiologic findings, and pulmonary functions rapidly improved after the treatment of corticosteroids. The two cases showed that secondary organizing pneumonia may be a cause of persistent respiratory failure after COVID-19. In this condition, corticosteroids may be effective.
Abbreviations
BALbronchoalveolar lavage
COVID-19coronavirus disease 2019
CRPC-reactive protein
CTcomputed tomography
DLCOdiffusing capacity of the lungs for carbon monoxide
GGOsground glass opacities
PCRpolymerase chain reaction
RNAribonucleic acid
SARS-CoV2severe acute respiratory syndrome coronavirus 2
SpO2percutaneous oxygen saturation
TBLBtransbronchial lung biopsy
1 Introduction
Coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), has spread worldwide and resulted in a pandemic [1]. The overall fatality rate of patients diagnosed with COVID-19 was reported to be 2.3% [2]. Even if patients with COVID-19 survived and were discharged, some of them experienced persistent symptoms [3]. Two months after the symptom onset, 66% and 30% of non-critical COVID-19 patients who needed admission experienced one or more symptoms and dyspnea, respectively [4]. With respect to objective findings, 52.6% of patients showed less than 80% of predicted values of diffusing capacity of the lungs for carbon monoxide (DLCO) 1 month after discharge [5]. Moreover, 47% of patients showed a persistent abnormality in computed tomography (CT) findings 3 weeks after discharge [6]. As to how long these dysfunctions persist remain unclear. Although many COVID-19 survivors suffered from a so-called “sequelae,” the pathophysiology of this condition and efficient treatments has not been established yet [7].
Secondary organizing pneumonia can develop after various infectious pneumonias, including viruses [8]. The typical clinical findings of organizing pneumonia include fever and elevation of inflammation reaction, consolidation and bilateral distribution in CT, restrictive ventilatory defect and dysfunction in diffusion capacity, and elevation of lymphocytes in bronchoalveolar lavage (BAL) fluid [8,9]. However, because these findings are not specific, a histopathological diagnosis is required [8].
Herein, we present two cases of secondary organizing pneumonia after COVID-19, in which corticosteroids had been effective.
2 Case reports
2.1 Case 1
A 56-year-old man with no remarkable medical history presented with a 7-day history of fever and body malaise and a 1-day history of cough and dyspnea. On admission, his body temperature, heart rate, blood pressure, respiratory rate, and percutaneous oxygen saturation (SpO2) on room air was 37.9 °C, 100 beats/min, 113/79 mmHg, 28 breaths/min, and 83%, respectively. He tested positive for polymerase chain reaction (PCR) of SARS-CoV2 ribonucleic acid (RNA) on his nasopharyngeal sample. Chest CT showed posterior ground glass opacities (GGOs) in both lungs (Fig. 1A). Laboratory blood tests exhibited an increase in the level of C-reactive protein (CRP) (11.55 mg/dL). Despite the initiation of favipiravir and dexamethasone, his SpO2 rapidly deteriorated to 88% with supplemental oxygen of 5 L/min within a day. We introduced invasive mechanical ventilation, and transferred him to another hospital exclusively for critical COVID-19 patients. He was extubated on illness day 13 because of respiratory condition improvement. Concurrently, favipiravir and dexamethasone were stopped. He tested negative for PCR of SARS-CoV2 RNA twice, on illness days 14 and 15, and returned to our hospital on illness day 16. However, upon re-hospitalization to our hospital, his respiratory failure persisted, and a nasal oxygen supplementation of 4 L/min was required to maintain a SpO2 of 97%. On illness day 26, he no longer had fever, and the serum CRP level declined to the normal range. However, he still needed a nasal oxygen supplementation of 3 L/min. Chest CT showed that GGOs remained and partially became consolidations in both lobes (Fig. 1B). We performed BAL and transbronchial lung biopsy (TBLB) on illness day 29. The BAL fluid from the left B4 (recovery rate 35%, 53/150 mL) showed a cell count of 9.6×105 cells/mL with 94% macrophages, 5% lymphocytes, and 1% neutrophils. The PCR of SARS-CoV2 RNA from the BAL fluid was negative. A microscopic examination of the TBLB from left B4 and B5 revealed intra-alveolar granulation, interstitial lymphocytes infiltration, and fibroblastic tissue proliferation in the interstitium (Fig. 2). Considering his clinical course and pathological findings, we diagnosed secondary organizing pneumonia after COVID-19. We initiated an oral administration of prednisolone 60 mg/day (1 mg/kg/day) on illness day 35. After, his respiratory condition rapidly improved, and maintained a SpO2 of 95% on room air on illness day 42. Furthermore, the CT on illness day 41 showed a remarkable improvement of consolidations (Fig. 1C). We decreased the prednisolone dose to 30 mg/day (0.5 mg/kg/day) on illness day 42. On illness day 56, he was discharged without oxygen supplementation. Spirometry on illness day 61 was within the normal range, and the DLCO was 82.8% of predicted values. We tapered the prednisolone dose to 15 mg/day on illness day 84 without recurrence.Fig. 1 Chest CT images of case 1 on illness day 7, on the first admission to our hospital (A), on illness day 26, before prednisolone introduction (B), and on illness day 41, 6 days after the introduction of prednisolone (C). Peripheral ground glass opacities in the bilateral posterior lobes progressed to consolidation, and improved after the treatment of prednisolone.
Fig. 1Fig. 2 Histopathological findings of TBLB in case 1 (hematoxylin and eosin stain; ×10). Arrow indicates an intra-alveolar granulation. There were interstitial lymphocyte infiltrations and fibroblastic tissue proliferation in the interstitium.
Fig. 2
2.2 Case 2
An 84-year-old woman with a medical history of hypertension, hypercholesterolemia and hypothyroidism presented with a 9-day history of body malaise. She did not complain of dyspnea. On admission, her body temperature, heart rate, blood pressure, respiratory rate, and SpO2 on room air was 36.7 °C, 78 beats/min, 148/87 mm Hg, 24 breaths/min, and 90%, respectively. She tested positive for the PCR of SARS-CoV2 RNA on her nasopharyngeal sample. Chest CT showed patchy GGOs dominantly in the periphery of the right lung lobe (Fig. 3A). Laboratory blood tests exhibited a slight increase in CRP (2.62 mg/dL). We initiated favipiravir and dexamethasone after the admission. She temporarily needed a nasal oxygen supplementation of 4 L/min on the next day of admission, but then, her symptom and oxygenation gradually improved. We discontinued dexamethasone and favipiravir on illness days 20 and 24, respectively. She tested negative for the PCR of SARS-CoV2 RNA twice, on illness days 30 and 31. However, she remained in the hospital because of persistent dyspnea. She did not present with fever, and the serum CRP level declined to the normal range on illness day 36. She did not need oxygen supplementation; however, her SpO2 decreased to less than 90% with just a 30-m-walk on illness day 43. In addition, the CT on illness days 23 and 43 showed the presence of GGOs and consolidations in both lungs (Fig. 3B and C). A pulmonary function test on illness day 44 also showed a reduced DLCO. We performed bronchoscopy on illness day 45. The BAL fluid from right B5 (recovery rate 67%, 101/150 mL) showed a cell count of 3.0×105 cells/mL with 93.5% macrophages, 3.5% lymphocytes, 1.5% neutrophils, and 1.5% eosinophils. The PCR of SARS-CoV2 RNA from the BAL fluid was negative. A microscopic examination of the TBLB from right B3 and B4 revealed an interstitial and intra-alveolar infiltration of lymphocytes and macrophages as well as fibroblastic connective tissue proliferation. We did not find severe fibrotic changes, eosinophil or neutrophil infiltrations, and lung structure disorganization (Fig. 4). We diagnosed the patient as secondary organizing pneumonia after COVID-19. We initiated an oral administration of prednisolone 60 mg/day (1 mg/kg/day) on illness day 51. After, her symptoms and oxygen saturation rapidly improved. On illness day 58, her SpO2 remained higher than 95% on room air when she walked a distance of more than 100 m. Furthermore, the CT on illness day 57 showed a remarkable improvement of consolidations and GGOs (Fig. 3D). Pulmonary function tests showed the DLCO of predicted values increased from 49.6% on illness day 44 to 71.7% on illness day 58, before and after the prednisolone treatment, respectively (Table 1). On illness day 58, we decreased prednisolone dose to 30 mg/day (0.5 mg/kg/day), and she was discharged on illness day 65. We tapered prednisolone dose to 20 mg/day on illness day 86 without recurrence.Fig. 3 Chest CT images of case 2 on illness day 9, on the admission to our hospital (A), on illness day 23, soon after the discontinuation of dexamethasone (B), on 43 days after the onset, before prednisolone introduction (C), and illness day 57, 6 days after the introduction of prednisolone (D). Bilateral ground glass opacities partially turned to consolidations and improved after the treatment of prednisolone.
Fig. 3Fig. 4 Histopathological findings of TBLB in case 2 (hematoxylin and eosin stain; ×10). Arrow indicates interstitial and intra-alveolar infiltrations of lymphocytes and macrophages. There were fibroblastic connective tissue proliferations in the interstitium.
Fig. 4Table 1 Results of pulmonary function test before and after administration of corticosteroids in case 2.
Table 1Parameter before steroidsa after steroidsb
Spirometry
VC (L) 1.66[85.9]c 1.57[81.5]
FEV1 (L) 1.29[80.6] 1.43[89.3]
FEV1/FVC (%) 79.1 86.7
Lung volume
TLC (L) 3.07[113.7] 3.66[135.6]
RV (L) 1.41[133.9] 2.09[198.2]
RV/TLC 46[132.7] 57.1[164.6]
Diffusion capacity
DLCO (mL/min/mmHg) 7.09[49.6] 10[71.7]
DLCO/VA (mL/min/mmHg/L) 2.79[69.9] 3.36[84.3]
DLCO: diffusing capacity of the lungs for carbon monoxide; FEF50%: forced expiratory flow at 50% of forced vital capacity; FEV1: forced expiratory volume; RV: residual volume; TLC: total lung capacity; VC: vital capacity.
a Results before initiation of corticosteroids (on illness day 44).
b Results 7 days after initiation of corticosteroids (on illness day 58).
c Values in square brackets mean % of predicted.
3 Discussion
We reported two cases that pathologically showed secondary organizing pneumonia after COVID-19. To the best of our knowledge, there was only one report of pathologically confirmed secondary organizing pneumonia after COVID-19 [10]. Our two cases and the previous Korean case commonly showed radiological improvements after the treatment of corticosteroids. However, our cases were different from the previous case in terms of following two clinical courses: 1) our diagnosis was based on TBLB, while the previous case was based on invasive surgical biopsy, and 2) we objectively confirmed improvements of pulmonary lung function before and after the treatment of corticosteroids in case 2.
Secondary organizing pneumonia may be responsible for the persistent respiratory failure in patients recovering from COVID-19. Findings of CT and pulmonary function tests in our two cases correspond to those reported in previous studies of organizing pneumonia: however, symptom, inflammation reaction, and low proportion of lymphocytes in the BAL fluid were not typical [8,9]. Conversely, organizing pneumonia could not be excluded from clinical findings alone [8]. For example, a previous study showed that 35% of patients with organizing pneumonia did not present fever, and another study revealed that 24% of patients did not present an elevation of serum CRP level [9,11]. Considering the risk of complications, it is not practical to perform TBLB for all the cases suspected of organizing pneumonia. However, we should not hesitate histological analysis from TBLB specimen for unclear or critical cases. We should consider organizing pneumonia as a sequela after COVID-19. TBLB is an option when the diagnosis of organizing pneumonia is difficult only from radiological and microbiological findings.
Secondary organizing pneumonia after COVID-19 is also a reversible condition owing to a sufficient treatment of corticosteroids. Systemic corticosteroid treatments have been shown to decreased COVID-19 mortality. Dexamethasone was recommended for use in the acute phase [12,13]. However, there was no evidence regarding systemic corticosteroid treatments for patients with persistent respiratory failure in patients recovering from acute COVID-19 infection. We used corticosteroids for our two cases because aside from being effective for cryptogenic organizing pneumonia, they are also typically used for secondary organizing pneumonia [8,9]. Both of our patients had objectively improved in terms of oxygenation, CT findings, and DLCO. We initiated a prednisolone dose of 1 mg/kg/day for 1 week according to the guideline for the treatment of cryptogenic organizing pneumonia [14]. Owing to the rapid improvement of our patients after the introduction of prednisolone, we decreased the prednisolone dose to 0.5 mg/kg/day 1 week after in order to shorten the duration of corticosteroid treatment. Further studies are needed to find the optimal initial dose and tapering schedule for secondary organizing pneumonia after COVID-19.
In conclusion, we present two cases of secondary organizing pneumonia after COVID-19, in which systemic corticosteroids improved patients’ oxygenation, radiological findings and pulmonary function. We should consider secondary organizing pneumonia as a differential diagnosis when respiratory failure persists among patients after COVID-19.
Author contributions
Kensuke Kanaoka, Seigo Minami, Shoich Ihara, Tsunehiro Tanaka and Kiyoshi Komuta were involved in treatment and care of these patients. Hironao Yasuoka performed pathological diagnosis of organizing pneumonia. Kensuke Kanaoka drafted the report. All authors read and critically reviewed the report and approved the final submitted version.
Declaration of competing interest
All authors declare no potential conflicts of interest related to the publication.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Acknowledgment
We would like to thank Enago (www.enago.jp) for the English language review. | DEXAMETHASONE, FAVIPIRAVIR | DrugsGivenReaction | CC BY-NC-ND | 33598398 | 19,253,264 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapeutic product effect incomplete'. | Secondary organizing pneumonia after coronavirus disease 2019: Two cases.
Coronavirus disease 2019 (COVID-19) has been reported to induce persistent symptoms even after an acute phase. However, the pathophysiology and treatment of this condition have been unclear. We report two patients who recovered from COVID-19, but presented persistent respiratory symptoms. Their respiratory conditions deteriorated, and computed tomography showed remaining ground glass opacities and consolidations. The pathological findings of transbronchial lung biopsy corresponded to organizing pneumonia. We diagnosed them with secondary organizing pneumonia after COVID-19. Subsequently, we administered systemic corticosteroids. Their symptoms, oxygenations, radiologic findings, and pulmonary functions rapidly improved after the treatment of corticosteroids. The two cases showed that secondary organizing pneumonia may be a cause of persistent respiratory failure after COVID-19. In this condition, corticosteroids may be effective.
Abbreviations
BALbronchoalveolar lavage
COVID-19coronavirus disease 2019
CRPC-reactive protein
CTcomputed tomography
DLCOdiffusing capacity of the lungs for carbon monoxide
GGOsground glass opacities
PCRpolymerase chain reaction
RNAribonucleic acid
SARS-CoV2severe acute respiratory syndrome coronavirus 2
SpO2percutaneous oxygen saturation
TBLBtransbronchial lung biopsy
1 Introduction
Coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), has spread worldwide and resulted in a pandemic [1]. The overall fatality rate of patients diagnosed with COVID-19 was reported to be 2.3% [2]. Even if patients with COVID-19 survived and were discharged, some of them experienced persistent symptoms [3]. Two months after the symptom onset, 66% and 30% of non-critical COVID-19 patients who needed admission experienced one or more symptoms and dyspnea, respectively [4]. With respect to objective findings, 52.6% of patients showed less than 80% of predicted values of diffusing capacity of the lungs for carbon monoxide (DLCO) 1 month after discharge [5]. Moreover, 47% of patients showed a persistent abnormality in computed tomography (CT) findings 3 weeks after discharge [6]. As to how long these dysfunctions persist remain unclear. Although many COVID-19 survivors suffered from a so-called “sequelae,” the pathophysiology of this condition and efficient treatments has not been established yet [7].
Secondary organizing pneumonia can develop after various infectious pneumonias, including viruses [8]. The typical clinical findings of organizing pneumonia include fever and elevation of inflammation reaction, consolidation and bilateral distribution in CT, restrictive ventilatory defect and dysfunction in diffusion capacity, and elevation of lymphocytes in bronchoalveolar lavage (BAL) fluid [8,9]. However, because these findings are not specific, a histopathological diagnosis is required [8].
Herein, we present two cases of secondary organizing pneumonia after COVID-19, in which corticosteroids had been effective.
2 Case reports
2.1 Case 1
A 56-year-old man with no remarkable medical history presented with a 7-day history of fever and body malaise and a 1-day history of cough and dyspnea. On admission, his body temperature, heart rate, blood pressure, respiratory rate, and percutaneous oxygen saturation (SpO2) on room air was 37.9 °C, 100 beats/min, 113/79 mmHg, 28 breaths/min, and 83%, respectively. He tested positive for polymerase chain reaction (PCR) of SARS-CoV2 ribonucleic acid (RNA) on his nasopharyngeal sample. Chest CT showed posterior ground glass opacities (GGOs) in both lungs (Fig. 1A). Laboratory blood tests exhibited an increase in the level of C-reactive protein (CRP) (11.55 mg/dL). Despite the initiation of favipiravir and dexamethasone, his SpO2 rapidly deteriorated to 88% with supplemental oxygen of 5 L/min within a day. We introduced invasive mechanical ventilation, and transferred him to another hospital exclusively for critical COVID-19 patients. He was extubated on illness day 13 because of respiratory condition improvement. Concurrently, favipiravir and dexamethasone were stopped. He tested negative for PCR of SARS-CoV2 RNA twice, on illness days 14 and 15, and returned to our hospital on illness day 16. However, upon re-hospitalization to our hospital, his respiratory failure persisted, and a nasal oxygen supplementation of 4 L/min was required to maintain a SpO2 of 97%. On illness day 26, he no longer had fever, and the serum CRP level declined to the normal range. However, he still needed a nasal oxygen supplementation of 3 L/min. Chest CT showed that GGOs remained and partially became consolidations in both lobes (Fig. 1B). We performed BAL and transbronchial lung biopsy (TBLB) on illness day 29. The BAL fluid from the left B4 (recovery rate 35%, 53/150 mL) showed a cell count of 9.6×105 cells/mL with 94% macrophages, 5% lymphocytes, and 1% neutrophils. The PCR of SARS-CoV2 RNA from the BAL fluid was negative. A microscopic examination of the TBLB from left B4 and B5 revealed intra-alveolar granulation, interstitial lymphocytes infiltration, and fibroblastic tissue proliferation in the interstitium (Fig. 2). Considering his clinical course and pathological findings, we diagnosed secondary organizing pneumonia after COVID-19. We initiated an oral administration of prednisolone 60 mg/day (1 mg/kg/day) on illness day 35. After, his respiratory condition rapidly improved, and maintained a SpO2 of 95% on room air on illness day 42. Furthermore, the CT on illness day 41 showed a remarkable improvement of consolidations (Fig. 1C). We decreased the prednisolone dose to 30 mg/day (0.5 mg/kg/day) on illness day 42. On illness day 56, he was discharged without oxygen supplementation. Spirometry on illness day 61 was within the normal range, and the DLCO was 82.8% of predicted values. We tapered the prednisolone dose to 15 mg/day on illness day 84 without recurrence.Fig. 1 Chest CT images of case 1 on illness day 7, on the first admission to our hospital (A), on illness day 26, before prednisolone introduction (B), and on illness day 41, 6 days after the introduction of prednisolone (C). Peripheral ground glass opacities in the bilateral posterior lobes progressed to consolidation, and improved after the treatment of prednisolone.
Fig. 1Fig. 2 Histopathological findings of TBLB in case 1 (hematoxylin and eosin stain; ×10). Arrow indicates an intra-alveolar granulation. There were interstitial lymphocyte infiltrations and fibroblastic tissue proliferation in the interstitium.
Fig. 2
2.2 Case 2
An 84-year-old woman with a medical history of hypertension, hypercholesterolemia and hypothyroidism presented with a 9-day history of body malaise. She did not complain of dyspnea. On admission, her body temperature, heart rate, blood pressure, respiratory rate, and SpO2 on room air was 36.7 °C, 78 beats/min, 148/87 mm Hg, 24 breaths/min, and 90%, respectively. She tested positive for the PCR of SARS-CoV2 RNA on her nasopharyngeal sample. Chest CT showed patchy GGOs dominantly in the periphery of the right lung lobe (Fig. 3A). Laboratory blood tests exhibited a slight increase in CRP (2.62 mg/dL). We initiated favipiravir and dexamethasone after the admission. She temporarily needed a nasal oxygen supplementation of 4 L/min on the next day of admission, but then, her symptom and oxygenation gradually improved. We discontinued dexamethasone and favipiravir on illness days 20 and 24, respectively. She tested negative for the PCR of SARS-CoV2 RNA twice, on illness days 30 and 31. However, she remained in the hospital because of persistent dyspnea. She did not present with fever, and the serum CRP level declined to the normal range on illness day 36. She did not need oxygen supplementation; however, her SpO2 decreased to less than 90% with just a 30-m-walk on illness day 43. In addition, the CT on illness days 23 and 43 showed the presence of GGOs and consolidations in both lungs (Fig. 3B and C). A pulmonary function test on illness day 44 also showed a reduced DLCO. We performed bronchoscopy on illness day 45. The BAL fluid from right B5 (recovery rate 67%, 101/150 mL) showed a cell count of 3.0×105 cells/mL with 93.5% macrophages, 3.5% lymphocytes, 1.5% neutrophils, and 1.5% eosinophils. The PCR of SARS-CoV2 RNA from the BAL fluid was negative. A microscopic examination of the TBLB from right B3 and B4 revealed an interstitial and intra-alveolar infiltration of lymphocytes and macrophages as well as fibroblastic connective tissue proliferation. We did not find severe fibrotic changes, eosinophil or neutrophil infiltrations, and lung structure disorganization (Fig. 4). We diagnosed the patient as secondary organizing pneumonia after COVID-19. We initiated an oral administration of prednisolone 60 mg/day (1 mg/kg/day) on illness day 51. After, her symptoms and oxygen saturation rapidly improved. On illness day 58, her SpO2 remained higher than 95% on room air when she walked a distance of more than 100 m. Furthermore, the CT on illness day 57 showed a remarkable improvement of consolidations and GGOs (Fig. 3D). Pulmonary function tests showed the DLCO of predicted values increased from 49.6% on illness day 44 to 71.7% on illness day 58, before and after the prednisolone treatment, respectively (Table 1). On illness day 58, we decreased prednisolone dose to 30 mg/day (0.5 mg/kg/day), and she was discharged on illness day 65. We tapered prednisolone dose to 20 mg/day on illness day 86 without recurrence.Fig. 3 Chest CT images of case 2 on illness day 9, on the admission to our hospital (A), on illness day 23, soon after the discontinuation of dexamethasone (B), on 43 days after the onset, before prednisolone introduction (C), and illness day 57, 6 days after the introduction of prednisolone (D). Bilateral ground glass opacities partially turned to consolidations and improved after the treatment of prednisolone.
Fig. 3Fig. 4 Histopathological findings of TBLB in case 2 (hematoxylin and eosin stain; ×10). Arrow indicates interstitial and intra-alveolar infiltrations of lymphocytes and macrophages. There were fibroblastic connective tissue proliferations in the interstitium.
Fig. 4Table 1 Results of pulmonary function test before and after administration of corticosteroids in case 2.
Table 1Parameter before steroidsa after steroidsb
Spirometry
VC (L) 1.66[85.9]c 1.57[81.5]
FEV1 (L) 1.29[80.6] 1.43[89.3]
FEV1/FVC (%) 79.1 86.7
Lung volume
TLC (L) 3.07[113.7] 3.66[135.6]
RV (L) 1.41[133.9] 2.09[198.2]
RV/TLC 46[132.7] 57.1[164.6]
Diffusion capacity
DLCO (mL/min/mmHg) 7.09[49.6] 10[71.7]
DLCO/VA (mL/min/mmHg/L) 2.79[69.9] 3.36[84.3]
DLCO: diffusing capacity of the lungs for carbon monoxide; FEF50%: forced expiratory flow at 50% of forced vital capacity; FEV1: forced expiratory volume; RV: residual volume; TLC: total lung capacity; VC: vital capacity.
a Results before initiation of corticosteroids (on illness day 44).
b Results 7 days after initiation of corticosteroids (on illness day 58).
c Values in square brackets mean % of predicted.
3 Discussion
We reported two cases that pathologically showed secondary organizing pneumonia after COVID-19. To the best of our knowledge, there was only one report of pathologically confirmed secondary organizing pneumonia after COVID-19 [10]. Our two cases and the previous Korean case commonly showed radiological improvements after the treatment of corticosteroids. However, our cases were different from the previous case in terms of following two clinical courses: 1) our diagnosis was based on TBLB, while the previous case was based on invasive surgical biopsy, and 2) we objectively confirmed improvements of pulmonary lung function before and after the treatment of corticosteroids in case 2.
Secondary organizing pneumonia may be responsible for the persistent respiratory failure in patients recovering from COVID-19. Findings of CT and pulmonary function tests in our two cases correspond to those reported in previous studies of organizing pneumonia: however, symptom, inflammation reaction, and low proportion of lymphocytes in the BAL fluid were not typical [8,9]. Conversely, organizing pneumonia could not be excluded from clinical findings alone [8]. For example, a previous study showed that 35% of patients with organizing pneumonia did not present fever, and another study revealed that 24% of patients did not present an elevation of serum CRP level [9,11]. Considering the risk of complications, it is not practical to perform TBLB for all the cases suspected of organizing pneumonia. However, we should not hesitate histological analysis from TBLB specimen for unclear or critical cases. We should consider organizing pneumonia as a sequela after COVID-19. TBLB is an option when the diagnosis of organizing pneumonia is difficult only from radiological and microbiological findings.
Secondary organizing pneumonia after COVID-19 is also a reversible condition owing to a sufficient treatment of corticosteroids. Systemic corticosteroid treatments have been shown to decreased COVID-19 mortality. Dexamethasone was recommended for use in the acute phase [12,13]. However, there was no evidence regarding systemic corticosteroid treatments for patients with persistent respiratory failure in patients recovering from acute COVID-19 infection. We used corticosteroids for our two cases because aside from being effective for cryptogenic organizing pneumonia, they are also typically used for secondary organizing pneumonia [8,9]. Both of our patients had objectively improved in terms of oxygenation, CT findings, and DLCO. We initiated a prednisolone dose of 1 mg/kg/day for 1 week according to the guideline for the treatment of cryptogenic organizing pneumonia [14]. Owing to the rapid improvement of our patients after the introduction of prednisolone, we decreased the prednisolone dose to 0.5 mg/kg/day 1 week after in order to shorten the duration of corticosteroid treatment. Further studies are needed to find the optimal initial dose and tapering schedule for secondary organizing pneumonia after COVID-19.
In conclusion, we present two cases of secondary organizing pneumonia after COVID-19, in which systemic corticosteroids improved patients’ oxygenation, radiological findings and pulmonary function. We should consider secondary organizing pneumonia as a differential diagnosis when respiratory failure persists among patients after COVID-19.
Author contributions
Kensuke Kanaoka, Seigo Minami, Shoich Ihara, Tsunehiro Tanaka and Kiyoshi Komuta were involved in treatment and care of these patients. Hironao Yasuoka performed pathological diagnosis of organizing pneumonia. Kensuke Kanaoka drafted the report. All authors read and critically reviewed the report and approved the final submitted version.
Declaration of competing interest
All authors declare no potential conflicts of interest related to the publication.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Acknowledgment
We would like to thank Enago (www.enago.jp) for the English language review. | DEXAMETHASONE, FAVIPIRAVIR | DrugsGivenReaction | CC BY-NC-ND | 33598398 | 19,254,957 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Aphasia'. | Successful implementation of classical ketogenic dietary therapy in a patient with Niemann-Pick disease type C.
Niemann-Pick disease type C (NP-C) is a neurodegenerative disease for which only palliative treatment exists, and only miglustat is effective in stabilizing neurological manifestations of NP-C. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders, including those associated with various inherited metabolic diseases (IMD), to reduce seizure frequency and medication requirement as well as to confer neuroprotection. Since patients with NP-C suffer pharmacorefractory seizures associated with ongoing neurodegeneration, KDT might be beneficial. The concomitant use of miglustat and KDT in patients with NP-C has not been reported.
We describe our experience in a now 17-year-old female with NP-C manifest early in childhood who has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y. Although the neurodegeneration of NP-C progressed, she benefited from a reduction in seizure activity, fewer hospital stays related to seizure exacerbation, and increased alertness.
KDT could be safely deployed in our patient with NP-C, in whom its effects have been beneficial. Generally KDT is demonstratedly efficacious in patients with epilepsy and IMD. It reduces seizure activity and medication requirements and confers neuroprotection. Intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake.
1 Introduction
Niemann-Pick disease type C (NP-C) is a rare neurovisceral lysosomal disorder with autosomal recessive inheritance caused by mutations in either NPC1 (95%) or NPC2 (~4%) [1].
NP-C is characterized by abnormal lysosomal accumulation of unesterified cholesterol and glycolipids that results in progressive neurological deterioration, severe loss of quality of life, and premature death [2]. The only available drug effective in stabilizing neurological manifestations is miglustat [[2], [3], [4], [5]].
Yet NP-C is an invariably progressive disease and therapy is limited to delaying deterioration. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders and various inherited metabolic diseases (IMD) that conduce to seizure disorders. They reduce seizure activity and medication requirements and protect neurologic function [6,7]. Although dietary carbohydrate modification and restriction in patients with NP-C is discussed to ameliorate the gastrointestinal side effects associated with miglustat therapy [8], the concomitant use of miglustat and KDT in patients with NP-C is not described. In a case series where the long-term effects of intrathecal 2-Hydroxypropyl-β-Cyclodextrin treatment was evaluated, one patient who was on KDT prior to diagnosis and miglustat therapy was included who did not show any apparent benefit of KDT [9].
2 Case report
We describe our experience in attending a now 17-year-old female with NP-C manifest aged 3y that has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y at this writing. This therapy reduced seizure frequency and hospital stays and improved patient alertness.
2.1 Initial findings and diagnosis
Our patient was born at term after an uneventful second pregnancy to non-consanguineous Caucasian parents. The first pregnancy ended in spontaneous abortion. The mother has epilepsy treated with carbamazepine.
The parents reported motor and language developmental delay apparent at age 3y. The patient was seen in our clinic first at age 5y; no diagnosis was assigned. Behavioral disturbances began at age 9y, with self-harming and injury to others, ataxia, dysphagia, and repetitive seizures. This prompted re-assessment. Bilateral oculomotor palsy was found, with exotropia. Abdominal sonography showed mesenteric lymphadenopathy and hepatosplenomegaly. A lysosomal storage disease was suspected. Filipin staining of skin fibroblasts found accumulation of unesterified cholesterol in the endosomal/lysosomal compartment, permitting the diagnosis of NP-C. The patient proved to harbor biallelic mutations in NPC1 (c.1421C>T/p.Pro474Leu, known [10], and c.3289_3291del/p.Asp1097del).
2.2 Treatment and clinical course
Anti-epileptic treatment with levetiracetam (LEV; initial target dose, 30 mg/kg/d) was initiated empirically at age 9y, when seizures began. Immediately after definitive diagnosis (still at age 9y), substrate reduction therapy with miglustat was initiated (400 mg/m2 body surface area/d). Emesis and diarrhoea were mild. After 2mo, seizures worsened and expressive speech was entirely lost. LEV therapy was thus increased stagewise (dose achieved, 50 mg/kg/d).
At age 10y exotropia and hand-eye-coordination improved. Over the next 2y, however, neurodegenerative worsening was volatile, with emergence of swallowing difficulties that led to malnutrition. A gastrostomy thus was placed at age 12y and an overnight partial continuous feeding regimen (1/3 of estimated total energy expenditure = 500 kcal) was established. At the same time, the patient lost ability to walk. Alternating patterns of high- and low- (1–2 seizures a day) seizure frequency (respectively 20 seizures/h and 1–2/d) characterized the patient's 12th and 13th years of life. At age 13y gastrointestinal manifestations emerged (chronic constipation, successfully treated with soluble fibre). At age 14y exacerbations of seizures led to escalation of anti-epileptic treatment. Buccal midazolam (10 mg) was used as rescue medication for seizures lasting longer than 5 min. The patient's LEV was enhanced (dose achieved, 70 mg/kg/d) and complemented with clobazam (CLB; 0.15 mg/kg/d). Yet neurological deterioration progressed, in particular seizure severity and seizure frequency.
After 3mo of unsatisfactory drug therapy, we re-considered the therapeutic options. Expecting more side effects without improvements if another anti-epileptic drug was begun, we decided to initiate a classical KDT with a ketogenic ratio of 4:1 whilst continuing the drug regimen then in place.
Enteral feeding via gastrostomy facilitated this, using a ketogenic formula (fat to non-fat 4:1). KDT is traditionally introduced by increasing the ketogenic ratio stepwise. We replaced one-third of calories/d until full tolerance was achieved (1560 kcal/d, 45 kcal/kg). Within 5d whole blood β-hydroxybutyrate (B-OHB) levels rose to 2.7 mmol/L (Fig. 1). Duration and frequency of seizures fell (Fig. 1) and alertness increased. Although neurodegeneration was thought to progress, with persistent and worsening signs, during the first 3y of KDT, average hospital admissions and inpatient days were fewer within 3y under KDT than during the 3y before (10 vs. 14 and 94 vs. 113 respectively).Fig. 1 Ketosis (serum B-OHB levels) and seizure frequency during KDT.
Fig. 1
As electroencephalography (EEG) was stressful for our patient and little clinical benefit was expected, it was limited to a minimum. EEG 10mo prior to KDT showed multifocal as well as generalized epileptogenic activity as typically seen in patients with Lennox-Gastaut syndrome. After initiation of KDT, little changed yet stabilized epileptogenic activity was observed. Changes included slowing of background rhythm and continuous disorganization of sleep related elements. Generalized seizures were solely identified by an increased activity from 6 to 8/s to 14-30/s for 30 to 120 s.
The 3rd year of KDT saw an abrupt rise in hospital admissions and inpatient days that we ascribe to personnel and structural changes in the care facility where the patient lives rather than to a change in her disorder. After initiation of KDT no further hospital admissions due to seizure exacerbation were necessary (Fig. 2). Seizure duration remains <5 min even after 3y on KDT. The patient now, at age 17y, has received KDT for 3y without any identified KDT-associated side effects.Fig. 2 Hospital admissions and inpatient days before and after initiation of KDT.
Fig. 2
3 Discussion
Concomitant use of miglustat and KDT (“Syner-G”) improves survival in patients with GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease) [11]. Ketosis may increase miglustat uptake and accumulation in forebrain of the β-hexosaminidase (Hexb) knockout (−/−) murine model of Sandhoff disease [12].
How KDT acts in pharmacoresistant epilepsy is not fully understood. Proposed mechanisms are linked either to direct effects of ketones and of glucose restriction or to interactions with receptors, channels, and metabolic enzymes [13]. KDTs in IMDs are used either to target the underlying metabolic disorder (e.g., glucose transporter type 1 deficiency syndrome) or to target symptoms (e.g., seizures in non-ketotic hyperglycinemia) [14]. They efficaciously reduce seizure activity and medication requirements and confer neuroprotection. One of the hypotheses of underlying pathophysiology in NP-C is that it triggers oxidative stress damage and apoptotic cell death [15]. Chronic ketosis as induced via KDT is thought to limit reactive oxygen species generation and thus might prevent apoptosis [16]. In addition, carbohydrate modification and reduction as derived by KDT could show successful amelioration of gastrointestinal side effects associated with miglustat in two patients with NP-C [8].
Although intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake, fat-rich KDT can perhaps be safely deployed in patients with NP-C, in whom its effects may be beneficial.
4 Conclusion
In a non-terminal palliative care setting, KDT could temporarily improve quality of life through reduction in seizure activity, increased alertness, and reduction in both hospital admissions and inpatient days in a 14-year-old female patient with NP-C. Our experience may encourage further research into how KDT can be beneficially deployed in NP-C patients.
Synopsis
Over 3y beginning at age 14y in a girl with NP-C, classical KDT combined with miglustat, levetiracetam, and clobazam improved quality of life over that achieved with miglustat, levetiracetam, and clobazam. KDT reduced seizure activity and increased patient alertness.
Details of contribution of individual authors
Alexander Höller is a pediatric dietitian specializing in inborn disorders of metabolism and neuropediatrics.
Daniela Karall, Sabine Scholl-Bürgi, Sara Baumgartner Sigl, and Ursula Albrecht are pediatricians specializing in inborn disorders of metabolism and neuropediatrics.
Thomas Zöggeler, Gabriele Ramoser, and Benoit Bernar are physicians training in pediatrics.
Author who serves as guarantor for the article: Sabine Scholl-Bürgi.
Declaration of Competing Interest
All authors declare that they have no competing interest. | CLOBAZAM, LEVETIRACETAM, MIDAZOLAM, MIGLUSTAT | DrugsGivenReaction | CC BY-NC-ND | 33598405 | 19,465,164 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Constipation'. | Successful implementation of classical ketogenic dietary therapy in a patient with Niemann-Pick disease type C.
Niemann-Pick disease type C (NP-C) is a neurodegenerative disease for which only palliative treatment exists, and only miglustat is effective in stabilizing neurological manifestations of NP-C. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders, including those associated with various inherited metabolic diseases (IMD), to reduce seizure frequency and medication requirement as well as to confer neuroprotection. Since patients with NP-C suffer pharmacorefractory seizures associated with ongoing neurodegeneration, KDT might be beneficial. The concomitant use of miglustat and KDT in patients with NP-C has not been reported.
We describe our experience in a now 17-year-old female with NP-C manifest early in childhood who has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y. Although the neurodegeneration of NP-C progressed, she benefited from a reduction in seizure activity, fewer hospital stays related to seizure exacerbation, and increased alertness.
KDT could be safely deployed in our patient with NP-C, in whom its effects have been beneficial. Generally KDT is demonstratedly efficacious in patients with epilepsy and IMD. It reduces seizure activity and medication requirements and confers neuroprotection. Intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake.
1 Introduction
Niemann-Pick disease type C (NP-C) is a rare neurovisceral lysosomal disorder with autosomal recessive inheritance caused by mutations in either NPC1 (95%) or NPC2 (~4%) [1].
NP-C is characterized by abnormal lysosomal accumulation of unesterified cholesterol and glycolipids that results in progressive neurological deterioration, severe loss of quality of life, and premature death [2]. The only available drug effective in stabilizing neurological manifestations is miglustat [[2], [3], [4], [5]].
Yet NP-C is an invariably progressive disease and therapy is limited to delaying deterioration. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders and various inherited metabolic diseases (IMD) that conduce to seizure disorders. They reduce seizure activity and medication requirements and protect neurologic function [6,7]. Although dietary carbohydrate modification and restriction in patients with NP-C is discussed to ameliorate the gastrointestinal side effects associated with miglustat therapy [8], the concomitant use of miglustat and KDT in patients with NP-C is not described. In a case series where the long-term effects of intrathecal 2-Hydroxypropyl-β-Cyclodextrin treatment was evaluated, one patient who was on KDT prior to diagnosis and miglustat therapy was included who did not show any apparent benefit of KDT [9].
2 Case report
We describe our experience in attending a now 17-year-old female with NP-C manifest aged 3y that has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y at this writing. This therapy reduced seizure frequency and hospital stays and improved patient alertness.
2.1 Initial findings and diagnosis
Our patient was born at term after an uneventful second pregnancy to non-consanguineous Caucasian parents. The first pregnancy ended in spontaneous abortion. The mother has epilepsy treated with carbamazepine.
The parents reported motor and language developmental delay apparent at age 3y. The patient was seen in our clinic first at age 5y; no diagnosis was assigned. Behavioral disturbances began at age 9y, with self-harming and injury to others, ataxia, dysphagia, and repetitive seizures. This prompted re-assessment. Bilateral oculomotor palsy was found, with exotropia. Abdominal sonography showed mesenteric lymphadenopathy and hepatosplenomegaly. A lysosomal storage disease was suspected. Filipin staining of skin fibroblasts found accumulation of unesterified cholesterol in the endosomal/lysosomal compartment, permitting the diagnosis of NP-C. The patient proved to harbor biallelic mutations in NPC1 (c.1421C>T/p.Pro474Leu, known [10], and c.3289_3291del/p.Asp1097del).
2.2 Treatment and clinical course
Anti-epileptic treatment with levetiracetam (LEV; initial target dose, 30 mg/kg/d) was initiated empirically at age 9y, when seizures began. Immediately after definitive diagnosis (still at age 9y), substrate reduction therapy with miglustat was initiated (400 mg/m2 body surface area/d). Emesis and diarrhoea were mild. After 2mo, seizures worsened and expressive speech was entirely lost. LEV therapy was thus increased stagewise (dose achieved, 50 mg/kg/d).
At age 10y exotropia and hand-eye-coordination improved. Over the next 2y, however, neurodegenerative worsening was volatile, with emergence of swallowing difficulties that led to malnutrition. A gastrostomy thus was placed at age 12y and an overnight partial continuous feeding regimen (1/3 of estimated total energy expenditure = 500 kcal) was established. At the same time, the patient lost ability to walk. Alternating patterns of high- and low- (1–2 seizures a day) seizure frequency (respectively 20 seizures/h and 1–2/d) characterized the patient's 12th and 13th years of life. At age 13y gastrointestinal manifestations emerged (chronic constipation, successfully treated with soluble fibre). At age 14y exacerbations of seizures led to escalation of anti-epileptic treatment. Buccal midazolam (10 mg) was used as rescue medication for seizures lasting longer than 5 min. The patient's LEV was enhanced (dose achieved, 70 mg/kg/d) and complemented with clobazam (CLB; 0.15 mg/kg/d). Yet neurological deterioration progressed, in particular seizure severity and seizure frequency.
After 3mo of unsatisfactory drug therapy, we re-considered the therapeutic options. Expecting more side effects without improvements if another anti-epileptic drug was begun, we decided to initiate a classical KDT with a ketogenic ratio of 4:1 whilst continuing the drug regimen then in place.
Enteral feeding via gastrostomy facilitated this, using a ketogenic formula (fat to non-fat 4:1). KDT is traditionally introduced by increasing the ketogenic ratio stepwise. We replaced one-third of calories/d until full tolerance was achieved (1560 kcal/d, 45 kcal/kg). Within 5d whole blood β-hydroxybutyrate (B-OHB) levels rose to 2.7 mmol/L (Fig. 1). Duration and frequency of seizures fell (Fig. 1) and alertness increased. Although neurodegeneration was thought to progress, with persistent and worsening signs, during the first 3y of KDT, average hospital admissions and inpatient days were fewer within 3y under KDT than during the 3y before (10 vs. 14 and 94 vs. 113 respectively).Fig. 1 Ketosis (serum B-OHB levels) and seizure frequency during KDT.
Fig. 1
As electroencephalography (EEG) was stressful for our patient and little clinical benefit was expected, it was limited to a minimum. EEG 10mo prior to KDT showed multifocal as well as generalized epileptogenic activity as typically seen in patients with Lennox-Gastaut syndrome. After initiation of KDT, little changed yet stabilized epileptogenic activity was observed. Changes included slowing of background rhythm and continuous disorganization of sleep related elements. Generalized seizures were solely identified by an increased activity from 6 to 8/s to 14-30/s for 30 to 120 s.
The 3rd year of KDT saw an abrupt rise in hospital admissions and inpatient days that we ascribe to personnel and structural changes in the care facility where the patient lives rather than to a change in her disorder. After initiation of KDT no further hospital admissions due to seizure exacerbation were necessary (Fig. 2). Seizure duration remains <5 min even after 3y on KDT. The patient now, at age 17y, has received KDT for 3y without any identified KDT-associated side effects.Fig. 2 Hospital admissions and inpatient days before and after initiation of KDT.
Fig. 2
3 Discussion
Concomitant use of miglustat and KDT (“Syner-G”) improves survival in patients with GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease) [11]. Ketosis may increase miglustat uptake and accumulation in forebrain of the β-hexosaminidase (Hexb) knockout (−/−) murine model of Sandhoff disease [12].
How KDT acts in pharmacoresistant epilepsy is not fully understood. Proposed mechanisms are linked either to direct effects of ketones and of glucose restriction or to interactions with receptors, channels, and metabolic enzymes [13]. KDTs in IMDs are used either to target the underlying metabolic disorder (e.g., glucose transporter type 1 deficiency syndrome) or to target symptoms (e.g., seizures in non-ketotic hyperglycinemia) [14]. They efficaciously reduce seizure activity and medication requirements and confer neuroprotection. One of the hypotheses of underlying pathophysiology in NP-C is that it triggers oxidative stress damage and apoptotic cell death [15]. Chronic ketosis as induced via KDT is thought to limit reactive oxygen species generation and thus might prevent apoptosis [16]. In addition, carbohydrate modification and reduction as derived by KDT could show successful amelioration of gastrointestinal side effects associated with miglustat in two patients with NP-C [8].
Although intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake, fat-rich KDT can perhaps be safely deployed in patients with NP-C, in whom its effects may be beneficial.
4 Conclusion
In a non-terminal palliative care setting, KDT could temporarily improve quality of life through reduction in seizure activity, increased alertness, and reduction in both hospital admissions and inpatient days in a 14-year-old female patient with NP-C. Our experience may encourage further research into how KDT can be beneficially deployed in NP-C patients.
Synopsis
Over 3y beginning at age 14y in a girl with NP-C, classical KDT combined with miglustat, levetiracetam, and clobazam improved quality of life over that achieved with miglustat, levetiracetam, and clobazam. KDT reduced seizure activity and increased patient alertness.
Details of contribution of individual authors
Alexander Höller is a pediatric dietitian specializing in inborn disorders of metabolism and neuropediatrics.
Daniela Karall, Sabine Scholl-Bürgi, Sara Baumgartner Sigl, and Ursula Albrecht are pediatricians specializing in inborn disorders of metabolism and neuropediatrics.
Thomas Zöggeler, Gabriele Ramoser, and Benoit Bernar are physicians training in pediatrics.
Author who serves as guarantor for the article: Sabine Scholl-Bürgi.
Declaration of Competing Interest
All authors declare that they have no competing interest. | CLOBAZAM, LEVETIRACETAM, MIDAZOLAM, MIGLUSTAT | DrugsGivenReaction | CC BY-NC-ND | 33598405 | 19,465,164 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diarrhoea'. | Successful implementation of classical ketogenic dietary therapy in a patient with Niemann-Pick disease type C.
Niemann-Pick disease type C (NP-C) is a neurodegenerative disease for which only palliative treatment exists, and only miglustat is effective in stabilizing neurological manifestations of NP-C. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders, including those associated with various inherited metabolic diseases (IMD), to reduce seizure frequency and medication requirement as well as to confer neuroprotection. Since patients with NP-C suffer pharmacorefractory seizures associated with ongoing neurodegeneration, KDT might be beneficial. The concomitant use of miglustat and KDT in patients with NP-C has not been reported.
We describe our experience in a now 17-year-old female with NP-C manifest early in childhood who has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y. Although the neurodegeneration of NP-C progressed, she benefited from a reduction in seizure activity, fewer hospital stays related to seizure exacerbation, and increased alertness.
KDT could be safely deployed in our patient with NP-C, in whom its effects have been beneficial. Generally KDT is demonstratedly efficacious in patients with epilepsy and IMD. It reduces seizure activity and medication requirements and confers neuroprotection. Intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake.
1 Introduction
Niemann-Pick disease type C (NP-C) is a rare neurovisceral lysosomal disorder with autosomal recessive inheritance caused by mutations in either NPC1 (95%) or NPC2 (~4%) [1].
NP-C is characterized by abnormal lysosomal accumulation of unesterified cholesterol and glycolipids that results in progressive neurological deterioration, severe loss of quality of life, and premature death [2]. The only available drug effective in stabilizing neurological manifestations is miglustat [[2], [3], [4], [5]].
Yet NP-C is an invariably progressive disease and therapy is limited to delaying deterioration. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders and various inherited metabolic diseases (IMD) that conduce to seizure disorders. They reduce seizure activity and medication requirements and protect neurologic function [6,7]. Although dietary carbohydrate modification and restriction in patients with NP-C is discussed to ameliorate the gastrointestinal side effects associated with miglustat therapy [8], the concomitant use of miglustat and KDT in patients with NP-C is not described. In a case series where the long-term effects of intrathecal 2-Hydroxypropyl-β-Cyclodextrin treatment was evaluated, one patient who was on KDT prior to diagnosis and miglustat therapy was included who did not show any apparent benefit of KDT [9].
2 Case report
We describe our experience in attending a now 17-year-old female with NP-C manifest aged 3y that has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y at this writing. This therapy reduced seizure frequency and hospital stays and improved patient alertness.
2.1 Initial findings and diagnosis
Our patient was born at term after an uneventful second pregnancy to non-consanguineous Caucasian parents. The first pregnancy ended in spontaneous abortion. The mother has epilepsy treated with carbamazepine.
The parents reported motor and language developmental delay apparent at age 3y. The patient was seen in our clinic first at age 5y; no diagnosis was assigned. Behavioral disturbances began at age 9y, with self-harming and injury to others, ataxia, dysphagia, and repetitive seizures. This prompted re-assessment. Bilateral oculomotor palsy was found, with exotropia. Abdominal sonography showed mesenteric lymphadenopathy and hepatosplenomegaly. A lysosomal storage disease was suspected. Filipin staining of skin fibroblasts found accumulation of unesterified cholesterol in the endosomal/lysosomal compartment, permitting the diagnosis of NP-C. The patient proved to harbor biallelic mutations in NPC1 (c.1421C>T/p.Pro474Leu, known [10], and c.3289_3291del/p.Asp1097del).
2.2 Treatment and clinical course
Anti-epileptic treatment with levetiracetam (LEV; initial target dose, 30 mg/kg/d) was initiated empirically at age 9y, when seizures began. Immediately after definitive diagnosis (still at age 9y), substrate reduction therapy with miglustat was initiated (400 mg/m2 body surface area/d). Emesis and diarrhoea were mild. After 2mo, seizures worsened and expressive speech was entirely lost. LEV therapy was thus increased stagewise (dose achieved, 50 mg/kg/d).
At age 10y exotropia and hand-eye-coordination improved. Over the next 2y, however, neurodegenerative worsening was volatile, with emergence of swallowing difficulties that led to malnutrition. A gastrostomy thus was placed at age 12y and an overnight partial continuous feeding regimen (1/3 of estimated total energy expenditure = 500 kcal) was established. At the same time, the patient lost ability to walk. Alternating patterns of high- and low- (1–2 seizures a day) seizure frequency (respectively 20 seizures/h and 1–2/d) characterized the patient's 12th and 13th years of life. At age 13y gastrointestinal manifestations emerged (chronic constipation, successfully treated with soluble fibre). At age 14y exacerbations of seizures led to escalation of anti-epileptic treatment. Buccal midazolam (10 mg) was used as rescue medication for seizures lasting longer than 5 min. The patient's LEV was enhanced (dose achieved, 70 mg/kg/d) and complemented with clobazam (CLB; 0.15 mg/kg/d). Yet neurological deterioration progressed, in particular seizure severity and seizure frequency.
After 3mo of unsatisfactory drug therapy, we re-considered the therapeutic options. Expecting more side effects without improvements if another anti-epileptic drug was begun, we decided to initiate a classical KDT with a ketogenic ratio of 4:1 whilst continuing the drug regimen then in place.
Enteral feeding via gastrostomy facilitated this, using a ketogenic formula (fat to non-fat 4:1). KDT is traditionally introduced by increasing the ketogenic ratio stepwise. We replaced one-third of calories/d until full tolerance was achieved (1560 kcal/d, 45 kcal/kg). Within 5d whole blood β-hydroxybutyrate (B-OHB) levels rose to 2.7 mmol/L (Fig. 1). Duration and frequency of seizures fell (Fig. 1) and alertness increased. Although neurodegeneration was thought to progress, with persistent and worsening signs, during the first 3y of KDT, average hospital admissions and inpatient days were fewer within 3y under KDT than during the 3y before (10 vs. 14 and 94 vs. 113 respectively).Fig. 1 Ketosis (serum B-OHB levels) and seizure frequency during KDT.
Fig. 1
As electroencephalography (EEG) was stressful for our patient and little clinical benefit was expected, it was limited to a minimum. EEG 10mo prior to KDT showed multifocal as well as generalized epileptogenic activity as typically seen in patients with Lennox-Gastaut syndrome. After initiation of KDT, little changed yet stabilized epileptogenic activity was observed. Changes included slowing of background rhythm and continuous disorganization of sleep related elements. Generalized seizures were solely identified by an increased activity from 6 to 8/s to 14-30/s for 30 to 120 s.
The 3rd year of KDT saw an abrupt rise in hospital admissions and inpatient days that we ascribe to personnel and structural changes in the care facility where the patient lives rather than to a change in her disorder. After initiation of KDT no further hospital admissions due to seizure exacerbation were necessary (Fig. 2). Seizure duration remains <5 min even after 3y on KDT. The patient now, at age 17y, has received KDT for 3y without any identified KDT-associated side effects.Fig. 2 Hospital admissions and inpatient days before and after initiation of KDT.
Fig. 2
3 Discussion
Concomitant use of miglustat and KDT (“Syner-G”) improves survival in patients with GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease) [11]. Ketosis may increase miglustat uptake and accumulation in forebrain of the β-hexosaminidase (Hexb) knockout (−/−) murine model of Sandhoff disease [12].
How KDT acts in pharmacoresistant epilepsy is not fully understood. Proposed mechanisms are linked either to direct effects of ketones and of glucose restriction or to interactions with receptors, channels, and metabolic enzymes [13]. KDTs in IMDs are used either to target the underlying metabolic disorder (e.g., glucose transporter type 1 deficiency syndrome) or to target symptoms (e.g., seizures in non-ketotic hyperglycinemia) [14]. They efficaciously reduce seizure activity and medication requirements and confer neuroprotection. One of the hypotheses of underlying pathophysiology in NP-C is that it triggers oxidative stress damage and apoptotic cell death [15]. Chronic ketosis as induced via KDT is thought to limit reactive oxygen species generation and thus might prevent apoptosis [16]. In addition, carbohydrate modification and reduction as derived by KDT could show successful amelioration of gastrointestinal side effects associated with miglustat in two patients with NP-C [8].
Although intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake, fat-rich KDT can perhaps be safely deployed in patients with NP-C, in whom its effects may be beneficial.
4 Conclusion
In a non-terminal palliative care setting, KDT could temporarily improve quality of life through reduction in seizure activity, increased alertness, and reduction in both hospital admissions and inpatient days in a 14-year-old female patient with NP-C. Our experience may encourage further research into how KDT can be beneficially deployed in NP-C patients.
Synopsis
Over 3y beginning at age 14y in a girl with NP-C, classical KDT combined with miglustat, levetiracetam, and clobazam improved quality of life over that achieved with miglustat, levetiracetam, and clobazam. KDT reduced seizure activity and increased patient alertness.
Details of contribution of individual authors
Alexander Höller is a pediatric dietitian specializing in inborn disorders of metabolism and neuropediatrics.
Daniela Karall, Sabine Scholl-Bürgi, Sara Baumgartner Sigl, and Ursula Albrecht are pediatricians specializing in inborn disorders of metabolism and neuropediatrics.
Thomas Zöggeler, Gabriele Ramoser, and Benoit Bernar are physicians training in pediatrics.
Author who serves as guarantor for the article: Sabine Scholl-Bürgi.
Declaration of Competing Interest
All authors declare that they have no competing interest. | CLOBAZAM, LEVETIRACETAM, MIDAZOLAM, MIGLUSTAT | DrugsGivenReaction | CC BY-NC-ND | 33598405 | 19,465,164 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Multiple-drug resistance'. | Successful implementation of classical ketogenic dietary therapy in a patient with Niemann-Pick disease type C.
Niemann-Pick disease type C (NP-C) is a neurodegenerative disease for which only palliative treatment exists, and only miglustat is effective in stabilizing neurological manifestations of NP-C. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders, including those associated with various inherited metabolic diseases (IMD), to reduce seizure frequency and medication requirement as well as to confer neuroprotection. Since patients with NP-C suffer pharmacorefractory seizures associated with ongoing neurodegeneration, KDT might be beneficial. The concomitant use of miglustat and KDT in patients with NP-C has not been reported.
We describe our experience in a now 17-year-old female with NP-C manifest early in childhood who has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y. Although the neurodegeneration of NP-C progressed, she benefited from a reduction in seizure activity, fewer hospital stays related to seizure exacerbation, and increased alertness.
KDT could be safely deployed in our patient with NP-C, in whom its effects have been beneficial. Generally KDT is demonstratedly efficacious in patients with epilepsy and IMD. It reduces seizure activity and medication requirements and confers neuroprotection. Intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake.
1 Introduction
Niemann-Pick disease type C (NP-C) is a rare neurovisceral lysosomal disorder with autosomal recessive inheritance caused by mutations in either NPC1 (95%) or NPC2 (~4%) [1].
NP-C is characterized by abnormal lysosomal accumulation of unesterified cholesterol and glycolipids that results in progressive neurological deterioration, severe loss of quality of life, and premature death [2]. The only available drug effective in stabilizing neurological manifestations is miglustat [[2], [3], [4], [5]].
Yet NP-C is an invariably progressive disease and therapy is limited to delaying deterioration. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders and various inherited metabolic diseases (IMD) that conduce to seizure disorders. They reduce seizure activity and medication requirements and protect neurologic function [6,7]. Although dietary carbohydrate modification and restriction in patients with NP-C is discussed to ameliorate the gastrointestinal side effects associated with miglustat therapy [8], the concomitant use of miglustat and KDT in patients with NP-C is not described. In a case series where the long-term effects of intrathecal 2-Hydroxypropyl-β-Cyclodextrin treatment was evaluated, one patient who was on KDT prior to diagnosis and miglustat therapy was included who did not show any apparent benefit of KDT [9].
2 Case report
We describe our experience in attending a now 17-year-old female with NP-C manifest aged 3y that has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y at this writing. This therapy reduced seizure frequency and hospital stays and improved patient alertness.
2.1 Initial findings and diagnosis
Our patient was born at term after an uneventful second pregnancy to non-consanguineous Caucasian parents. The first pregnancy ended in spontaneous abortion. The mother has epilepsy treated with carbamazepine.
The parents reported motor and language developmental delay apparent at age 3y. The patient was seen in our clinic first at age 5y; no diagnosis was assigned. Behavioral disturbances began at age 9y, with self-harming and injury to others, ataxia, dysphagia, and repetitive seizures. This prompted re-assessment. Bilateral oculomotor palsy was found, with exotropia. Abdominal sonography showed mesenteric lymphadenopathy and hepatosplenomegaly. A lysosomal storage disease was suspected. Filipin staining of skin fibroblasts found accumulation of unesterified cholesterol in the endosomal/lysosomal compartment, permitting the diagnosis of NP-C. The patient proved to harbor biallelic mutations in NPC1 (c.1421C>T/p.Pro474Leu, known [10], and c.3289_3291del/p.Asp1097del).
2.2 Treatment and clinical course
Anti-epileptic treatment with levetiracetam (LEV; initial target dose, 30 mg/kg/d) was initiated empirically at age 9y, when seizures began. Immediately after definitive diagnosis (still at age 9y), substrate reduction therapy with miglustat was initiated (400 mg/m2 body surface area/d). Emesis and diarrhoea were mild. After 2mo, seizures worsened and expressive speech was entirely lost. LEV therapy was thus increased stagewise (dose achieved, 50 mg/kg/d).
At age 10y exotropia and hand-eye-coordination improved. Over the next 2y, however, neurodegenerative worsening was volatile, with emergence of swallowing difficulties that led to malnutrition. A gastrostomy thus was placed at age 12y and an overnight partial continuous feeding regimen (1/3 of estimated total energy expenditure = 500 kcal) was established. At the same time, the patient lost ability to walk. Alternating patterns of high- and low- (1–2 seizures a day) seizure frequency (respectively 20 seizures/h and 1–2/d) characterized the patient's 12th and 13th years of life. At age 13y gastrointestinal manifestations emerged (chronic constipation, successfully treated with soluble fibre). At age 14y exacerbations of seizures led to escalation of anti-epileptic treatment. Buccal midazolam (10 mg) was used as rescue medication for seizures lasting longer than 5 min. The patient's LEV was enhanced (dose achieved, 70 mg/kg/d) and complemented with clobazam (CLB; 0.15 mg/kg/d). Yet neurological deterioration progressed, in particular seizure severity and seizure frequency.
After 3mo of unsatisfactory drug therapy, we re-considered the therapeutic options. Expecting more side effects without improvements if another anti-epileptic drug was begun, we decided to initiate a classical KDT with a ketogenic ratio of 4:1 whilst continuing the drug regimen then in place.
Enteral feeding via gastrostomy facilitated this, using a ketogenic formula (fat to non-fat 4:1). KDT is traditionally introduced by increasing the ketogenic ratio stepwise. We replaced one-third of calories/d until full tolerance was achieved (1560 kcal/d, 45 kcal/kg). Within 5d whole blood β-hydroxybutyrate (B-OHB) levels rose to 2.7 mmol/L (Fig. 1). Duration and frequency of seizures fell (Fig. 1) and alertness increased. Although neurodegeneration was thought to progress, with persistent and worsening signs, during the first 3y of KDT, average hospital admissions and inpatient days were fewer within 3y under KDT than during the 3y before (10 vs. 14 and 94 vs. 113 respectively).Fig. 1 Ketosis (serum B-OHB levels) and seizure frequency during KDT.
Fig. 1
As electroencephalography (EEG) was stressful for our patient and little clinical benefit was expected, it was limited to a minimum. EEG 10mo prior to KDT showed multifocal as well as generalized epileptogenic activity as typically seen in patients with Lennox-Gastaut syndrome. After initiation of KDT, little changed yet stabilized epileptogenic activity was observed. Changes included slowing of background rhythm and continuous disorganization of sleep related elements. Generalized seizures were solely identified by an increased activity from 6 to 8/s to 14-30/s for 30 to 120 s.
The 3rd year of KDT saw an abrupt rise in hospital admissions and inpatient days that we ascribe to personnel and structural changes in the care facility where the patient lives rather than to a change in her disorder. After initiation of KDT no further hospital admissions due to seizure exacerbation were necessary (Fig. 2). Seizure duration remains <5 min even after 3y on KDT. The patient now, at age 17y, has received KDT for 3y without any identified KDT-associated side effects.Fig. 2 Hospital admissions and inpatient days before and after initiation of KDT.
Fig. 2
3 Discussion
Concomitant use of miglustat and KDT (“Syner-G”) improves survival in patients with GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease) [11]. Ketosis may increase miglustat uptake and accumulation in forebrain of the β-hexosaminidase (Hexb) knockout (−/−) murine model of Sandhoff disease [12].
How KDT acts in pharmacoresistant epilepsy is not fully understood. Proposed mechanisms are linked either to direct effects of ketones and of glucose restriction or to interactions with receptors, channels, and metabolic enzymes [13]. KDTs in IMDs are used either to target the underlying metabolic disorder (e.g., glucose transporter type 1 deficiency syndrome) or to target symptoms (e.g., seizures in non-ketotic hyperglycinemia) [14]. They efficaciously reduce seizure activity and medication requirements and confer neuroprotection. One of the hypotheses of underlying pathophysiology in NP-C is that it triggers oxidative stress damage and apoptotic cell death [15]. Chronic ketosis as induced via KDT is thought to limit reactive oxygen species generation and thus might prevent apoptosis [16]. In addition, carbohydrate modification and reduction as derived by KDT could show successful amelioration of gastrointestinal side effects associated with miglustat in two patients with NP-C [8].
Although intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake, fat-rich KDT can perhaps be safely deployed in patients with NP-C, in whom its effects may be beneficial.
4 Conclusion
In a non-terminal palliative care setting, KDT could temporarily improve quality of life through reduction in seizure activity, increased alertness, and reduction in both hospital admissions and inpatient days in a 14-year-old female patient with NP-C. Our experience may encourage further research into how KDT can be beneficially deployed in NP-C patients.
Synopsis
Over 3y beginning at age 14y in a girl with NP-C, classical KDT combined with miglustat, levetiracetam, and clobazam improved quality of life over that achieved with miglustat, levetiracetam, and clobazam. KDT reduced seizure activity and increased patient alertness.
Details of contribution of individual authors
Alexander Höller is a pediatric dietitian specializing in inborn disorders of metabolism and neuropediatrics.
Daniela Karall, Sabine Scholl-Bürgi, Sara Baumgartner Sigl, and Ursula Albrecht are pediatricians specializing in inborn disorders of metabolism and neuropediatrics.
Thomas Zöggeler, Gabriele Ramoser, and Benoit Bernar are physicians training in pediatrics.
Author who serves as guarantor for the article: Sabine Scholl-Bürgi.
Declaration of Competing Interest
All authors declare that they have no competing interest. | CLOBAZAM, LEVETIRACETAM, MIDAZOLAM, MIGLUSTAT | DrugsGivenReaction | CC BY-NC-ND | 33598405 | 19,465,164 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Seizure'. | Successful implementation of classical ketogenic dietary therapy in a patient with Niemann-Pick disease type C.
Niemann-Pick disease type C (NP-C) is a neurodegenerative disease for which only palliative treatment exists, and only miglustat is effective in stabilizing neurological manifestations of NP-C. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders, including those associated with various inherited metabolic diseases (IMD), to reduce seizure frequency and medication requirement as well as to confer neuroprotection. Since patients with NP-C suffer pharmacorefractory seizures associated with ongoing neurodegeneration, KDT might be beneficial. The concomitant use of miglustat and KDT in patients with NP-C has not been reported.
We describe our experience in a now 17-year-old female with NP-C manifest early in childhood who has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y. Although the neurodegeneration of NP-C progressed, she benefited from a reduction in seizure activity, fewer hospital stays related to seizure exacerbation, and increased alertness.
KDT could be safely deployed in our patient with NP-C, in whom its effects have been beneficial. Generally KDT is demonstratedly efficacious in patients with epilepsy and IMD. It reduces seizure activity and medication requirements and confers neuroprotection. Intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake.
1 Introduction
Niemann-Pick disease type C (NP-C) is a rare neurovisceral lysosomal disorder with autosomal recessive inheritance caused by mutations in either NPC1 (95%) or NPC2 (~4%) [1].
NP-C is characterized by abnormal lysosomal accumulation of unesterified cholesterol and glycolipids that results in progressive neurological deterioration, severe loss of quality of life, and premature death [2]. The only available drug effective in stabilizing neurological manifestations is miglustat [[2], [3], [4], [5]].
Yet NP-C is an invariably progressive disease and therapy is limited to delaying deterioration. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders and various inherited metabolic diseases (IMD) that conduce to seizure disorders. They reduce seizure activity and medication requirements and protect neurologic function [6,7]. Although dietary carbohydrate modification and restriction in patients with NP-C is discussed to ameliorate the gastrointestinal side effects associated with miglustat therapy [8], the concomitant use of miglustat and KDT in patients with NP-C is not described. In a case series where the long-term effects of intrathecal 2-Hydroxypropyl-β-Cyclodextrin treatment was evaluated, one patient who was on KDT prior to diagnosis and miglustat therapy was included who did not show any apparent benefit of KDT [9].
2 Case report
We describe our experience in attending a now 17-year-old female with NP-C manifest aged 3y that has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y at this writing. This therapy reduced seizure frequency and hospital stays and improved patient alertness.
2.1 Initial findings and diagnosis
Our patient was born at term after an uneventful second pregnancy to non-consanguineous Caucasian parents. The first pregnancy ended in spontaneous abortion. The mother has epilepsy treated with carbamazepine.
The parents reported motor and language developmental delay apparent at age 3y. The patient was seen in our clinic first at age 5y; no diagnosis was assigned. Behavioral disturbances began at age 9y, with self-harming and injury to others, ataxia, dysphagia, and repetitive seizures. This prompted re-assessment. Bilateral oculomotor palsy was found, with exotropia. Abdominal sonography showed mesenteric lymphadenopathy and hepatosplenomegaly. A lysosomal storage disease was suspected. Filipin staining of skin fibroblasts found accumulation of unesterified cholesterol in the endosomal/lysosomal compartment, permitting the diagnosis of NP-C. The patient proved to harbor biallelic mutations in NPC1 (c.1421C>T/p.Pro474Leu, known [10], and c.3289_3291del/p.Asp1097del).
2.2 Treatment and clinical course
Anti-epileptic treatment with levetiracetam (LEV; initial target dose, 30 mg/kg/d) was initiated empirically at age 9y, when seizures began. Immediately after definitive diagnosis (still at age 9y), substrate reduction therapy with miglustat was initiated (400 mg/m2 body surface area/d). Emesis and diarrhoea were mild. After 2mo, seizures worsened and expressive speech was entirely lost. LEV therapy was thus increased stagewise (dose achieved, 50 mg/kg/d).
At age 10y exotropia and hand-eye-coordination improved. Over the next 2y, however, neurodegenerative worsening was volatile, with emergence of swallowing difficulties that led to malnutrition. A gastrostomy thus was placed at age 12y and an overnight partial continuous feeding regimen (1/3 of estimated total energy expenditure = 500 kcal) was established. At the same time, the patient lost ability to walk. Alternating patterns of high- and low- (1–2 seizures a day) seizure frequency (respectively 20 seizures/h and 1–2/d) characterized the patient's 12th and 13th years of life. At age 13y gastrointestinal manifestations emerged (chronic constipation, successfully treated with soluble fibre). At age 14y exacerbations of seizures led to escalation of anti-epileptic treatment. Buccal midazolam (10 mg) was used as rescue medication for seizures lasting longer than 5 min. The patient's LEV was enhanced (dose achieved, 70 mg/kg/d) and complemented with clobazam (CLB; 0.15 mg/kg/d). Yet neurological deterioration progressed, in particular seizure severity and seizure frequency.
After 3mo of unsatisfactory drug therapy, we re-considered the therapeutic options. Expecting more side effects without improvements if another anti-epileptic drug was begun, we decided to initiate a classical KDT with a ketogenic ratio of 4:1 whilst continuing the drug regimen then in place.
Enteral feeding via gastrostomy facilitated this, using a ketogenic formula (fat to non-fat 4:1). KDT is traditionally introduced by increasing the ketogenic ratio stepwise. We replaced one-third of calories/d until full tolerance was achieved (1560 kcal/d, 45 kcal/kg). Within 5d whole blood β-hydroxybutyrate (B-OHB) levels rose to 2.7 mmol/L (Fig. 1). Duration and frequency of seizures fell (Fig. 1) and alertness increased. Although neurodegeneration was thought to progress, with persistent and worsening signs, during the first 3y of KDT, average hospital admissions and inpatient days were fewer within 3y under KDT than during the 3y before (10 vs. 14 and 94 vs. 113 respectively).Fig. 1 Ketosis (serum B-OHB levels) and seizure frequency during KDT.
Fig. 1
As electroencephalography (EEG) was stressful for our patient and little clinical benefit was expected, it was limited to a minimum. EEG 10mo prior to KDT showed multifocal as well as generalized epileptogenic activity as typically seen in patients with Lennox-Gastaut syndrome. After initiation of KDT, little changed yet stabilized epileptogenic activity was observed. Changes included slowing of background rhythm and continuous disorganization of sleep related elements. Generalized seizures were solely identified by an increased activity from 6 to 8/s to 14-30/s for 30 to 120 s.
The 3rd year of KDT saw an abrupt rise in hospital admissions and inpatient days that we ascribe to personnel and structural changes in the care facility where the patient lives rather than to a change in her disorder. After initiation of KDT no further hospital admissions due to seizure exacerbation were necessary (Fig. 2). Seizure duration remains <5 min even after 3y on KDT. The patient now, at age 17y, has received KDT for 3y without any identified KDT-associated side effects.Fig. 2 Hospital admissions and inpatient days before and after initiation of KDT.
Fig. 2
3 Discussion
Concomitant use of miglustat and KDT (“Syner-G”) improves survival in patients with GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease) [11]. Ketosis may increase miglustat uptake and accumulation in forebrain of the β-hexosaminidase (Hexb) knockout (−/−) murine model of Sandhoff disease [12].
How KDT acts in pharmacoresistant epilepsy is not fully understood. Proposed mechanisms are linked either to direct effects of ketones and of glucose restriction or to interactions with receptors, channels, and metabolic enzymes [13]. KDTs in IMDs are used either to target the underlying metabolic disorder (e.g., glucose transporter type 1 deficiency syndrome) or to target symptoms (e.g., seizures in non-ketotic hyperglycinemia) [14]. They efficaciously reduce seizure activity and medication requirements and confer neuroprotection. One of the hypotheses of underlying pathophysiology in NP-C is that it triggers oxidative stress damage and apoptotic cell death [15]. Chronic ketosis as induced via KDT is thought to limit reactive oxygen species generation and thus might prevent apoptosis [16]. In addition, carbohydrate modification and reduction as derived by KDT could show successful amelioration of gastrointestinal side effects associated with miglustat in two patients with NP-C [8].
Although intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake, fat-rich KDT can perhaps be safely deployed in patients with NP-C, in whom its effects may be beneficial.
4 Conclusion
In a non-terminal palliative care setting, KDT could temporarily improve quality of life through reduction in seizure activity, increased alertness, and reduction in both hospital admissions and inpatient days in a 14-year-old female patient with NP-C. Our experience may encourage further research into how KDT can be beneficially deployed in NP-C patients.
Synopsis
Over 3y beginning at age 14y in a girl with NP-C, classical KDT combined with miglustat, levetiracetam, and clobazam improved quality of life over that achieved with miglustat, levetiracetam, and clobazam. KDT reduced seizure activity and increased patient alertness.
Details of contribution of individual authors
Alexander Höller is a pediatric dietitian specializing in inborn disorders of metabolism and neuropediatrics.
Daniela Karall, Sabine Scholl-Bürgi, Sara Baumgartner Sigl, and Ursula Albrecht are pediatricians specializing in inborn disorders of metabolism and neuropediatrics.
Thomas Zöggeler, Gabriele Ramoser, and Benoit Bernar are physicians training in pediatrics.
Author who serves as guarantor for the article: Sabine Scholl-Bürgi.
Declaration of Competing Interest
All authors declare that they have no competing interest. | CLOBAZAM, LEVETIRACETAM, MIDAZOLAM, MIGLUSTAT | DrugsGivenReaction | CC BY-NC-ND | 33598405 | 19,465,164 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vomiting'. | Successful implementation of classical ketogenic dietary therapy in a patient with Niemann-Pick disease type C.
Niemann-Pick disease type C (NP-C) is a neurodegenerative disease for which only palliative treatment exists, and only miglustat is effective in stabilizing neurological manifestations of NP-C. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders, including those associated with various inherited metabolic diseases (IMD), to reduce seizure frequency and medication requirement as well as to confer neuroprotection. Since patients with NP-C suffer pharmacorefractory seizures associated with ongoing neurodegeneration, KDT might be beneficial. The concomitant use of miglustat and KDT in patients with NP-C has not been reported.
We describe our experience in a now 17-year-old female with NP-C manifest early in childhood who has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y. Although the neurodegeneration of NP-C progressed, she benefited from a reduction in seizure activity, fewer hospital stays related to seizure exacerbation, and increased alertness.
KDT could be safely deployed in our patient with NP-C, in whom its effects have been beneficial. Generally KDT is demonstratedly efficacious in patients with epilepsy and IMD. It reduces seizure activity and medication requirements and confers neuroprotection. Intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake.
1 Introduction
Niemann-Pick disease type C (NP-C) is a rare neurovisceral lysosomal disorder with autosomal recessive inheritance caused by mutations in either NPC1 (95%) or NPC2 (~4%) [1].
NP-C is characterized by abnormal lysosomal accumulation of unesterified cholesterol and glycolipids that results in progressive neurological deterioration, severe loss of quality of life, and premature death [2]. The only available drug effective in stabilizing neurological manifestations is miglustat [[2], [3], [4], [5]].
Yet NP-C is an invariably progressive disease and therapy is limited to delaying deterioration. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders and various inherited metabolic diseases (IMD) that conduce to seizure disorders. They reduce seizure activity and medication requirements and protect neurologic function [6,7]. Although dietary carbohydrate modification and restriction in patients with NP-C is discussed to ameliorate the gastrointestinal side effects associated with miglustat therapy [8], the concomitant use of miglustat and KDT in patients with NP-C is not described. In a case series where the long-term effects of intrathecal 2-Hydroxypropyl-β-Cyclodextrin treatment was evaluated, one patient who was on KDT prior to diagnosis and miglustat therapy was included who did not show any apparent benefit of KDT [9].
2 Case report
We describe our experience in attending a now 17-year-old female with NP-C manifest aged 3y that has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y at this writing. This therapy reduced seizure frequency and hospital stays and improved patient alertness.
2.1 Initial findings and diagnosis
Our patient was born at term after an uneventful second pregnancy to non-consanguineous Caucasian parents. The first pregnancy ended in spontaneous abortion. The mother has epilepsy treated with carbamazepine.
The parents reported motor and language developmental delay apparent at age 3y. The patient was seen in our clinic first at age 5y; no diagnosis was assigned. Behavioral disturbances began at age 9y, with self-harming and injury to others, ataxia, dysphagia, and repetitive seizures. This prompted re-assessment. Bilateral oculomotor palsy was found, with exotropia. Abdominal sonography showed mesenteric lymphadenopathy and hepatosplenomegaly. A lysosomal storage disease was suspected. Filipin staining of skin fibroblasts found accumulation of unesterified cholesterol in the endosomal/lysosomal compartment, permitting the diagnosis of NP-C. The patient proved to harbor biallelic mutations in NPC1 (c.1421C>T/p.Pro474Leu, known [10], and c.3289_3291del/p.Asp1097del).
2.2 Treatment and clinical course
Anti-epileptic treatment with levetiracetam (LEV; initial target dose, 30 mg/kg/d) was initiated empirically at age 9y, when seizures began. Immediately after definitive diagnosis (still at age 9y), substrate reduction therapy with miglustat was initiated (400 mg/m2 body surface area/d). Emesis and diarrhoea were mild. After 2mo, seizures worsened and expressive speech was entirely lost. LEV therapy was thus increased stagewise (dose achieved, 50 mg/kg/d).
At age 10y exotropia and hand-eye-coordination improved. Over the next 2y, however, neurodegenerative worsening was volatile, with emergence of swallowing difficulties that led to malnutrition. A gastrostomy thus was placed at age 12y and an overnight partial continuous feeding regimen (1/3 of estimated total energy expenditure = 500 kcal) was established. At the same time, the patient lost ability to walk. Alternating patterns of high- and low- (1–2 seizures a day) seizure frequency (respectively 20 seizures/h and 1–2/d) characterized the patient's 12th and 13th years of life. At age 13y gastrointestinal manifestations emerged (chronic constipation, successfully treated with soluble fibre). At age 14y exacerbations of seizures led to escalation of anti-epileptic treatment. Buccal midazolam (10 mg) was used as rescue medication for seizures lasting longer than 5 min. The patient's LEV was enhanced (dose achieved, 70 mg/kg/d) and complemented with clobazam (CLB; 0.15 mg/kg/d). Yet neurological deterioration progressed, in particular seizure severity and seizure frequency.
After 3mo of unsatisfactory drug therapy, we re-considered the therapeutic options. Expecting more side effects without improvements if another anti-epileptic drug was begun, we decided to initiate a classical KDT with a ketogenic ratio of 4:1 whilst continuing the drug regimen then in place.
Enteral feeding via gastrostomy facilitated this, using a ketogenic formula (fat to non-fat 4:1). KDT is traditionally introduced by increasing the ketogenic ratio stepwise. We replaced one-third of calories/d until full tolerance was achieved (1560 kcal/d, 45 kcal/kg). Within 5d whole blood β-hydroxybutyrate (B-OHB) levels rose to 2.7 mmol/L (Fig. 1). Duration and frequency of seizures fell (Fig. 1) and alertness increased. Although neurodegeneration was thought to progress, with persistent and worsening signs, during the first 3y of KDT, average hospital admissions and inpatient days were fewer within 3y under KDT than during the 3y before (10 vs. 14 and 94 vs. 113 respectively).Fig. 1 Ketosis (serum B-OHB levels) and seizure frequency during KDT.
Fig. 1
As electroencephalography (EEG) was stressful for our patient and little clinical benefit was expected, it was limited to a minimum. EEG 10mo prior to KDT showed multifocal as well as generalized epileptogenic activity as typically seen in patients with Lennox-Gastaut syndrome. After initiation of KDT, little changed yet stabilized epileptogenic activity was observed. Changes included slowing of background rhythm and continuous disorganization of sleep related elements. Generalized seizures were solely identified by an increased activity from 6 to 8/s to 14-30/s for 30 to 120 s.
The 3rd year of KDT saw an abrupt rise in hospital admissions and inpatient days that we ascribe to personnel and structural changes in the care facility where the patient lives rather than to a change in her disorder. After initiation of KDT no further hospital admissions due to seizure exacerbation were necessary (Fig. 2). Seizure duration remains <5 min even after 3y on KDT. The patient now, at age 17y, has received KDT for 3y without any identified KDT-associated side effects.Fig. 2 Hospital admissions and inpatient days before and after initiation of KDT.
Fig. 2
3 Discussion
Concomitant use of miglustat and KDT (“Syner-G”) improves survival in patients with GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease) [11]. Ketosis may increase miglustat uptake and accumulation in forebrain of the β-hexosaminidase (Hexb) knockout (−/−) murine model of Sandhoff disease [12].
How KDT acts in pharmacoresistant epilepsy is not fully understood. Proposed mechanisms are linked either to direct effects of ketones and of glucose restriction or to interactions with receptors, channels, and metabolic enzymes [13]. KDTs in IMDs are used either to target the underlying metabolic disorder (e.g., glucose transporter type 1 deficiency syndrome) or to target symptoms (e.g., seizures in non-ketotic hyperglycinemia) [14]. They efficaciously reduce seizure activity and medication requirements and confer neuroprotection. One of the hypotheses of underlying pathophysiology in NP-C is that it triggers oxidative stress damage and apoptotic cell death [15]. Chronic ketosis as induced via KDT is thought to limit reactive oxygen species generation and thus might prevent apoptosis [16]. In addition, carbohydrate modification and reduction as derived by KDT could show successful amelioration of gastrointestinal side effects associated with miglustat in two patients with NP-C [8].
Although intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake, fat-rich KDT can perhaps be safely deployed in patients with NP-C, in whom its effects may be beneficial.
4 Conclusion
In a non-terminal palliative care setting, KDT could temporarily improve quality of life through reduction in seizure activity, increased alertness, and reduction in both hospital admissions and inpatient days in a 14-year-old female patient with NP-C. Our experience may encourage further research into how KDT can be beneficially deployed in NP-C patients.
Synopsis
Over 3y beginning at age 14y in a girl with NP-C, classical KDT combined with miglustat, levetiracetam, and clobazam improved quality of life over that achieved with miglustat, levetiracetam, and clobazam. KDT reduced seizure activity and increased patient alertness.
Details of contribution of individual authors
Alexander Höller is a pediatric dietitian specializing in inborn disorders of metabolism and neuropediatrics.
Daniela Karall, Sabine Scholl-Bürgi, Sara Baumgartner Sigl, and Ursula Albrecht are pediatricians specializing in inborn disorders of metabolism and neuropediatrics.
Thomas Zöggeler, Gabriele Ramoser, and Benoit Bernar are physicians training in pediatrics.
Author who serves as guarantor for the article: Sabine Scholl-Bürgi.
Declaration of Competing Interest
All authors declare that they have no competing interest. | CLOBAZAM, LEVETIRACETAM, MIDAZOLAM, MIGLUSTAT | DrugsGivenReaction | CC BY-NC-ND | 33598405 | 19,465,164 | 2021-06 |
What was the administration route of drug 'MIDAZOLAM'? | Successful implementation of classical ketogenic dietary therapy in a patient with Niemann-Pick disease type C.
Niemann-Pick disease type C (NP-C) is a neurodegenerative disease for which only palliative treatment exists, and only miglustat is effective in stabilizing neurological manifestations of NP-C. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders, including those associated with various inherited metabolic diseases (IMD), to reduce seizure frequency and medication requirement as well as to confer neuroprotection. Since patients with NP-C suffer pharmacorefractory seizures associated with ongoing neurodegeneration, KDT might be beneficial. The concomitant use of miglustat and KDT in patients with NP-C has not been reported.
We describe our experience in a now 17-year-old female with NP-C manifest early in childhood who has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y. Although the neurodegeneration of NP-C progressed, she benefited from a reduction in seizure activity, fewer hospital stays related to seizure exacerbation, and increased alertness.
KDT could be safely deployed in our patient with NP-C, in whom its effects have been beneficial. Generally KDT is demonstratedly efficacious in patients with epilepsy and IMD. It reduces seizure activity and medication requirements and confers neuroprotection. Intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake.
1 Introduction
Niemann-Pick disease type C (NP-C) is a rare neurovisceral lysosomal disorder with autosomal recessive inheritance caused by mutations in either NPC1 (95%) or NPC2 (~4%) [1].
NP-C is characterized by abnormal lysosomal accumulation of unesterified cholesterol and glycolipids that results in progressive neurological deterioration, severe loss of quality of life, and premature death [2]. The only available drug effective in stabilizing neurological manifestations is miglustat [[2], [3], [4], [5]].
Yet NP-C is an invariably progressive disease and therapy is limited to delaying deterioration. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders and various inherited metabolic diseases (IMD) that conduce to seizure disorders. They reduce seizure activity and medication requirements and protect neurologic function [6,7]. Although dietary carbohydrate modification and restriction in patients with NP-C is discussed to ameliorate the gastrointestinal side effects associated with miglustat therapy [8], the concomitant use of miglustat and KDT in patients with NP-C is not described. In a case series where the long-term effects of intrathecal 2-Hydroxypropyl-β-Cyclodextrin treatment was evaluated, one patient who was on KDT prior to diagnosis and miglustat therapy was included who did not show any apparent benefit of KDT [9].
2 Case report
We describe our experience in attending a now 17-year-old female with NP-C manifest aged 3y that has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y at this writing. This therapy reduced seizure frequency and hospital stays and improved patient alertness.
2.1 Initial findings and diagnosis
Our patient was born at term after an uneventful second pregnancy to non-consanguineous Caucasian parents. The first pregnancy ended in spontaneous abortion. The mother has epilepsy treated with carbamazepine.
The parents reported motor and language developmental delay apparent at age 3y. The patient was seen in our clinic first at age 5y; no diagnosis was assigned. Behavioral disturbances began at age 9y, with self-harming and injury to others, ataxia, dysphagia, and repetitive seizures. This prompted re-assessment. Bilateral oculomotor palsy was found, with exotropia. Abdominal sonography showed mesenteric lymphadenopathy and hepatosplenomegaly. A lysosomal storage disease was suspected. Filipin staining of skin fibroblasts found accumulation of unesterified cholesterol in the endosomal/lysosomal compartment, permitting the diagnosis of NP-C. The patient proved to harbor biallelic mutations in NPC1 (c.1421C>T/p.Pro474Leu, known [10], and c.3289_3291del/p.Asp1097del).
2.2 Treatment and clinical course
Anti-epileptic treatment with levetiracetam (LEV; initial target dose, 30 mg/kg/d) was initiated empirically at age 9y, when seizures began. Immediately after definitive diagnosis (still at age 9y), substrate reduction therapy with miglustat was initiated (400 mg/m2 body surface area/d). Emesis and diarrhoea were mild. After 2mo, seizures worsened and expressive speech was entirely lost. LEV therapy was thus increased stagewise (dose achieved, 50 mg/kg/d).
At age 10y exotropia and hand-eye-coordination improved. Over the next 2y, however, neurodegenerative worsening was volatile, with emergence of swallowing difficulties that led to malnutrition. A gastrostomy thus was placed at age 12y and an overnight partial continuous feeding regimen (1/3 of estimated total energy expenditure = 500 kcal) was established. At the same time, the patient lost ability to walk. Alternating patterns of high- and low- (1–2 seizures a day) seizure frequency (respectively 20 seizures/h and 1–2/d) characterized the patient's 12th and 13th years of life. At age 13y gastrointestinal manifestations emerged (chronic constipation, successfully treated with soluble fibre). At age 14y exacerbations of seizures led to escalation of anti-epileptic treatment. Buccal midazolam (10 mg) was used as rescue medication for seizures lasting longer than 5 min. The patient's LEV was enhanced (dose achieved, 70 mg/kg/d) and complemented with clobazam (CLB; 0.15 mg/kg/d). Yet neurological deterioration progressed, in particular seizure severity and seizure frequency.
After 3mo of unsatisfactory drug therapy, we re-considered the therapeutic options. Expecting more side effects without improvements if another anti-epileptic drug was begun, we decided to initiate a classical KDT with a ketogenic ratio of 4:1 whilst continuing the drug regimen then in place.
Enteral feeding via gastrostomy facilitated this, using a ketogenic formula (fat to non-fat 4:1). KDT is traditionally introduced by increasing the ketogenic ratio stepwise. We replaced one-third of calories/d until full tolerance was achieved (1560 kcal/d, 45 kcal/kg). Within 5d whole blood β-hydroxybutyrate (B-OHB) levels rose to 2.7 mmol/L (Fig. 1). Duration and frequency of seizures fell (Fig. 1) and alertness increased. Although neurodegeneration was thought to progress, with persistent and worsening signs, during the first 3y of KDT, average hospital admissions and inpatient days were fewer within 3y under KDT than during the 3y before (10 vs. 14 and 94 vs. 113 respectively).Fig. 1 Ketosis (serum B-OHB levels) and seizure frequency during KDT.
Fig. 1
As electroencephalography (EEG) was stressful for our patient and little clinical benefit was expected, it was limited to a minimum. EEG 10mo prior to KDT showed multifocal as well as generalized epileptogenic activity as typically seen in patients with Lennox-Gastaut syndrome. After initiation of KDT, little changed yet stabilized epileptogenic activity was observed. Changes included slowing of background rhythm and continuous disorganization of sleep related elements. Generalized seizures were solely identified by an increased activity from 6 to 8/s to 14-30/s for 30 to 120 s.
The 3rd year of KDT saw an abrupt rise in hospital admissions and inpatient days that we ascribe to personnel and structural changes in the care facility where the patient lives rather than to a change in her disorder. After initiation of KDT no further hospital admissions due to seizure exacerbation were necessary (Fig. 2). Seizure duration remains <5 min even after 3y on KDT. The patient now, at age 17y, has received KDT for 3y without any identified KDT-associated side effects.Fig. 2 Hospital admissions and inpatient days before and after initiation of KDT.
Fig. 2
3 Discussion
Concomitant use of miglustat and KDT (“Syner-G”) improves survival in patients with GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease) [11]. Ketosis may increase miglustat uptake and accumulation in forebrain of the β-hexosaminidase (Hexb) knockout (−/−) murine model of Sandhoff disease [12].
How KDT acts in pharmacoresistant epilepsy is not fully understood. Proposed mechanisms are linked either to direct effects of ketones and of glucose restriction or to interactions with receptors, channels, and metabolic enzymes [13]. KDTs in IMDs are used either to target the underlying metabolic disorder (e.g., glucose transporter type 1 deficiency syndrome) or to target symptoms (e.g., seizures in non-ketotic hyperglycinemia) [14]. They efficaciously reduce seizure activity and medication requirements and confer neuroprotection. One of the hypotheses of underlying pathophysiology in NP-C is that it triggers oxidative stress damage and apoptotic cell death [15]. Chronic ketosis as induced via KDT is thought to limit reactive oxygen species generation and thus might prevent apoptosis [16]. In addition, carbohydrate modification and reduction as derived by KDT could show successful amelioration of gastrointestinal side effects associated with miglustat in two patients with NP-C [8].
Although intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake, fat-rich KDT can perhaps be safely deployed in patients with NP-C, in whom its effects may be beneficial.
4 Conclusion
In a non-terminal palliative care setting, KDT could temporarily improve quality of life through reduction in seizure activity, increased alertness, and reduction in both hospital admissions and inpatient days in a 14-year-old female patient with NP-C. Our experience may encourage further research into how KDT can be beneficially deployed in NP-C patients.
Synopsis
Over 3y beginning at age 14y in a girl with NP-C, classical KDT combined with miglustat, levetiracetam, and clobazam improved quality of life over that achieved with miglustat, levetiracetam, and clobazam. KDT reduced seizure activity and increased patient alertness.
Details of contribution of individual authors
Alexander Höller is a pediatric dietitian specializing in inborn disorders of metabolism and neuropediatrics.
Daniela Karall, Sabine Scholl-Bürgi, Sara Baumgartner Sigl, and Ursula Albrecht are pediatricians specializing in inborn disorders of metabolism and neuropediatrics.
Thomas Zöggeler, Gabriele Ramoser, and Benoit Bernar are physicians training in pediatrics.
Author who serves as guarantor for the article: Sabine Scholl-Bürgi.
Declaration of Competing Interest
All authors declare that they have no competing interest. | Buccal | DrugAdministrationRoute | CC BY-NC-ND | 33598405 | 19,465,164 | 2021-06 |
What was the dosage of drug 'CLOBAZAM'? | Successful implementation of classical ketogenic dietary therapy in a patient with Niemann-Pick disease type C.
Niemann-Pick disease type C (NP-C) is a neurodegenerative disease for which only palliative treatment exists, and only miglustat is effective in stabilizing neurological manifestations of NP-C. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders, including those associated with various inherited metabolic diseases (IMD), to reduce seizure frequency and medication requirement as well as to confer neuroprotection. Since patients with NP-C suffer pharmacorefractory seizures associated with ongoing neurodegeneration, KDT might be beneficial. The concomitant use of miglustat and KDT in patients with NP-C has not been reported.
We describe our experience in a now 17-year-old female with NP-C manifest early in childhood who has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y. Although the neurodegeneration of NP-C progressed, she benefited from a reduction in seizure activity, fewer hospital stays related to seizure exacerbation, and increased alertness.
KDT could be safely deployed in our patient with NP-C, in whom its effects have been beneficial. Generally KDT is demonstratedly efficacious in patients with epilepsy and IMD. It reduces seizure activity and medication requirements and confers neuroprotection. Intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake.
1 Introduction
Niemann-Pick disease type C (NP-C) is a rare neurovisceral lysosomal disorder with autosomal recessive inheritance caused by mutations in either NPC1 (95%) or NPC2 (~4%) [1].
NP-C is characterized by abnormal lysosomal accumulation of unesterified cholesterol and glycolipids that results in progressive neurological deterioration, severe loss of quality of life, and premature death [2]. The only available drug effective in stabilizing neurological manifestations is miglustat [[2], [3], [4], [5]].
Yet NP-C is an invariably progressive disease and therapy is limited to delaying deterioration. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders and various inherited metabolic diseases (IMD) that conduce to seizure disorders. They reduce seizure activity and medication requirements and protect neurologic function [6,7]. Although dietary carbohydrate modification and restriction in patients with NP-C is discussed to ameliorate the gastrointestinal side effects associated with miglustat therapy [8], the concomitant use of miglustat and KDT in patients with NP-C is not described. In a case series where the long-term effects of intrathecal 2-Hydroxypropyl-β-Cyclodextrin treatment was evaluated, one patient who was on KDT prior to diagnosis and miglustat therapy was included who did not show any apparent benefit of KDT [9].
2 Case report
We describe our experience in attending a now 17-year-old female with NP-C manifest aged 3y that has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y at this writing. This therapy reduced seizure frequency and hospital stays and improved patient alertness.
2.1 Initial findings and diagnosis
Our patient was born at term after an uneventful second pregnancy to non-consanguineous Caucasian parents. The first pregnancy ended in spontaneous abortion. The mother has epilepsy treated with carbamazepine.
The parents reported motor and language developmental delay apparent at age 3y. The patient was seen in our clinic first at age 5y; no diagnosis was assigned. Behavioral disturbances began at age 9y, with self-harming and injury to others, ataxia, dysphagia, and repetitive seizures. This prompted re-assessment. Bilateral oculomotor palsy was found, with exotropia. Abdominal sonography showed mesenteric lymphadenopathy and hepatosplenomegaly. A lysosomal storage disease was suspected. Filipin staining of skin fibroblasts found accumulation of unesterified cholesterol in the endosomal/lysosomal compartment, permitting the diagnosis of NP-C. The patient proved to harbor biallelic mutations in NPC1 (c.1421C>T/p.Pro474Leu, known [10], and c.3289_3291del/p.Asp1097del).
2.2 Treatment and clinical course
Anti-epileptic treatment with levetiracetam (LEV; initial target dose, 30 mg/kg/d) was initiated empirically at age 9y, when seizures began. Immediately after definitive diagnosis (still at age 9y), substrate reduction therapy with miglustat was initiated (400 mg/m2 body surface area/d). Emesis and diarrhoea were mild. After 2mo, seizures worsened and expressive speech was entirely lost. LEV therapy was thus increased stagewise (dose achieved, 50 mg/kg/d).
At age 10y exotropia and hand-eye-coordination improved. Over the next 2y, however, neurodegenerative worsening was volatile, with emergence of swallowing difficulties that led to malnutrition. A gastrostomy thus was placed at age 12y and an overnight partial continuous feeding regimen (1/3 of estimated total energy expenditure = 500 kcal) was established. At the same time, the patient lost ability to walk. Alternating patterns of high- and low- (1–2 seizures a day) seizure frequency (respectively 20 seizures/h and 1–2/d) characterized the patient's 12th and 13th years of life. At age 13y gastrointestinal manifestations emerged (chronic constipation, successfully treated with soluble fibre). At age 14y exacerbations of seizures led to escalation of anti-epileptic treatment. Buccal midazolam (10 mg) was used as rescue medication for seizures lasting longer than 5 min. The patient's LEV was enhanced (dose achieved, 70 mg/kg/d) and complemented with clobazam (CLB; 0.15 mg/kg/d). Yet neurological deterioration progressed, in particular seizure severity and seizure frequency.
After 3mo of unsatisfactory drug therapy, we re-considered the therapeutic options. Expecting more side effects without improvements if another anti-epileptic drug was begun, we decided to initiate a classical KDT with a ketogenic ratio of 4:1 whilst continuing the drug regimen then in place.
Enteral feeding via gastrostomy facilitated this, using a ketogenic formula (fat to non-fat 4:1). KDT is traditionally introduced by increasing the ketogenic ratio stepwise. We replaced one-third of calories/d until full tolerance was achieved (1560 kcal/d, 45 kcal/kg). Within 5d whole blood β-hydroxybutyrate (B-OHB) levels rose to 2.7 mmol/L (Fig. 1). Duration and frequency of seizures fell (Fig. 1) and alertness increased. Although neurodegeneration was thought to progress, with persistent and worsening signs, during the first 3y of KDT, average hospital admissions and inpatient days were fewer within 3y under KDT than during the 3y before (10 vs. 14 and 94 vs. 113 respectively).Fig. 1 Ketosis (serum B-OHB levels) and seizure frequency during KDT.
Fig. 1
As electroencephalography (EEG) was stressful for our patient and little clinical benefit was expected, it was limited to a minimum. EEG 10mo prior to KDT showed multifocal as well as generalized epileptogenic activity as typically seen in patients with Lennox-Gastaut syndrome. After initiation of KDT, little changed yet stabilized epileptogenic activity was observed. Changes included slowing of background rhythm and continuous disorganization of sleep related elements. Generalized seizures were solely identified by an increased activity from 6 to 8/s to 14-30/s for 30 to 120 s.
The 3rd year of KDT saw an abrupt rise in hospital admissions and inpatient days that we ascribe to personnel and structural changes in the care facility where the patient lives rather than to a change in her disorder. After initiation of KDT no further hospital admissions due to seizure exacerbation were necessary (Fig. 2). Seizure duration remains <5 min even after 3y on KDT. The patient now, at age 17y, has received KDT for 3y without any identified KDT-associated side effects.Fig. 2 Hospital admissions and inpatient days before and after initiation of KDT.
Fig. 2
3 Discussion
Concomitant use of miglustat and KDT (“Syner-G”) improves survival in patients with GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease) [11]. Ketosis may increase miglustat uptake and accumulation in forebrain of the β-hexosaminidase (Hexb) knockout (−/−) murine model of Sandhoff disease [12].
How KDT acts in pharmacoresistant epilepsy is not fully understood. Proposed mechanisms are linked either to direct effects of ketones and of glucose restriction or to interactions with receptors, channels, and metabolic enzymes [13]. KDTs in IMDs are used either to target the underlying metabolic disorder (e.g., glucose transporter type 1 deficiency syndrome) or to target symptoms (e.g., seizures in non-ketotic hyperglycinemia) [14]. They efficaciously reduce seizure activity and medication requirements and confer neuroprotection. One of the hypotheses of underlying pathophysiology in NP-C is that it triggers oxidative stress damage and apoptotic cell death [15]. Chronic ketosis as induced via KDT is thought to limit reactive oxygen species generation and thus might prevent apoptosis [16]. In addition, carbohydrate modification and reduction as derived by KDT could show successful amelioration of gastrointestinal side effects associated with miglustat in two patients with NP-C [8].
Although intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake, fat-rich KDT can perhaps be safely deployed in patients with NP-C, in whom its effects may be beneficial.
4 Conclusion
In a non-terminal palliative care setting, KDT could temporarily improve quality of life through reduction in seizure activity, increased alertness, and reduction in both hospital admissions and inpatient days in a 14-year-old female patient with NP-C. Our experience may encourage further research into how KDT can be beneficially deployed in NP-C patients.
Synopsis
Over 3y beginning at age 14y in a girl with NP-C, classical KDT combined with miglustat, levetiracetam, and clobazam improved quality of life over that achieved with miglustat, levetiracetam, and clobazam. KDT reduced seizure activity and increased patient alertness.
Details of contribution of individual authors
Alexander Höller is a pediatric dietitian specializing in inborn disorders of metabolism and neuropediatrics.
Daniela Karall, Sabine Scholl-Bürgi, Sara Baumgartner Sigl, and Ursula Albrecht are pediatricians specializing in inborn disorders of metabolism and neuropediatrics.
Thomas Zöggeler, Gabriele Ramoser, and Benoit Bernar are physicians training in pediatrics.
Author who serves as guarantor for the article: Sabine Scholl-Bürgi.
Declaration of Competing Interest
All authors declare that they have no competing interest. | 0.15 MILLIGRAM/KILOGRAM/DAY | DrugDosageText | CC BY-NC-ND | 33598405 | 19,465,164 | 2021-06 |
What was the dosage of drug 'MIDAZOLAM'? | Successful implementation of classical ketogenic dietary therapy in a patient with Niemann-Pick disease type C.
Niemann-Pick disease type C (NP-C) is a neurodegenerative disease for which only palliative treatment exists, and only miglustat is effective in stabilizing neurological manifestations of NP-C. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders, including those associated with various inherited metabolic diseases (IMD), to reduce seizure frequency and medication requirement as well as to confer neuroprotection. Since patients with NP-C suffer pharmacorefractory seizures associated with ongoing neurodegeneration, KDT might be beneficial. The concomitant use of miglustat and KDT in patients with NP-C has not been reported.
We describe our experience in a now 17-year-old female with NP-C manifest early in childhood who has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y. Although the neurodegeneration of NP-C progressed, she benefited from a reduction in seizure activity, fewer hospital stays related to seizure exacerbation, and increased alertness.
KDT could be safely deployed in our patient with NP-C, in whom its effects have been beneficial. Generally KDT is demonstratedly efficacious in patients with epilepsy and IMD. It reduces seizure activity and medication requirements and confers neuroprotection. Intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake.
1 Introduction
Niemann-Pick disease type C (NP-C) is a rare neurovisceral lysosomal disorder with autosomal recessive inheritance caused by mutations in either NPC1 (95%) or NPC2 (~4%) [1].
NP-C is characterized by abnormal lysosomal accumulation of unesterified cholesterol and glycolipids that results in progressive neurological deterioration, severe loss of quality of life, and premature death [2]. The only available drug effective in stabilizing neurological manifestations is miglustat [[2], [3], [4], [5]].
Yet NP-C is an invariably progressive disease and therapy is limited to delaying deterioration. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders and various inherited metabolic diseases (IMD) that conduce to seizure disorders. They reduce seizure activity and medication requirements and protect neurologic function [6,7]. Although dietary carbohydrate modification and restriction in patients with NP-C is discussed to ameliorate the gastrointestinal side effects associated with miglustat therapy [8], the concomitant use of miglustat and KDT in patients with NP-C is not described. In a case series where the long-term effects of intrathecal 2-Hydroxypropyl-β-Cyclodextrin treatment was evaluated, one patient who was on KDT prior to diagnosis and miglustat therapy was included who did not show any apparent benefit of KDT [9].
2 Case report
We describe our experience in attending a now 17-year-old female with NP-C manifest aged 3y that has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y at this writing. This therapy reduced seizure frequency and hospital stays and improved patient alertness.
2.1 Initial findings and diagnosis
Our patient was born at term after an uneventful second pregnancy to non-consanguineous Caucasian parents. The first pregnancy ended in spontaneous abortion. The mother has epilepsy treated with carbamazepine.
The parents reported motor and language developmental delay apparent at age 3y. The patient was seen in our clinic first at age 5y; no diagnosis was assigned. Behavioral disturbances began at age 9y, with self-harming and injury to others, ataxia, dysphagia, and repetitive seizures. This prompted re-assessment. Bilateral oculomotor palsy was found, with exotropia. Abdominal sonography showed mesenteric lymphadenopathy and hepatosplenomegaly. A lysosomal storage disease was suspected. Filipin staining of skin fibroblasts found accumulation of unesterified cholesterol in the endosomal/lysosomal compartment, permitting the diagnosis of NP-C. The patient proved to harbor biallelic mutations in NPC1 (c.1421C>T/p.Pro474Leu, known [10], and c.3289_3291del/p.Asp1097del).
2.2 Treatment and clinical course
Anti-epileptic treatment with levetiracetam (LEV; initial target dose, 30 mg/kg/d) was initiated empirically at age 9y, when seizures began. Immediately after definitive diagnosis (still at age 9y), substrate reduction therapy with miglustat was initiated (400 mg/m2 body surface area/d). Emesis and diarrhoea were mild. After 2mo, seizures worsened and expressive speech was entirely lost. LEV therapy was thus increased stagewise (dose achieved, 50 mg/kg/d).
At age 10y exotropia and hand-eye-coordination improved. Over the next 2y, however, neurodegenerative worsening was volatile, with emergence of swallowing difficulties that led to malnutrition. A gastrostomy thus was placed at age 12y and an overnight partial continuous feeding regimen (1/3 of estimated total energy expenditure = 500 kcal) was established. At the same time, the patient lost ability to walk. Alternating patterns of high- and low- (1–2 seizures a day) seizure frequency (respectively 20 seizures/h and 1–2/d) characterized the patient's 12th and 13th years of life. At age 13y gastrointestinal manifestations emerged (chronic constipation, successfully treated with soluble fibre). At age 14y exacerbations of seizures led to escalation of anti-epileptic treatment. Buccal midazolam (10 mg) was used as rescue medication for seizures lasting longer than 5 min. The patient's LEV was enhanced (dose achieved, 70 mg/kg/d) and complemented with clobazam (CLB; 0.15 mg/kg/d). Yet neurological deterioration progressed, in particular seizure severity and seizure frequency.
After 3mo of unsatisfactory drug therapy, we re-considered the therapeutic options. Expecting more side effects without improvements if another anti-epileptic drug was begun, we decided to initiate a classical KDT with a ketogenic ratio of 4:1 whilst continuing the drug regimen then in place.
Enteral feeding via gastrostomy facilitated this, using a ketogenic formula (fat to non-fat 4:1). KDT is traditionally introduced by increasing the ketogenic ratio stepwise. We replaced one-third of calories/d until full tolerance was achieved (1560 kcal/d, 45 kcal/kg). Within 5d whole blood β-hydroxybutyrate (B-OHB) levels rose to 2.7 mmol/L (Fig. 1). Duration and frequency of seizures fell (Fig. 1) and alertness increased. Although neurodegeneration was thought to progress, with persistent and worsening signs, during the first 3y of KDT, average hospital admissions and inpatient days were fewer within 3y under KDT than during the 3y before (10 vs. 14 and 94 vs. 113 respectively).Fig. 1 Ketosis (serum B-OHB levels) and seizure frequency during KDT.
Fig. 1
As electroencephalography (EEG) was stressful for our patient and little clinical benefit was expected, it was limited to a minimum. EEG 10mo prior to KDT showed multifocal as well as generalized epileptogenic activity as typically seen in patients with Lennox-Gastaut syndrome. After initiation of KDT, little changed yet stabilized epileptogenic activity was observed. Changes included slowing of background rhythm and continuous disorganization of sleep related elements. Generalized seizures were solely identified by an increased activity from 6 to 8/s to 14-30/s for 30 to 120 s.
The 3rd year of KDT saw an abrupt rise in hospital admissions and inpatient days that we ascribe to personnel and structural changes in the care facility where the patient lives rather than to a change in her disorder. After initiation of KDT no further hospital admissions due to seizure exacerbation were necessary (Fig. 2). Seizure duration remains <5 min even after 3y on KDT. The patient now, at age 17y, has received KDT for 3y without any identified KDT-associated side effects.Fig. 2 Hospital admissions and inpatient days before and after initiation of KDT.
Fig. 2
3 Discussion
Concomitant use of miglustat and KDT (“Syner-G”) improves survival in patients with GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease) [11]. Ketosis may increase miglustat uptake and accumulation in forebrain of the β-hexosaminidase (Hexb) knockout (−/−) murine model of Sandhoff disease [12].
How KDT acts in pharmacoresistant epilepsy is not fully understood. Proposed mechanisms are linked either to direct effects of ketones and of glucose restriction or to interactions with receptors, channels, and metabolic enzymes [13]. KDTs in IMDs are used either to target the underlying metabolic disorder (e.g., glucose transporter type 1 deficiency syndrome) or to target symptoms (e.g., seizures in non-ketotic hyperglycinemia) [14]. They efficaciously reduce seizure activity and medication requirements and confer neuroprotection. One of the hypotheses of underlying pathophysiology in NP-C is that it triggers oxidative stress damage and apoptotic cell death [15]. Chronic ketosis as induced via KDT is thought to limit reactive oxygen species generation and thus might prevent apoptosis [16]. In addition, carbohydrate modification and reduction as derived by KDT could show successful amelioration of gastrointestinal side effects associated with miglustat in two patients with NP-C [8].
Although intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake, fat-rich KDT can perhaps be safely deployed in patients with NP-C, in whom its effects may be beneficial.
4 Conclusion
In a non-terminal palliative care setting, KDT could temporarily improve quality of life through reduction in seizure activity, increased alertness, and reduction in both hospital admissions and inpatient days in a 14-year-old female patient with NP-C. Our experience may encourage further research into how KDT can be beneficially deployed in NP-C patients.
Synopsis
Over 3y beginning at age 14y in a girl with NP-C, classical KDT combined with miglustat, levetiracetam, and clobazam improved quality of life over that achieved with miglustat, levetiracetam, and clobazam. KDT reduced seizure activity and increased patient alertness.
Details of contribution of individual authors
Alexander Höller is a pediatric dietitian specializing in inborn disorders of metabolism and neuropediatrics.
Daniela Karall, Sabine Scholl-Bürgi, Sara Baumgartner Sigl, and Ursula Albrecht are pediatricians specializing in inborn disorders of metabolism and neuropediatrics.
Thomas Zöggeler, Gabriele Ramoser, and Benoit Bernar are physicians training in pediatrics.
Author who serves as guarantor for the article: Sabine Scholl-Bürgi.
Declaration of Competing Interest
All authors declare that they have no competing interest. | 10 MILLIGRAM | DrugDosageText | CC BY-NC-ND | 33598405 | 19,465,164 | 2021-06 |
What was the dosage of drug 'MIGLUSTAT'? | Successful implementation of classical ketogenic dietary therapy in a patient with Niemann-Pick disease type C.
Niemann-Pick disease type C (NP-C) is a neurodegenerative disease for which only palliative treatment exists, and only miglustat is effective in stabilizing neurological manifestations of NP-C. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders, including those associated with various inherited metabolic diseases (IMD), to reduce seizure frequency and medication requirement as well as to confer neuroprotection. Since patients with NP-C suffer pharmacorefractory seizures associated with ongoing neurodegeneration, KDT might be beneficial. The concomitant use of miglustat and KDT in patients with NP-C has not been reported.
We describe our experience in a now 17-year-old female with NP-C manifest early in childhood who has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y. Although the neurodegeneration of NP-C progressed, she benefited from a reduction in seizure activity, fewer hospital stays related to seizure exacerbation, and increased alertness.
KDT could be safely deployed in our patient with NP-C, in whom its effects have been beneficial. Generally KDT is demonstratedly efficacious in patients with epilepsy and IMD. It reduces seizure activity and medication requirements and confers neuroprotection. Intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake.
1 Introduction
Niemann-Pick disease type C (NP-C) is a rare neurovisceral lysosomal disorder with autosomal recessive inheritance caused by mutations in either NPC1 (95%) or NPC2 (~4%) [1].
NP-C is characterized by abnormal lysosomal accumulation of unesterified cholesterol and glycolipids that results in progressive neurological deterioration, severe loss of quality of life, and premature death [2]. The only available drug effective in stabilizing neurological manifestations is miglustat [[2], [3], [4], [5]].
Yet NP-C is an invariably progressive disease and therapy is limited to delaying deterioration. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders and various inherited metabolic diseases (IMD) that conduce to seizure disorders. They reduce seizure activity and medication requirements and protect neurologic function [6,7]. Although dietary carbohydrate modification and restriction in patients with NP-C is discussed to ameliorate the gastrointestinal side effects associated with miglustat therapy [8], the concomitant use of miglustat and KDT in patients with NP-C is not described. In a case series where the long-term effects of intrathecal 2-Hydroxypropyl-β-Cyclodextrin treatment was evaluated, one patient who was on KDT prior to diagnosis and miglustat therapy was included who did not show any apparent benefit of KDT [9].
2 Case report
We describe our experience in attending a now 17-year-old female with NP-C manifest aged 3y that has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y at this writing. This therapy reduced seizure frequency and hospital stays and improved patient alertness.
2.1 Initial findings and diagnosis
Our patient was born at term after an uneventful second pregnancy to non-consanguineous Caucasian parents. The first pregnancy ended in spontaneous abortion. The mother has epilepsy treated with carbamazepine.
The parents reported motor and language developmental delay apparent at age 3y. The patient was seen in our clinic first at age 5y; no diagnosis was assigned. Behavioral disturbances began at age 9y, with self-harming and injury to others, ataxia, dysphagia, and repetitive seizures. This prompted re-assessment. Bilateral oculomotor palsy was found, with exotropia. Abdominal sonography showed mesenteric lymphadenopathy and hepatosplenomegaly. A lysosomal storage disease was suspected. Filipin staining of skin fibroblasts found accumulation of unesterified cholesterol in the endosomal/lysosomal compartment, permitting the diagnosis of NP-C. The patient proved to harbor biallelic mutations in NPC1 (c.1421C>T/p.Pro474Leu, known [10], and c.3289_3291del/p.Asp1097del).
2.2 Treatment and clinical course
Anti-epileptic treatment with levetiracetam (LEV; initial target dose, 30 mg/kg/d) was initiated empirically at age 9y, when seizures began. Immediately after definitive diagnosis (still at age 9y), substrate reduction therapy with miglustat was initiated (400 mg/m2 body surface area/d). Emesis and diarrhoea were mild. After 2mo, seizures worsened and expressive speech was entirely lost. LEV therapy was thus increased stagewise (dose achieved, 50 mg/kg/d).
At age 10y exotropia and hand-eye-coordination improved. Over the next 2y, however, neurodegenerative worsening was volatile, with emergence of swallowing difficulties that led to malnutrition. A gastrostomy thus was placed at age 12y and an overnight partial continuous feeding regimen (1/3 of estimated total energy expenditure = 500 kcal) was established. At the same time, the patient lost ability to walk. Alternating patterns of high- and low- (1–2 seizures a day) seizure frequency (respectively 20 seizures/h and 1–2/d) characterized the patient's 12th and 13th years of life. At age 13y gastrointestinal manifestations emerged (chronic constipation, successfully treated with soluble fibre). At age 14y exacerbations of seizures led to escalation of anti-epileptic treatment. Buccal midazolam (10 mg) was used as rescue medication for seizures lasting longer than 5 min. The patient's LEV was enhanced (dose achieved, 70 mg/kg/d) and complemented with clobazam (CLB; 0.15 mg/kg/d). Yet neurological deterioration progressed, in particular seizure severity and seizure frequency.
After 3mo of unsatisfactory drug therapy, we re-considered the therapeutic options. Expecting more side effects without improvements if another anti-epileptic drug was begun, we decided to initiate a classical KDT with a ketogenic ratio of 4:1 whilst continuing the drug regimen then in place.
Enteral feeding via gastrostomy facilitated this, using a ketogenic formula (fat to non-fat 4:1). KDT is traditionally introduced by increasing the ketogenic ratio stepwise. We replaced one-third of calories/d until full tolerance was achieved (1560 kcal/d, 45 kcal/kg). Within 5d whole blood β-hydroxybutyrate (B-OHB) levels rose to 2.7 mmol/L (Fig. 1). Duration and frequency of seizures fell (Fig. 1) and alertness increased. Although neurodegeneration was thought to progress, with persistent and worsening signs, during the first 3y of KDT, average hospital admissions and inpatient days were fewer within 3y under KDT than during the 3y before (10 vs. 14 and 94 vs. 113 respectively).Fig. 1 Ketosis (serum B-OHB levels) and seizure frequency during KDT.
Fig. 1
As electroencephalography (EEG) was stressful for our patient and little clinical benefit was expected, it was limited to a minimum. EEG 10mo prior to KDT showed multifocal as well as generalized epileptogenic activity as typically seen in patients with Lennox-Gastaut syndrome. After initiation of KDT, little changed yet stabilized epileptogenic activity was observed. Changes included slowing of background rhythm and continuous disorganization of sleep related elements. Generalized seizures were solely identified by an increased activity from 6 to 8/s to 14-30/s for 30 to 120 s.
The 3rd year of KDT saw an abrupt rise in hospital admissions and inpatient days that we ascribe to personnel and structural changes in the care facility where the patient lives rather than to a change in her disorder. After initiation of KDT no further hospital admissions due to seizure exacerbation were necessary (Fig. 2). Seizure duration remains <5 min even after 3y on KDT. The patient now, at age 17y, has received KDT for 3y without any identified KDT-associated side effects.Fig. 2 Hospital admissions and inpatient days before and after initiation of KDT.
Fig. 2
3 Discussion
Concomitant use of miglustat and KDT (“Syner-G”) improves survival in patients with GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease) [11]. Ketosis may increase miglustat uptake and accumulation in forebrain of the β-hexosaminidase (Hexb) knockout (−/−) murine model of Sandhoff disease [12].
How KDT acts in pharmacoresistant epilepsy is not fully understood. Proposed mechanisms are linked either to direct effects of ketones and of glucose restriction or to interactions with receptors, channels, and metabolic enzymes [13]. KDTs in IMDs are used either to target the underlying metabolic disorder (e.g., glucose transporter type 1 deficiency syndrome) or to target symptoms (e.g., seizures in non-ketotic hyperglycinemia) [14]. They efficaciously reduce seizure activity and medication requirements and confer neuroprotection. One of the hypotheses of underlying pathophysiology in NP-C is that it triggers oxidative stress damage and apoptotic cell death [15]. Chronic ketosis as induced via KDT is thought to limit reactive oxygen species generation and thus might prevent apoptosis [16]. In addition, carbohydrate modification and reduction as derived by KDT could show successful amelioration of gastrointestinal side effects associated with miglustat in two patients with NP-C [8].
Although intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake, fat-rich KDT can perhaps be safely deployed in patients with NP-C, in whom its effects may be beneficial.
4 Conclusion
In a non-terminal palliative care setting, KDT could temporarily improve quality of life through reduction in seizure activity, increased alertness, and reduction in both hospital admissions and inpatient days in a 14-year-old female patient with NP-C. Our experience may encourage further research into how KDT can be beneficially deployed in NP-C patients.
Synopsis
Over 3y beginning at age 14y in a girl with NP-C, classical KDT combined with miglustat, levetiracetam, and clobazam improved quality of life over that achieved with miglustat, levetiracetam, and clobazam. KDT reduced seizure activity and increased patient alertness.
Details of contribution of individual authors
Alexander Höller is a pediatric dietitian specializing in inborn disorders of metabolism and neuropediatrics.
Daniela Karall, Sabine Scholl-Bürgi, Sara Baumgartner Sigl, and Ursula Albrecht are pediatricians specializing in inborn disorders of metabolism and neuropediatrics.
Thomas Zöggeler, Gabriele Ramoser, and Benoit Bernar are physicians training in pediatrics.
Author who serves as guarantor for the article: Sabine Scholl-Bürgi.
Declaration of Competing Interest
All authors declare that they have no competing interest. | 400 MG/M2 | DrugDosageText | CC BY-NC-ND | 33598405 | 19,465,164 | 2021-06 |
What was the outcome of reaction 'Seizure'? | Successful implementation of classical ketogenic dietary therapy in a patient with Niemann-Pick disease type C.
Niemann-Pick disease type C (NP-C) is a neurodegenerative disease for which only palliative treatment exists, and only miglustat is effective in stabilizing neurological manifestations of NP-C. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders, including those associated with various inherited metabolic diseases (IMD), to reduce seizure frequency and medication requirement as well as to confer neuroprotection. Since patients with NP-C suffer pharmacorefractory seizures associated with ongoing neurodegeneration, KDT might be beneficial. The concomitant use of miglustat and KDT in patients with NP-C has not been reported.
We describe our experience in a now 17-year-old female with NP-C manifest early in childhood who has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y. Although the neurodegeneration of NP-C progressed, she benefited from a reduction in seizure activity, fewer hospital stays related to seizure exacerbation, and increased alertness.
KDT could be safely deployed in our patient with NP-C, in whom its effects have been beneficial. Generally KDT is demonstratedly efficacious in patients with epilepsy and IMD. It reduces seizure activity and medication requirements and confers neuroprotection. Intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake.
1 Introduction
Niemann-Pick disease type C (NP-C) is a rare neurovisceral lysosomal disorder with autosomal recessive inheritance caused by mutations in either NPC1 (95%) or NPC2 (~4%) [1].
NP-C is characterized by abnormal lysosomal accumulation of unesterified cholesterol and glycolipids that results in progressive neurological deterioration, severe loss of quality of life, and premature death [2]. The only available drug effective in stabilizing neurological manifestations is miglustat [[2], [3], [4], [5]].
Yet NP-C is an invariably progressive disease and therapy is limited to delaying deterioration. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders and various inherited metabolic diseases (IMD) that conduce to seizure disorders. They reduce seizure activity and medication requirements and protect neurologic function [6,7]. Although dietary carbohydrate modification and restriction in patients with NP-C is discussed to ameliorate the gastrointestinal side effects associated with miglustat therapy [8], the concomitant use of miglustat and KDT in patients with NP-C is not described. In a case series where the long-term effects of intrathecal 2-Hydroxypropyl-β-Cyclodextrin treatment was evaluated, one patient who was on KDT prior to diagnosis and miglustat therapy was included who did not show any apparent benefit of KDT [9].
2 Case report
We describe our experience in attending a now 17-year-old female with NP-C manifest aged 3y that has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y at this writing. This therapy reduced seizure frequency and hospital stays and improved patient alertness.
2.1 Initial findings and diagnosis
Our patient was born at term after an uneventful second pregnancy to non-consanguineous Caucasian parents. The first pregnancy ended in spontaneous abortion. The mother has epilepsy treated with carbamazepine.
The parents reported motor and language developmental delay apparent at age 3y. The patient was seen in our clinic first at age 5y; no diagnosis was assigned. Behavioral disturbances began at age 9y, with self-harming and injury to others, ataxia, dysphagia, and repetitive seizures. This prompted re-assessment. Bilateral oculomotor palsy was found, with exotropia. Abdominal sonography showed mesenteric lymphadenopathy and hepatosplenomegaly. A lysosomal storage disease was suspected. Filipin staining of skin fibroblasts found accumulation of unesterified cholesterol in the endosomal/lysosomal compartment, permitting the diagnosis of NP-C. The patient proved to harbor biallelic mutations in NPC1 (c.1421C>T/p.Pro474Leu, known [10], and c.3289_3291del/p.Asp1097del).
2.2 Treatment and clinical course
Anti-epileptic treatment with levetiracetam (LEV; initial target dose, 30 mg/kg/d) was initiated empirically at age 9y, when seizures began. Immediately after definitive diagnosis (still at age 9y), substrate reduction therapy with miglustat was initiated (400 mg/m2 body surface area/d). Emesis and diarrhoea were mild. After 2mo, seizures worsened and expressive speech was entirely lost. LEV therapy was thus increased stagewise (dose achieved, 50 mg/kg/d).
At age 10y exotropia and hand-eye-coordination improved. Over the next 2y, however, neurodegenerative worsening was volatile, with emergence of swallowing difficulties that led to malnutrition. A gastrostomy thus was placed at age 12y and an overnight partial continuous feeding regimen (1/3 of estimated total energy expenditure = 500 kcal) was established. At the same time, the patient lost ability to walk. Alternating patterns of high- and low- (1–2 seizures a day) seizure frequency (respectively 20 seizures/h and 1–2/d) characterized the patient's 12th and 13th years of life. At age 13y gastrointestinal manifestations emerged (chronic constipation, successfully treated with soluble fibre). At age 14y exacerbations of seizures led to escalation of anti-epileptic treatment. Buccal midazolam (10 mg) was used as rescue medication for seizures lasting longer than 5 min. The patient's LEV was enhanced (dose achieved, 70 mg/kg/d) and complemented with clobazam (CLB; 0.15 mg/kg/d). Yet neurological deterioration progressed, in particular seizure severity and seizure frequency.
After 3mo of unsatisfactory drug therapy, we re-considered the therapeutic options. Expecting more side effects without improvements if another anti-epileptic drug was begun, we decided to initiate a classical KDT with a ketogenic ratio of 4:1 whilst continuing the drug regimen then in place.
Enteral feeding via gastrostomy facilitated this, using a ketogenic formula (fat to non-fat 4:1). KDT is traditionally introduced by increasing the ketogenic ratio stepwise. We replaced one-third of calories/d until full tolerance was achieved (1560 kcal/d, 45 kcal/kg). Within 5d whole blood β-hydroxybutyrate (B-OHB) levels rose to 2.7 mmol/L (Fig. 1). Duration and frequency of seizures fell (Fig. 1) and alertness increased. Although neurodegeneration was thought to progress, with persistent and worsening signs, during the first 3y of KDT, average hospital admissions and inpatient days were fewer within 3y under KDT than during the 3y before (10 vs. 14 and 94 vs. 113 respectively).Fig. 1 Ketosis (serum B-OHB levels) and seizure frequency during KDT.
Fig. 1
As electroencephalography (EEG) was stressful for our patient and little clinical benefit was expected, it was limited to a minimum. EEG 10mo prior to KDT showed multifocal as well as generalized epileptogenic activity as typically seen in patients with Lennox-Gastaut syndrome. After initiation of KDT, little changed yet stabilized epileptogenic activity was observed. Changes included slowing of background rhythm and continuous disorganization of sleep related elements. Generalized seizures were solely identified by an increased activity from 6 to 8/s to 14-30/s for 30 to 120 s.
The 3rd year of KDT saw an abrupt rise in hospital admissions and inpatient days that we ascribe to personnel and structural changes in the care facility where the patient lives rather than to a change in her disorder. After initiation of KDT no further hospital admissions due to seizure exacerbation were necessary (Fig. 2). Seizure duration remains <5 min even after 3y on KDT. The patient now, at age 17y, has received KDT for 3y without any identified KDT-associated side effects.Fig. 2 Hospital admissions and inpatient days before and after initiation of KDT.
Fig. 2
3 Discussion
Concomitant use of miglustat and KDT (“Syner-G”) improves survival in patients with GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease) [11]. Ketosis may increase miglustat uptake and accumulation in forebrain of the β-hexosaminidase (Hexb) knockout (−/−) murine model of Sandhoff disease [12].
How KDT acts in pharmacoresistant epilepsy is not fully understood. Proposed mechanisms are linked either to direct effects of ketones and of glucose restriction or to interactions with receptors, channels, and metabolic enzymes [13]. KDTs in IMDs are used either to target the underlying metabolic disorder (e.g., glucose transporter type 1 deficiency syndrome) or to target symptoms (e.g., seizures in non-ketotic hyperglycinemia) [14]. They efficaciously reduce seizure activity and medication requirements and confer neuroprotection. One of the hypotheses of underlying pathophysiology in NP-C is that it triggers oxidative stress damage and apoptotic cell death [15]. Chronic ketosis as induced via KDT is thought to limit reactive oxygen species generation and thus might prevent apoptosis [16]. In addition, carbohydrate modification and reduction as derived by KDT could show successful amelioration of gastrointestinal side effects associated with miglustat in two patients with NP-C [8].
Although intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake, fat-rich KDT can perhaps be safely deployed in patients with NP-C, in whom its effects may be beneficial.
4 Conclusion
In a non-terminal palliative care setting, KDT could temporarily improve quality of life through reduction in seizure activity, increased alertness, and reduction in both hospital admissions and inpatient days in a 14-year-old female patient with NP-C. Our experience may encourage further research into how KDT can be beneficially deployed in NP-C patients.
Synopsis
Over 3y beginning at age 14y in a girl with NP-C, classical KDT combined with miglustat, levetiracetam, and clobazam improved quality of life over that achieved with miglustat, levetiracetam, and clobazam. KDT reduced seizure activity and increased patient alertness.
Details of contribution of individual authors
Alexander Höller is a pediatric dietitian specializing in inborn disorders of metabolism and neuropediatrics.
Daniela Karall, Sabine Scholl-Bürgi, Sara Baumgartner Sigl, and Ursula Albrecht are pediatricians specializing in inborn disorders of metabolism and neuropediatrics.
Thomas Zöggeler, Gabriele Ramoser, and Benoit Bernar are physicians training in pediatrics.
Author who serves as guarantor for the article: Sabine Scholl-Bürgi.
Declaration of Competing Interest
All authors declare that they have no competing interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33598405 | 19,465,164 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Prostatic artery embolization for bladder outlet obstruction in the setting of prior posterior urethroplasty.
This case presents a patient with a remote history of complex posterior urethral repair related to a prior motorcycle accident who presented to the urology clinic in urinary retention with associated lower urinary tract symptoms. Due to his altered anatomy, traditional outlet procedures were deferred due to significant reported risks of post treatment urinary incontinence. Decision was made to proceed with prostatic artery embolization, and at follow up he reported resolution of his urinary retention and significant symptomatic improvement in his voiding without development of urinary incontinence.
Introduction
Prostatic artery embolization (PAE) is an alternative to traditional interventions for patients with lower urinary tract symptoms (LUTS) interested in more minimally invasive solutions. PAE is not yet part of the standard pathway for treating benign prostatic hyperplasia (BPH) and more studies are needed to improve patient selection for this technically challenging treatment modality. Historically, its use has been in poor surgical candidates with prostatic sizes >40mL and LUTS unrelated to neurologic causes, though the only relative contraindication to PAE is severe atherosclerotic disease.1 A comprehensive literature review suggests that patients with adenomatous dominant BPH or who are catheter dependent prior to PAE could predict a higher likelihood of success as compared to patients otherwise.2
One of the most significant risks with traditional BPH therapies, like transurethral resection of the prostate (TURP) is urinary incontinence. Incontinence is related to sphincter trauma (30%), detrusor irritability (20%), mixed urinary incontinence (30%), incomplete resection (5%), and bladder neck contracture or urethral stricture (10%). Post-TURP incontinence is more common in the setting of posterior urethral reconstruction as these patients have a damaged external sphincter and are dependent on their bladder neck/internal sphincter. The bladder neck is routinely resected during TURP.
We report the evaluation and treatment of BPH related LUTS via PAE in a 77-year-old man with a history of posterior urethroplasty and its implications in maintenance of continence.
Case presentation
A 77-year-old male with remote history of MVA resulting in closed pelvic straddle injury and bulbous urethral stricture presented to the urology clinic with LUTS. Following his injury, the patient developed a long segment posterior urethral defect requiring complex posterior urethroplasty with associated supra-crural urethral rerouting. Rerouting required translocation of the urethra around the lateral side of the right corporal body and through the bony defect created by the pubectomy, allowing the urethra to pass through a small furrow in the pubis to avoid compression between the corpus and the bone. As is typical of posterior urethroplasties, especially those this complex, his continence depended exclusively on the internal sphincter/bladder neck.
Following repair he initially did well, but eventually developed urinary retention. In December 2019, he was found to have a wide-caliber urethral stricture and underwent direct vision internal urethrotomy with placement of indwelling Foley catheter for two weeks. Afterwards, he performed clean intermittent catheterization (CIC) three times daily with no periods of spontaneous urination suggesting that the stricture was not responsible for his symptoms.
He was then referred to our reconstructive urology clinic for evaluation. In addition to urinary retention requiring CIC, he endorsed frequency, nocturia, hesitancy, and weak stream despite medical therapy with tamsulosin and finasteride. He had not had prior outlet procedures. Estimated prostate size was 72g by TRUS. International Prostate Symptom Score (IPSS) was 34 with a quality-of-life (QoL) score of 4. Cystoscopy demonstrated a bulbar urethral narrowing behind the right corpus cavernosum, but easy passage of the 16.5 French flexible cystoscope, as well as bilobar prostate enlargement with apparent outlet obstruction. Urodynamic testing demonstrated normal compliance and obstructive voiding, low peak flow (4 mL/sec) and voiding pressures of up to 73 cm H2O and video images suggestive of BOO, not urethral stricture obstruction.
Due to concern for post-TURP incontinence related to his prior PFUDD, traditional outlet procedures were deferred, and he was referred to interventional radiology to discuss PAE (Fig. 1). He subsequently underwent PAE, and at follow up reported significantly improved symptoms without any reported incontinence or CIC requirements at the three and six-month follow ups (Fig. 2). IPSS reduced to 14 with QoL score of 3. He will continue to be followed in clinic at yearly intervals for repeat Uroflow and PVR measures.Fig. 1 Right Internal Iliac Angiogram (SVa = Sup Vesicular artery, InPu = Internal Pudendal, SuGl = Superior Gluteal, InfGlu = Inferior Gluteal, PA = Prostate artery).
Fig. 1Fig. 2 Coronal Cone Beam CT Prostate Enhancement (red arrows = bladder; blue arrows = prostate). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2
Discussion
The most common cause of posterior urethral injuries is motor vehicle crash, with the most common complications related to repair of these injuries being incontinence and erectile dysfunction. The primary deciding factor in repair of the injury is the length of defect and how to achieve a tension free anastomosis. Patients with defects <2cm can often be repaired with urethral mobilization alone, 29.6% require splitting of the corporal bodies, and 31.6% require inferior pubectomy. Although controversial, corporal re-routing is reserved for very long defects, especially those with compromised bulbar urethras (2–4.7% of cases) with an average defect length of 4.75cm.3
TURP is the gold standard operative intervention for BOO secondary to an enlarged prostate to which other modalities are often compared. PAE has become an increasingly popular modality since the late 2000s as an alternative for patients who are not suitable or are high risk for TURP-related complications. Ray et al. compared 89 patients undergoing TURP to 216 patients undergoing PAE, with subsequent retrograde ejaculation in 24.1% of patients undergoing PAE versus 47.5% of patients undergoing TURP.4 In terms of incontinence, these studies found only 2 patients in each arm developed incontinence, but none of these patients had any history of urethral stenosis or prior reconstruction.4
TURP following posterior urethroplasty carries an increased risk of incontinence, as continence following posterior urethroplasty relies solely on the proximal mechanisms, chiefly the bladder neck, which is often sacrificed during TURP. Even when urethral rerouting is not utilized, the external sphincter must be sacrificed in order to complete the anastomosis, as the most common site of injury is at the membranous urethra. PAE has been demonstrated non-inferior to TURP when performed by highly trained interventional radiologists with proper patient selection.5
Traumatic posterior urethral injury is more likely to occur earlier in life preceding the need for BPH treatments. In counseling these patients, it is important to address the risk of postoperative urinary incontinence associated with outlet procedures that address the bladder neck. PAE can be considered as a possible solution for these patients, though data remains sparse, as well as availability of this modality.
Conclusion
This case presents a novel indication and excellent outcome for PAE in the setting of BOO in a patient with prior posterior urethral repair without development of post treatment urinary incontinence. Further investigation is necessary, though PAE shows promise in this setting.
Declaration of competing interest
All authors have no conflict of interest to declare. | FINASTERIDE, TAMSULOSIN | DrugsGivenReaction | CC BY-NC-ND | 33598406 | 18,980,748 | 2021-05 |
What was the administration route of drug 'FINASTERIDE'? | Prostatic artery embolization for bladder outlet obstruction in the setting of prior posterior urethroplasty.
This case presents a patient with a remote history of complex posterior urethral repair related to a prior motorcycle accident who presented to the urology clinic in urinary retention with associated lower urinary tract symptoms. Due to his altered anatomy, traditional outlet procedures were deferred due to significant reported risks of post treatment urinary incontinence. Decision was made to proceed with prostatic artery embolization, and at follow up he reported resolution of his urinary retention and significant symptomatic improvement in his voiding without development of urinary incontinence.
Introduction
Prostatic artery embolization (PAE) is an alternative to traditional interventions for patients with lower urinary tract symptoms (LUTS) interested in more minimally invasive solutions. PAE is not yet part of the standard pathway for treating benign prostatic hyperplasia (BPH) and more studies are needed to improve patient selection for this technically challenging treatment modality. Historically, its use has been in poor surgical candidates with prostatic sizes >40mL and LUTS unrelated to neurologic causes, though the only relative contraindication to PAE is severe atherosclerotic disease.1 A comprehensive literature review suggests that patients with adenomatous dominant BPH or who are catheter dependent prior to PAE could predict a higher likelihood of success as compared to patients otherwise.2
One of the most significant risks with traditional BPH therapies, like transurethral resection of the prostate (TURP) is urinary incontinence. Incontinence is related to sphincter trauma (30%), detrusor irritability (20%), mixed urinary incontinence (30%), incomplete resection (5%), and bladder neck contracture or urethral stricture (10%). Post-TURP incontinence is more common in the setting of posterior urethral reconstruction as these patients have a damaged external sphincter and are dependent on their bladder neck/internal sphincter. The bladder neck is routinely resected during TURP.
We report the evaluation and treatment of BPH related LUTS via PAE in a 77-year-old man with a history of posterior urethroplasty and its implications in maintenance of continence.
Case presentation
A 77-year-old male with remote history of MVA resulting in closed pelvic straddle injury and bulbous urethral stricture presented to the urology clinic with LUTS. Following his injury, the patient developed a long segment posterior urethral defect requiring complex posterior urethroplasty with associated supra-crural urethral rerouting. Rerouting required translocation of the urethra around the lateral side of the right corporal body and through the bony defect created by the pubectomy, allowing the urethra to pass through a small furrow in the pubis to avoid compression between the corpus and the bone. As is typical of posterior urethroplasties, especially those this complex, his continence depended exclusively on the internal sphincter/bladder neck.
Following repair he initially did well, but eventually developed urinary retention. In December 2019, he was found to have a wide-caliber urethral stricture and underwent direct vision internal urethrotomy with placement of indwelling Foley catheter for two weeks. Afterwards, he performed clean intermittent catheterization (CIC) three times daily with no periods of spontaneous urination suggesting that the stricture was not responsible for his symptoms.
He was then referred to our reconstructive urology clinic for evaluation. In addition to urinary retention requiring CIC, he endorsed frequency, nocturia, hesitancy, and weak stream despite medical therapy with tamsulosin and finasteride. He had not had prior outlet procedures. Estimated prostate size was 72g by TRUS. International Prostate Symptom Score (IPSS) was 34 with a quality-of-life (QoL) score of 4. Cystoscopy demonstrated a bulbar urethral narrowing behind the right corpus cavernosum, but easy passage of the 16.5 French flexible cystoscope, as well as bilobar prostate enlargement with apparent outlet obstruction. Urodynamic testing demonstrated normal compliance and obstructive voiding, low peak flow (4 mL/sec) and voiding pressures of up to 73 cm H2O and video images suggestive of BOO, not urethral stricture obstruction.
Due to concern for post-TURP incontinence related to his prior PFUDD, traditional outlet procedures were deferred, and he was referred to interventional radiology to discuss PAE (Fig. 1). He subsequently underwent PAE, and at follow up reported significantly improved symptoms without any reported incontinence or CIC requirements at the three and six-month follow ups (Fig. 2). IPSS reduced to 14 with QoL score of 3. He will continue to be followed in clinic at yearly intervals for repeat Uroflow and PVR measures.Fig. 1 Right Internal Iliac Angiogram (SVa = Sup Vesicular artery, InPu = Internal Pudendal, SuGl = Superior Gluteal, InfGlu = Inferior Gluteal, PA = Prostate artery).
Fig. 1Fig. 2 Coronal Cone Beam CT Prostate Enhancement (red arrows = bladder; blue arrows = prostate). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2
Discussion
The most common cause of posterior urethral injuries is motor vehicle crash, with the most common complications related to repair of these injuries being incontinence and erectile dysfunction. The primary deciding factor in repair of the injury is the length of defect and how to achieve a tension free anastomosis. Patients with defects <2cm can often be repaired with urethral mobilization alone, 29.6% require splitting of the corporal bodies, and 31.6% require inferior pubectomy. Although controversial, corporal re-routing is reserved for very long defects, especially those with compromised bulbar urethras (2–4.7% of cases) with an average defect length of 4.75cm.3
TURP is the gold standard operative intervention for BOO secondary to an enlarged prostate to which other modalities are often compared. PAE has become an increasingly popular modality since the late 2000s as an alternative for patients who are not suitable or are high risk for TURP-related complications. Ray et al. compared 89 patients undergoing TURP to 216 patients undergoing PAE, with subsequent retrograde ejaculation in 24.1% of patients undergoing PAE versus 47.5% of patients undergoing TURP.4 In terms of incontinence, these studies found only 2 patients in each arm developed incontinence, but none of these patients had any history of urethral stenosis or prior reconstruction.4
TURP following posterior urethroplasty carries an increased risk of incontinence, as continence following posterior urethroplasty relies solely on the proximal mechanisms, chiefly the bladder neck, which is often sacrificed during TURP. Even when urethral rerouting is not utilized, the external sphincter must be sacrificed in order to complete the anastomosis, as the most common site of injury is at the membranous urethra. PAE has been demonstrated non-inferior to TURP when performed by highly trained interventional radiologists with proper patient selection.5
Traumatic posterior urethral injury is more likely to occur earlier in life preceding the need for BPH treatments. In counseling these patients, it is important to address the risk of postoperative urinary incontinence associated with outlet procedures that address the bladder neck. PAE can be considered as a possible solution for these patients, though data remains sparse, as well as availability of this modality.
Conclusion
This case presents a novel indication and excellent outcome for PAE in the setting of BOO in a patient with prior posterior urethral repair without development of post treatment urinary incontinence. Further investigation is necessary, though PAE shows promise in this setting.
Declaration of competing interest
All authors have no conflict of interest to declare. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33598406 | 18,980,748 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abdominal pain'. | The addition of deep hyperthermia to gemcitabine-based chemoradiation may achieve enhanced survival in unresectable locally advanced adenocarcinoma of the pancreas.
Driven by the current unsatisfactory outcomes for patients with locally advanced pancreatic cancer (LAPC), a biologically intensified clinical protocol was developed to explore the feasibility and efficacy of FOLFORINOX chemotherapy followed by deep hyperthermia concomitant with chemoradiation and subsequent FOLFORINOX chemotherapy in patients with LAPC.
Nine patients with LAPC were treated according to the HEATPAC Phase II trial protocol which consists of 4 cycles of FOLFORINOX chemotherapy followed by gemcitabine-based chemoradiation to 56 Gy combined with weekly deep hyperthermia and then a further 8 cycles of FOLFORINOX chemotherapy.
One grade three related toxicity was reported and two tumours became resectable. The median overall survival was 24 months and 1 year overall survival was 100%.
Intensification of chemoradiation with deep hyperthermia was feasible in nine consecutive patients with LAPC.
1 Introduction
The incidence and mortality of pancreatic ductal adenocarcinoma (PDAC) are similar and this highly fatal disease has a 5 year survival rate of only 5% [1]. 50% of patients have metastatic disease at diagnosis and 30% present with locally advanced non-metastatic but inoperable pancreatic cancer (LAPC) [2] which has a median overall survival (OS) of 15 months [3]. At presentation, 10–20% of cases qualify for surgical resection, which is the only curative treatment option. The high percentage of patients presenting with LAPC and the frequent microscopic incomplete resections provide a strong rationale for clinical research into increasing the efficacy of non-surgical therapies. In 2013, a comprehensive review and meta-analysis regarding neoadjuvant therapies in LAPC summarised the limited evidence that combination chemotherapy (CT) might induce resectability in up to 30%–40% of patients with LAPC [4]. Gemcitabine has long been the chemotherapeutic agent of choice [5] and chemoradiation (CRT) is the standard modality after induction chemotherapy in LAPC.
Clinical hyperthermia is a unique multifaceted, therapeutic modality that achieves cytotoxicity and radio- and chemosensitisation and is also an immunomodulator akin to in situ tumour vaccination [6]. Meta-analyses and network meta-analyses have confirmed the greater efficacy of thermoradiotherapy over radiotherapy and the lack of significant additional toxicity in various tumour entities [7], [8], [9], [10]. Gemcitabine is a proven radiosensitiser due to reduced radiotherapy-induced DNA repair, S phase cell cycle arrest and the triggering of apoptosis [11]. Furthermore, HT has been shown to sensitise the effects of gemcitabine at 43 °C. This has been best observed if gemcitabine is given 24 h after HT [12]. Hyperthermia increases the cytotoxicity of gemcitabine in human pancreatic cancer cell lines [12], [13] and thus a combination of HT, RT and gemcitabine would lead to triple sensitisation: thermal sensitisation of RT, thermal sensitisation of gemcitabine [14] and radiosensitisation by gemcitabine. A concurrent approach of gemcitabine, RT and HT (HTCRT) merits evaluation in LAPC and has been previously explored in a prospective single arm study reporting a median OS of 15 months and a 1 year OS of 67% [15].
Driven by the current unsatisfactory outcomes for patients with LAPC, a biologically intensified clinical protocol was developed to explore the feasibility and efficacy of FOLFORINOX chemotherapy followed by HTCRT with gemcitabine and additional FOLFORINOX chemotherapy in patients with LAPC.
2 Methods
Patients were treated according to the previously published ethics-approved protocol (HEATPAC Phase II trial, ClinicalTrials.gov: NCT02439593) [16] after the tumour was deemed inoperable [17] at a multidisciplinary tumour board. Between 06/2015 and 01/2019, nine patients with LAPC were identified and treated according to protocol. 7 of the 9 patients could not be included in the HEATPAC study as they either (a) were treated before the start of the HEATPAC study to check feasibility and logistics (n = 2), or (b) had been already started on pre-HTCTRT chemotherapy with FOLFIRINOX at other centres (n = 5) or (c) they did not fulfil the inclusion criterion of M0 disease (n = 2) due to suspicion of low volume metastases. Patients were commenced on 4 cycles of FOLFORINOX chemotherapy on a two weekly schedule [18]. CT, MRI or PETCT imaging was repeated four weeks after completion of chemotherapy and the resectability of the tumour was re-evaluated. In the event of persisting inoperability, patients received photon radiotherapy with 28 × 1.8 Gray (Gy) = 50.4 Gy to the clinical target volume, with a simultaneous integrated boost to the gross tumour volume and any involved regional lymph nodes to 56 Gy, delivered daily over 5.5 weeks with a VMAT technique combined with gemcitabine chemotherapy 400 mg/m2 weekly [16].
HT was delivered at Kantonsspital Aarau, Switzerland and regular quality assurance was carried out in accordance with European Society of Hyperthermia Oncology (ESHO) guidelines for clinical studies in regional deep HT [19], [20]. Deep HT was delivered with the BSD 2000 unit with the Sigma-60 or Sigma-Eye phased array applicator (M/s Pyrexar Medical, Salt Lake City, Utah, USA). To define the HT treatment volume, a planning CT was carried out in the HT treatment position on the HT planning support (hammock) adapted for CT. The tumor and the adjacent normal structures were contoured on these scans. The HT treatment planning target volume was based on the radiotherapy PTV/CTV and planned using the HT treatment planning Sigma HYPERPLAN software (M/s Dr. Sennewald Medizintechnik GmbH, Munich, Germany) by segmentation and creation of a grid model of the various body tissues according to their dielectric properties (e.g. tumor, intestine, abdominal organs, muscle, bone, fat) followed by simulation of the electric fields. Suitable power and steering parameters were used to generate a specific absorption rate distribution in the target volume using finite element modeling. A warm-up heating phase of 30 min followed by 60 min of HT treatment were applied.
Prior to each hyperthermia session, a multisensor (8 sensors) thermometric probe (FISO, FISO Technologies Inc. Quebec, Canada) was placed endoscopically in the C-loop of the duodenum. The position of the probes was checked under fluoroscopy and with a CT scan to ensure correct placement adjacent to the primary tumor. Direct intratumoral temperature measurements were not possible without undue risk to the patients, thus the temperatures recorded approximated those achieved in the tumor. Maximum power, ranging between 650 and 750 W (median: 700 W), was delivered according to the tolerance of the patient and temperature was continuously recorded during the heating session. Eight cycles of two weekly FOLFORINOX chemotherapy [18] were commenced four weeks later and imaging was performed three months after completion of therapy.
Response assessment: Response was assessed by comparing the pre-treatment tumor volume and metabolic activity with measurements taken 4 weeks after completion of radiotherapy.
Therapeutic response was assessed by PET-CT and MRI and contrast-enhanced CT in addition if available. Radiological response was evaluated as per the revised Response Evaluation Criteria in Solid Tumors (RECIST, Version 1.1) [21] and the metabolic response according to the PERCIST criteria [22].
Statistical analysis: Survival analysis was performed using Kaplan-Meier statistics. All survival estimates were computed from the first day of FOLFIRINOX chemotherapy. Progression-free survival represented the length of time during and after the treatment of disease, during which the patient had either complete, partial or stable response as defined in the “response assessment”. Progressive disease and death due to any cause irrespective of the disease status were considered as events for calculation of PFS. The overall survival period was computed from the first day of FOLFIRINOX until last follow-up or death. Death due to any cause was considered as an event for overall survival.
3 Results
Follow-up data were available for all nine patients and are summarised in Table 1. Seven patients received the planned four cycles of neoadjuvant FOLFORINOX, one received five and one received nine. All tumours were subsequently restaged and remained inoperable according to radiological criteria and discussion at a multidisciplinary team meeting. Nine patients received subsequent RT (eight to 56 Gy and one patient to 50.4 Gy) combined with gemcitabine and hyperthermia. The median temperature recorded on the endoscopic duodenal probe during delivery of hyperthermia was 39.9 °C (39.1–40.8 °C). The RT boost was omitted in one patient due to grade 3 nausea and vomiting. Another patient received only 2 cycles of gemcitabine and 2 sessions of hyperthermia due to rapidly increasing ascites of uncertain origin which resolved completely.Table 1 Patient demographics.
Gender Age TNM No. of cycles FOLFORINOX pre HTCTRT Total RT dose (Gy) Total no. of hyperthermia sessions Maximum Recorded endogastric hyperthermia (°C) Toxicity CTC AE v5.0 No. of cycles FOLFORINOX post HTCTRT Further therapy PFS from start of neoadj. chemo (mths) OS from start of neoadj. chemo (mths)
M 68 T3N1M0 4 56 2 39.9 Abdominal pain Gr 2 0 SBRT of lung metastases 4 34
M 77 T4N1M0 5 56 6 40.0 Nausea Gr 1
Diarrhoea Gr 1 4 Nab-Paclitaxel/Gemcitabine 12 17
M 81 T4N0M0 4 56 4 40.5 Abdominal pain Gr 1 8 21 24
M 44 T3N1M1 4 56 6 38.7 Vomiting Gr 1 2 Pancreatico-duodenectomy 29 30
F 58 T2N1M1 4 56 5 39.1 Abdominal pain Gr 1 Nausea Gr 1 8 Gemcitabine 11 13
F 56 T4N1M0 4 56 6 40.8 Nausea Gr 2
Diarrhoea Gr 1 1 Pancreatico-duodenectomy 11 22
M 70 T3N1M0 4 56 4 39.8 Vomiting Gr 2 0 16 18
M 79 T3N1M0 4 56 6 39.2 Abdominal pain Gr 1
Gastric ulceration Gr 2 4 29 29
F 60 T4N1M0 9 50.4 5 39.9 Nausea Gr 3 0 Nab-Paclitaxel/ Gemcitabine 15 24
A PETCT scan was scheduled after completion of first line FOLFORINOX chemotherapy and after completion of HTCTRT to assess response and resectability according to the PERCIST criteria [22]. Paired scans were available in 8 of 9 patients. The PET scans after FOLFORINOX chemotherapy showed a metabolic partial remission (PR) in 6/8 patients and stable disease (SD) in 2/8 patients. A PETCT scan repeated 3 months after completion of HTCTRT showed that 4/8 patients achieved a metabolic complete response (CR), 1/8 a PR and 3/8 SD when compared with the post chemotherapy PETCT scan. Two tumours became resectable and the postoperative stages were ypT0 ypN0 (pCR) and ypT2 ypN0 (pPR). Five patients received between 1 and 12 cycles of additional FOLFORINOX chemotherapy and two patients subsequently received palliative gemcitabine chemotherapy at disease progression. As of 20th September 2020, two patients are alive and seven have died.
All nine patients (100%) were alive 1 year after commencing induction chemotherapy and five of nine patients (56%) were alive 2 years from the same time point. The median OS was 24 months (95% CI 21.2–26.8 mths) (Fig. 1a), which remained unchanged when the two patients with resected tumours were excluded. One of the two patients with a complete pathological response and a R0 resected tumour is still alive with no evidence of disease 34 months from start of induction chemotherapy, despite M1 disease (a solitary liver metastasis, later resected) at diagnosis. The second patient with M1 disease survived 1 year. Median radiological progression-free survival was 15 months (95% CI 6.2–23.7 mths) (Fig. 1b) and 1 year PFS was 64.8%. Most patients reported transient Grade 1–2 nausea and abdominal discomfort during HTCRT and one patient required antiemetics and hydration for grade 3 nausea (Table 1). The ascites in the above-mentioned patient disappeared within months after completion of treatment.Fig. 1 According to the Kaplan-Meier curves, median overall survival was 24 months (95% CI 21.2–26.8 mths) (Fig. 1a) and median progression-free survival was 15 months (95% CI 6.2–23.7 mths) (Fig. 1a).
4 Discussion
We report the results of nine consecutive patients treated with an intensified HTCTRT regimen designed for optimal biological interaction between all three therapeutic modalities. The median overall survival of 24 months reported here appears superior when compared with recent trials of photon-based chemoradiation.
Pancreatic cancer is notable for its resistance to photon radiotherapy, chemotherapy and targeted therapies. Chemoradiation has long been used in locally advanced pancreatic cancer in attempt to render tumours operable or achieve local control. The LAP07 study has called the radiation component into question however, as overall survival with gemcitabine-based chemoradiation to 54 Gy (15.2 months) was not superior to that observed with gemcitabine chemotherapy alone (16.5 months) [23]. A similar median OS of 15 months has recently been reported in the interim analysis of the CONKO-007 randomised trial of chemotherapy versus chemoradiotherapy in inoperable pancreatic cancer [3]. One clinical trial of photon chemoradiation compared with chemoradiation and hyperthermia has been published previously. Maluta et al. reported a comparative cohort trial of 68 patients treated with 3-D radiotherapy between 30 Gy in 10 fractions and 66 Gy in 33 fractions combined with gemcitabine alone or with oxaliplatin, cisplatin or 5-fluorouracil, with or without twice-weekly deep hyperthermia. The overall survival in the first group was 11 months and was 15 months in the hyperthermia group (p = 0.025) without additional toxicity, demonstrating feasibility and suggesting a modest but significant overall survival benefit from hyperthermia [15]. Of note, some of the patients received only a palliative dose of radiotherapy. Two small trials of gemcitabine and regional hyperthermia have been reported. In patients with LAPC and metastatic pancreatic cancer, median survival was 17.7 months in 6 patients with M0 disease [24] and 15 months was following sequential gemcitabine and cisplatin combined with hyperthermia [14].
The present study used intraduodenal temperature instead of intratumoral thermometric measurements. This pragmatic thermometric assessment was chosen to be safe and acceptable to the patients during the 6 weeks of treatment. A multisensor probe with 8 sensors (at 2 cm intervals) was placed in the C-loop of the duodenum prior to each weekly hyperthermia session. This provided information regarding the locoregional temperature in the heated volume. Invasive thermometry for intratumoral measurement would have been limited to one or few thermal sensors and would only represent the temperature adjacent to the tip of the probe. Our centre presently has no facilities for non-invasive thermometry using MRI. Moreover, non-invasive thermometry has challenges associated with pancreatic motion [6].
Investigations into alternative forms of irradiation with protons and carbon ions in LAPC have been recently published. 42 patients received proton beam irradiation combined with gemcitabine chemotherapy, 32 of whom also received hyperthermia. OS from the initial treatment was 84.5% at 1 year and 58.7% at 2 years with a median OS of 27.5 months and 2 patients (4%) became resectable [25]. In a trial of carbon ion therapy in 72 patients with LAPC, the majority received induction and concurrent gemcitabine chemotherapy, and OS rates were 73% at 1 year, and 46% at 2 years with a median OS of 21.5 months [26]. Both series report superior outcomes to photon CRT and the median OS are very similar to the HEATPAC series. Indeed it has been suggested that hyperthermia could modify the radiobiological properties of photons to resemble those of neutrons without additional toxicity [27] and that proton irradiation hyperthermia combined with would have the properties of high LET carbon ions [28].
When designing the HEATPAC protocol, multi-agent FOLFORINOX was chosen as the induction and additive chemotherapy due to the increased efficacy over gemcitabine in the palliative setting reported by Conroy et al. [18]. All nine tumours remained inoperable after neoadjuvant chemotherapy however and the chemoradiation with hyperthermia is the most therapeutically active component of the protocol. A Phase II trial with similar design recently reported a 60% R0 resection rate in patients with LAPC using 8 cycles of FOLFORINOX/losartan followed by 5 × 5 Gy proton therapy with capecitabine or 55.8 Gy photon radiotherapy with concurrent 5-fluorouracil or capecitabine. In the interim analysis of the CONKO-007 trial, median OS was significantly better (26.5 months) in patients with an R0 resection after neoadjuvant treatment than in non-operated patients (16.5 months) [3]. Patients in the non-surgical HEATPAC cohort had a similar median OS (24 months) to patients achieving an R0 resection in CONKO-007 and these data highlight the potential role of HTCRT as part of 'total neoadjuvant therapy' [29].
Immunotherapy is recognised as the fourth pillar of cancer therapy. Modulation of the tumor immune microenvironment, along with the other mechanistic effects of hyperthermia, make it a compelling area of active research in therapy-refractory tumours such as PDAC. A current European phase III trial (HEAT) will compare overall survival and progression-free survival following the addition of hyperthermia to gemcitabine or gemcitabine and cisplatin as adjuvant therapy following a R0 or R1 resection in patients with resectable pancreatic cancer.
The clinical outcomes of this selected patient cohort are provocative as the median OS of 24 months with HTCRT far exceeds the median OS of 15.2 months (95% CI, 13.9–17.3 months) with CRT reported in LAP07, and this despite two patients having M1 disease. This multimodality approach of triple sensitisation to achieve biological intensification of therapy has yielded very encouraging data but accrual to the HEATPAC protocol has unfortunately been limited by the low incidence of eligible cases in a small population and there only being one deep hyperthermia unit in Switzerland. Multicentre international cooperation is urgently required for adequate recruitment to the HEATPAC randomised trial to draw conclusions regarding efficacy.
5 Conclusions
Triple sensitisation with HTCRT was associated with promising feasibility, toxicity and efficacy in this small cohort of patients. Median overall and progression free survival exceeded those currently seen with gemcitabine-based CRT in LAPC.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The study is partly funded by the “Günter und Regine Kelm Stiftung,” and the “Hugo und Elsa Isler-Fonds,” Switzerland. | FLUOROURACIL, GEMCITABINE, IRINOTECAN, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY-NC-ND | 33598571 | 19,202,901 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastric ulcer'. | The addition of deep hyperthermia to gemcitabine-based chemoradiation may achieve enhanced survival in unresectable locally advanced adenocarcinoma of the pancreas.
Driven by the current unsatisfactory outcomes for patients with locally advanced pancreatic cancer (LAPC), a biologically intensified clinical protocol was developed to explore the feasibility and efficacy of FOLFORINOX chemotherapy followed by deep hyperthermia concomitant with chemoradiation and subsequent FOLFORINOX chemotherapy in patients with LAPC.
Nine patients with LAPC were treated according to the HEATPAC Phase II trial protocol which consists of 4 cycles of FOLFORINOX chemotherapy followed by gemcitabine-based chemoradiation to 56 Gy combined with weekly deep hyperthermia and then a further 8 cycles of FOLFORINOX chemotherapy.
One grade three related toxicity was reported and two tumours became resectable. The median overall survival was 24 months and 1 year overall survival was 100%.
Intensification of chemoradiation with deep hyperthermia was feasible in nine consecutive patients with LAPC.
1 Introduction
The incidence and mortality of pancreatic ductal adenocarcinoma (PDAC) are similar and this highly fatal disease has a 5 year survival rate of only 5% [1]. 50% of patients have metastatic disease at diagnosis and 30% present with locally advanced non-metastatic but inoperable pancreatic cancer (LAPC) [2] which has a median overall survival (OS) of 15 months [3]. At presentation, 10–20% of cases qualify for surgical resection, which is the only curative treatment option. The high percentage of patients presenting with LAPC and the frequent microscopic incomplete resections provide a strong rationale for clinical research into increasing the efficacy of non-surgical therapies. In 2013, a comprehensive review and meta-analysis regarding neoadjuvant therapies in LAPC summarised the limited evidence that combination chemotherapy (CT) might induce resectability in up to 30%–40% of patients with LAPC [4]. Gemcitabine has long been the chemotherapeutic agent of choice [5] and chemoradiation (CRT) is the standard modality after induction chemotherapy in LAPC.
Clinical hyperthermia is a unique multifaceted, therapeutic modality that achieves cytotoxicity and radio- and chemosensitisation and is also an immunomodulator akin to in situ tumour vaccination [6]. Meta-analyses and network meta-analyses have confirmed the greater efficacy of thermoradiotherapy over radiotherapy and the lack of significant additional toxicity in various tumour entities [7], [8], [9], [10]. Gemcitabine is a proven radiosensitiser due to reduced radiotherapy-induced DNA repair, S phase cell cycle arrest and the triggering of apoptosis [11]. Furthermore, HT has been shown to sensitise the effects of gemcitabine at 43 °C. This has been best observed if gemcitabine is given 24 h after HT [12]. Hyperthermia increases the cytotoxicity of gemcitabine in human pancreatic cancer cell lines [12], [13] and thus a combination of HT, RT and gemcitabine would lead to triple sensitisation: thermal sensitisation of RT, thermal sensitisation of gemcitabine [14] and radiosensitisation by gemcitabine. A concurrent approach of gemcitabine, RT and HT (HTCRT) merits evaluation in LAPC and has been previously explored in a prospective single arm study reporting a median OS of 15 months and a 1 year OS of 67% [15].
Driven by the current unsatisfactory outcomes for patients with LAPC, a biologically intensified clinical protocol was developed to explore the feasibility and efficacy of FOLFORINOX chemotherapy followed by HTCRT with gemcitabine and additional FOLFORINOX chemotherapy in patients with LAPC.
2 Methods
Patients were treated according to the previously published ethics-approved protocol (HEATPAC Phase II trial, ClinicalTrials.gov: NCT02439593) [16] after the tumour was deemed inoperable [17] at a multidisciplinary tumour board. Between 06/2015 and 01/2019, nine patients with LAPC were identified and treated according to protocol. 7 of the 9 patients could not be included in the HEATPAC study as they either (a) were treated before the start of the HEATPAC study to check feasibility and logistics (n = 2), or (b) had been already started on pre-HTCTRT chemotherapy with FOLFIRINOX at other centres (n = 5) or (c) they did not fulfil the inclusion criterion of M0 disease (n = 2) due to suspicion of low volume metastases. Patients were commenced on 4 cycles of FOLFORINOX chemotherapy on a two weekly schedule [18]. CT, MRI or PETCT imaging was repeated four weeks after completion of chemotherapy and the resectability of the tumour was re-evaluated. In the event of persisting inoperability, patients received photon radiotherapy with 28 × 1.8 Gray (Gy) = 50.4 Gy to the clinical target volume, with a simultaneous integrated boost to the gross tumour volume and any involved regional lymph nodes to 56 Gy, delivered daily over 5.5 weeks with a VMAT technique combined with gemcitabine chemotherapy 400 mg/m2 weekly [16].
HT was delivered at Kantonsspital Aarau, Switzerland and regular quality assurance was carried out in accordance with European Society of Hyperthermia Oncology (ESHO) guidelines for clinical studies in regional deep HT [19], [20]. Deep HT was delivered with the BSD 2000 unit with the Sigma-60 or Sigma-Eye phased array applicator (M/s Pyrexar Medical, Salt Lake City, Utah, USA). To define the HT treatment volume, a planning CT was carried out in the HT treatment position on the HT planning support (hammock) adapted for CT. The tumor and the adjacent normal structures were contoured on these scans. The HT treatment planning target volume was based on the radiotherapy PTV/CTV and planned using the HT treatment planning Sigma HYPERPLAN software (M/s Dr. Sennewald Medizintechnik GmbH, Munich, Germany) by segmentation and creation of a grid model of the various body tissues according to their dielectric properties (e.g. tumor, intestine, abdominal organs, muscle, bone, fat) followed by simulation of the electric fields. Suitable power and steering parameters were used to generate a specific absorption rate distribution in the target volume using finite element modeling. A warm-up heating phase of 30 min followed by 60 min of HT treatment were applied.
Prior to each hyperthermia session, a multisensor (8 sensors) thermometric probe (FISO, FISO Technologies Inc. Quebec, Canada) was placed endoscopically in the C-loop of the duodenum. The position of the probes was checked under fluoroscopy and with a CT scan to ensure correct placement adjacent to the primary tumor. Direct intratumoral temperature measurements were not possible without undue risk to the patients, thus the temperatures recorded approximated those achieved in the tumor. Maximum power, ranging between 650 and 750 W (median: 700 W), was delivered according to the tolerance of the patient and temperature was continuously recorded during the heating session. Eight cycles of two weekly FOLFORINOX chemotherapy [18] were commenced four weeks later and imaging was performed three months after completion of therapy.
Response assessment: Response was assessed by comparing the pre-treatment tumor volume and metabolic activity with measurements taken 4 weeks after completion of radiotherapy.
Therapeutic response was assessed by PET-CT and MRI and contrast-enhanced CT in addition if available. Radiological response was evaluated as per the revised Response Evaluation Criteria in Solid Tumors (RECIST, Version 1.1) [21] and the metabolic response according to the PERCIST criteria [22].
Statistical analysis: Survival analysis was performed using Kaplan-Meier statistics. All survival estimates were computed from the first day of FOLFIRINOX chemotherapy. Progression-free survival represented the length of time during and after the treatment of disease, during which the patient had either complete, partial or stable response as defined in the “response assessment”. Progressive disease and death due to any cause irrespective of the disease status were considered as events for calculation of PFS. The overall survival period was computed from the first day of FOLFIRINOX until last follow-up or death. Death due to any cause was considered as an event for overall survival.
3 Results
Follow-up data were available for all nine patients and are summarised in Table 1. Seven patients received the planned four cycles of neoadjuvant FOLFORINOX, one received five and one received nine. All tumours were subsequently restaged and remained inoperable according to radiological criteria and discussion at a multidisciplinary team meeting. Nine patients received subsequent RT (eight to 56 Gy and one patient to 50.4 Gy) combined with gemcitabine and hyperthermia. The median temperature recorded on the endoscopic duodenal probe during delivery of hyperthermia was 39.9 °C (39.1–40.8 °C). The RT boost was omitted in one patient due to grade 3 nausea and vomiting. Another patient received only 2 cycles of gemcitabine and 2 sessions of hyperthermia due to rapidly increasing ascites of uncertain origin which resolved completely.Table 1 Patient demographics.
Gender Age TNM No. of cycles FOLFORINOX pre HTCTRT Total RT dose (Gy) Total no. of hyperthermia sessions Maximum Recorded endogastric hyperthermia (°C) Toxicity CTC AE v5.0 No. of cycles FOLFORINOX post HTCTRT Further therapy PFS from start of neoadj. chemo (mths) OS from start of neoadj. chemo (mths)
M 68 T3N1M0 4 56 2 39.9 Abdominal pain Gr 2 0 SBRT of lung metastases 4 34
M 77 T4N1M0 5 56 6 40.0 Nausea Gr 1
Diarrhoea Gr 1 4 Nab-Paclitaxel/Gemcitabine 12 17
M 81 T4N0M0 4 56 4 40.5 Abdominal pain Gr 1 8 21 24
M 44 T3N1M1 4 56 6 38.7 Vomiting Gr 1 2 Pancreatico-duodenectomy 29 30
F 58 T2N1M1 4 56 5 39.1 Abdominal pain Gr 1 Nausea Gr 1 8 Gemcitabine 11 13
F 56 T4N1M0 4 56 6 40.8 Nausea Gr 2
Diarrhoea Gr 1 1 Pancreatico-duodenectomy 11 22
M 70 T3N1M0 4 56 4 39.8 Vomiting Gr 2 0 16 18
M 79 T3N1M0 4 56 6 39.2 Abdominal pain Gr 1
Gastric ulceration Gr 2 4 29 29
F 60 T4N1M0 9 50.4 5 39.9 Nausea Gr 3 0 Nab-Paclitaxel/ Gemcitabine 15 24
A PETCT scan was scheduled after completion of first line FOLFORINOX chemotherapy and after completion of HTCTRT to assess response and resectability according to the PERCIST criteria [22]. Paired scans were available in 8 of 9 patients. The PET scans after FOLFORINOX chemotherapy showed a metabolic partial remission (PR) in 6/8 patients and stable disease (SD) in 2/8 patients. A PETCT scan repeated 3 months after completion of HTCTRT showed that 4/8 patients achieved a metabolic complete response (CR), 1/8 a PR and 3/8 SD when compared with the post chemotherapy PETCT scan. Two tumours became resectable and the postoperative stages were ypT0 ypN0 (pCR) and ypT2 ypN0 (pPR). Five patients received between 1 and 12 cycles of additional FOLFORINOX chemotherapy and two patients subsequently received palliative gemcitabine chemotherapy at disease progression. As of 20th September 2020, two patients are alive and seven have died.
All nine patients (100%) were alive 1 year after commencing induction chemotherapy and five of nine patients (56%) were alive 2 years from the same time point. The median OS was 24 months (95% CI 21.2–26.8 mths) (Fig. 1a), which remained unchanged when the two patients with resected tumours were excluded. One of the two patients with a complete pathological response and a R0 resected tumour is still alive with no evidence of disease 34 months from start of induction chemotherapy, despite M1 disease (a solitary liver metastasis, later resected) at diagnosis. The second patient with M1 disease survived 1 year. Median radiological progression-free survival was 15 months (95% CI 6.2–23.7 mths) (Fig. 1b) and 1 year PFS was 64.8%. Most patients reported transient Grade 1–2 nausea and abdominal discomfort during HTCRT and one patient required antiemetics and hydration for grade 3 nausea (Table 1). The ascites in the above-mentioned patient disappeared within months after completion of treatment.Fig. 1 According to the Kaplan-Meier curves, median overall survival was 24 months (95% CI 21.2–26.8 mths) (Fig. 1a) and median progression-free survival was 15 months (95% CI 6.2–23.7 mths) (Fig. 1a).
4 Discussion
We report the results of nine consecutive patients treated with an intensified HTCTRT regimen designed for optimal biological interaction between all three therapeutic modalities. The median overall survival of 24 months reported here appears superior when compared with recent trials of photon-based chemoradiation.
Pancreatic cancer is notable for its resistance to photon radiotherapy, chemotherapy and targeted therapies. Chemoradiation has long been used in locally advanced pancreatic cancer in attempt to render tumours operable or achieve local control. The LAP07 study has called the radiation component into question however, as overall survival with gemcitabine-based chemoradiation to 54 Gy (15.2 months) was not superior to that observed with gemcitabine chemotherapy alone (16.5 months) [23]. A similar median OS of 15 months has recently been reported in the interim analysis of the CONKO-007 randomised trial of chemotherapy versus chemoradiotherapy in inoperable pancreatic cancer [3]. One clinical trial of photon chemoradiation compared with chemoradiation and hyperthermia has been published previously. Maluta et al. reported a comparative cohort trial of 68 patients treated with 3-D radiotherapy between 30 Gy in 10 fractions and 66 Gy in 33 fractions combined with gemcitabine alone or with oxaliplatin, cisplatin or 5-fluorouracil, with or without twice-weekly deep hyperthermia. The overall survival in the first group was 11 months and was 15 months in the hyperthermia group (p = 0.025) without additional toxicity, demonstrating feasibility and suggesting a modest but significant overall survival benefit from hyperthermia [15]. Of note, some of the patients received only a palliative dose of radiotherapy. Two small trials of gemcitabine and regional hyperthermia have been reported. In patients with LAPC and metastatic pancreatic cancer, median survival was 17.7 months in 6 patients with M0 disease [24] and 15 months was following sequential gemcitabine and cisplatin combined with hyperthermia [14].
The present study used intraduodenal temperature instead of intratumoral thermometric measurements. This pragmatic thermometric assessment was chosen to be safe and acceptable to the patients during the 6 weeks of treatment. A multisensor probe with 8 sensors (at 2 cm intervals) was placed in the C-loop of the duodenum prior to each weekly hyperthermia session. This provided information regarding the locoregional temperature in the heated volume. Invasive thermometry for intratumoral measurement would have been limited to one or few thermal sensors and would only represent the temperature adjacent to the tip of the probe. Our centre presently has no facilities for non-invasive thermometry using MRI. Moreover, non-invasive thermometry has challenges associated with pancreatic motion [6].
Investigations into alternative forms of irradiation with protons and carbon ions in LAPC have been recently published. 42 patients received proton beam irradiation combined with gemcitabine chemotherapy, 32 of whom also received hyperthermia. OS from the initial treatment was 84.5% at 1 year and 58.7% at 2 years with a median OS of 27.5 months and 2 patients (4%) became resectable [25]. In a trial of carbon ion therapy in 72 patients with LAPC, the majority received induction and concurrent gemcitabine chemotherapy, and OS rates were 73% at 1 year, and 46% at 2 years with a median OS of 21.5 months [26]. Both series report superior outcomes to photon CRT and the median OS are very similar to the HEATPAC series. Indeed it has been suggested that hyperthermia could modify the radiobiological properties of photons to resemble those of neutrons without additional toxicity [27] and that proton irradiation hyperthermia combined with would have the properties of high LET carbon ions [28].
When designing the HEATPAC protocol, multi-agent FOLFORINOX was chosen as the induction and additive chemotherapy due to the increased efficacy over gemcitabine in the palliative setting reported by Conroy et al. [18]. All nine tumours remained inoperable after neoadjuvant chemotherapy however and the chemoradiation with hyperthermia is the most therapeutically active component of the protocol. A Phase II trial with similar design recently reported a 60% R0 resection rate in patients with LAPC using 8 cycles of FOLFORINOX/losartan followed by 5 × 5 Gy proton therapy with capecitabine or 55.8 Gy photon radiotherapy with concurrent 5-fluorouracil or capecitabine. In the interim analysis of the CONKO-007 trial, median OS was significantly better (26.5 months) in patients with an R0 resection after neoadjuvant treatment than in non-operated patients (16.5 months) [3]. Patients in the non-surgical HEATPAC cohort had a similar median OS (24 months) to patients achieving an R0 resection in CONKO-007 and these data highlight the potential role of HTCRT as part of 'total neoadjuvant therapy' [29].
Immunotherapy is recognised as the fourth pillar of cancer therapy. Modulation of the tumor immune microenvironment, along with the other mechanistic effects of hyperthermia, make it a compelling area of active research in therapy-refractory tumours such as PDAC. A current European phase III trial (HEAT) will compare overall survival and progression-free survival following the addition of hyperthermia to gemcitabine or gemcitabine and cisplatin as adjuvant therapy following a R0 or R1 resection in patients with resectable pancreatic cancer.
The clinical outcomes of this selected patient cohort are provocative as the median OS of 24 months with HTCRT far exceeds the median OS of 15.2 months (95% CI, 13.9–17.3 months) with CRT reported in LAP07, and this despite two patients having M1 disease. This multimodality approach of triple sensitisation to achieve biological intensification of therapy has yielded very encouraging data but accrual to the HEATPAC protocol has unfortunately been limited by the low incidence of eligible cases in a small population and there only being one deep hyperthermia unit in Switzerland. Multicentre international cooperation is urgently required for adequate recruitment to the HEATPAC randomised trial to draw conclusions regarding efficacy.
5 Conclusions
Triple sensitisation with HTCRT was associated with promising feasibility, toxicity and efficacy in this small cohort of patients. Median overall and progression free survival exceeded those currently seen with gemcitabine-based CRT in LAPC.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The study is partly funded by the “Günter und Regine Kelm Stiftung,” and the “Hugo und Elsa Isler-Fonds,” Switzerland. | FLUOROURACIL, GEMCITABINE, IRINOTECAN, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY-NC-ND | 33598571 | 19,202,901 | 2021-03 |
What was the dosage of drug 'GEMCITABINE'? | The addition of deep hyperthermia to gemcitabine-based chemoradiation may achieve enhanced survival in unresectable locally advanced adenocarcinoma of the pancreas.
Driven by the current unsatisfactory outcomes for patients with locally advanced pancreatic cancer (LAPC), a biologically intensified clinical protocol was developed to explore the feasibility and efficacy of FOLFORINOX chemotherapy followed by deep hyperthermia concomitant with chemoradiation and subsequent FOLFORINOX chemotherapy in patients with LAPC.
Nine patients with LAPC were treated according to the HEATPAC Phase II trial protocol which consists of 4 cycles of FOLFORINOX chemotherapy followed by gemcitabine-based chemoradiation to 56 Gy combined with weekly deep hyperthermia and then a further 8 cycles of FOLFORINOX chemotherapy.
One grade three related toxicity was reported and two tumours became resectable. The median overall survival was 24 months and 1 year overall survival was 100%.
Intensification of chemoradiation with deep hyperthermia was feasible in nine consecutive patients with LAPC.
1 Introduction
The incidence and mortality of pancreatic ductal adenocarcinoma (PDAC) are similar and this highly fatal disease has a 5 year survival rate of only 5% [1]. 50% of patients have metastatic disease at diagnosis and 30% present with locally advanced non-metastatic but inoperable pancreatic cancer (LAPC) [2] which has a median overall survival (OS) of 15 months [3]. At presentation, 10–20% of cases qualify for surgical resection, which is the only curative treatment option. The high percentage of patients presenting with LAPC and the frequent microscopic incomplete resections provide a strong rationale for clinical research into increasing the efficacy of non-surgical therapies. In 2013, a comprehensive review and meta-analysis regarding neoadjuvant therapies in LAPC summarised the limited evidence that combination chemotherapy (CT) might induce resectability in up to 30%–40% of patients with LAPC [4]. Gemcitabine has long been the chemotherapeutic agent of choice [5] and chemoradiation (CRT) is the standard modality after induction chemotherapy in LAPC.
Clinical hyperthermia is a unique multifaceted, therapeutic modality that achieves cytotoxicity and radio- and chemosensitisation and is also an immunomodulator akin to in situ tumour vaccination [6]. Meta-analyses and network meta-analyses have confirmed the greater efficacy of thermoradiotherapy over radiotherapy and the lack of significant additional toxicity in various tumour entities [7], [8], [9], [10]. Gemcitabine is a proven radiosensitiser due to reduced radiotherapy-induced DNA repair, S phase cell cycle arrest and the triggering of apoptosis [11]. Furthermore, HT has been shown to sensitise the effects of gemcitabine at 43 °C. This has been best observed if gemcitabine is given 24 h after HT [12]. Hyperthermia increases the cytotoxicity of gemcitabine in human pancreatic cancer cell lines [12], [13] and thus a combination of HT, RT and gemcitabine would lead to triple sensitisation: thermal sensitisation of RT, thermal sensitisation of gemcitabine [14] and radiosensitisation by gemcitabine. A concurrent approach of gemcitabine, RT and HT (HTCRT) merits evaluation in LAPC and has been previously explored in a prospective single arm study reporting a median OS of 15 months and a 1 year OS of 67% [15].
Driven by the current unsatisfactory outcomes for patients with LAPC, a biologically intensified clinical protocol was developed to explore the feasibility and efficacy of FOLFORINOX chemotherapy followed by HTCRT with gemcitabine and additional FOLFORINOX chemotherapy in patients with LAPC.
2 Methods
Patients were treated according to the previously published ethics-approved protocol (HEATPAC Phase II trial, ClinicalTrials.gov: NCT02439593) [16] after the tumour was deemed inoperable [17] at a multidisciplinary tumour board. Between 06/2015 and 01/2019, nine patients with LAPC were identified and treated according to protocol. 7 of the 9 patients could not be included in the HEATPAC study as they either (a) were treated before the start of the HEATPAC study to check feasibility and logistics (n = 2), or (b) had been already started on pre-HTCTRT chemotherapy with FOLFIRINOX at other centres (n = 5) or (c) they did not fulfil the inclusion criterion of M0 disease (n = 2) due to suspicion of low volume metastases. Patients were commenced on 4 cycles of FOLFORINOX chemotherapy on a two weekly schedule [18]. CT, MRI or PETCT imaging was repeated four weeks after completion of chemotherapy and the resectability of the tumour was re-evaluated. In the event of persisting inoperability, patients received photon radiotherapy with 28 × 1.8 Gray (Gy) = 50.4 Gy to the clinical target volume, with a simultaneous integrated boost to the gross tumour volume and any involved regional lymph nodes to 56 Gy, delivered daily over 5.5 weeks with a VMAT technique combined with gemcitabine chemotherapy 400 mg/m2 weekly [16].
HT was delivered at Kantonsspital Aarau, Switzerland and regular quality assurance was carried out in accordance with European Society of Hyperthermia Oncology (ESHO) guidelines for clinical studies in regional deep HT [19], [20]. Deep HT was delivered with the BSD 2000 unit with the Sigma-60 or Sigma-Eye phased array applicator (M/s Pyrexar Medical, Salt Lake City, Utah, USA). To define the HT treatment volume, a planning CT was carried out in the HT treatment position on the HT planning support (hammock) adapted for CT. The tumor and the adjacent normal structures were contoured on these scans. The HT treatment planning target volume was based on the radiotherapy PTV/CTV and planned using the HT treatment planning Sigma HYPERPLAN software (M/s Dr. Sennewald Medizintechnik GmbH, Munich, Germany) by segmentation and creation of a grid model of the various body tissues according to their dielectric properties (e.g. tumor, intestine, abdominal organs, muscle, bone, fat) followed by simulation of the electric fields. Suitable power and steering parameters were used to generate a specific absorption rate distribution in the target volume using finite element modeling. A warm-up heating phase of 30 min followed by 60 min of HT treatment were applied.
Prior to each hyperthermia session, a multisensor (8 sensors) thermometric probe (FISO, FISO Technologies Inc. Quebec, Canada) was placed endoscopically in the C-loop of the duodenum. The position of the probes was checked under fluoroscopy and with a CT scan to ensure correct placement adjacent to the primary tumor. Direct intratumoral temperature measurements were not possible without undue risk to the patients, thus the temperatures recorded approximated those achieved in the tumor. Maximum power, ranging between 650 and 750 W (median: 700 W), was delivered according to the tolerance of the patient and temperature was continuously recorded during the heating session. Eight cycles of two weekly FOLFORINOX chemotherapy [18] were commenced four weeks later and imaging was performed three months after completion of therapy.
Response assessment: Response was assessed by comparing the pre-treatment tumor volume and metabolic activity with measurements taken 4 weeks after completion of radiotherapy.
Therapeutic response was assessed by PET-CT and MRI and contrast-enhanced CT in addition if available. Radiological response was evaluated as per the revised Response Evaluation Criteria in Solid Tumors (RECIST, Version 1.1) [21] and the metabolic response according to the PERCIST criteria [22].
Statistical analysis: Survival analysis was performed using Kaplan-Meier statistics. All survival estimates were computed from the first day of FOLFIRINOX chemotherapy. Progression-free survival represented the length of time during and after the treatment of disease, during which the patient had either complete, partial or stable response as defined in the “response assessment”. Progressive disease and death due to any cause irrespective of the disease status were considered as events for calculation of PFS. The overall survival period was computed from the first day of FOLFIRINOX until last follow-up or death. Death due to any cause was considered as an event for overall survival.
3 Results
Follow-up data were available for all nine patients and are summarised in Table 1. Seven patients received the planned four cycles of neoadjuvant FOLFORINOX, one received five and one received nine. All tumours were subsequently restaged and remained inoperable according to radiological criteria and discussion at a multidisciplinary team meeting. Nine patients received subsequent RT (eight to 56 Gy and one patient to 50.4 Gy) combined with gemcitabine and hyperthermia. The median temperature recorded on the endoscopic duodenal probe during delivery of hyperthermia was 39.9 °C (39.1–40.8 °C). The RT boost was omitted in one patient due to grade 3 nausea and vomiting. Another patient received only 2 cycles of gemcitabine and 2 sessions of hyperthermia due to rapidly increasing ascites of uncertain origin which resolved completely.Table 1 Patient demographics.
Gender Age TNM No. of cycles FOLFORINOX pre HTCTRT Total RT dose (Gy) Total no. of hyperthermia sessions Maximum Recorded endogastric hyperthermia (°C) Toxicity CTC AE v5.0 No. of cycles FOLFORINOX post HTCTRT Further therapy PFS from start of neoadj. chemo (mths) OS from start of neoadj. chemo (mths)
M 68 T3N1M0 4 56 2 39.9 Abdominal pain Gr 2 0 SBRT of lung metastases 4 34
M 77 T4N1M0 5 56 6 40.0 Nausea Gr 1
Diarrhoea Gr 1 4 Nab-Paclitaxel/Gemcitabine 12 17
M 81 T4N0M0 4 56 4 40.5 Abdominal pain Gr 1 8 21 24
M 44 T3N1M1 4 56 6 38.7 Vomiting Gr 1 2 Pancreatico-duodenectomy 29 30
F 58 T2N1M1 4 56 5 39.1 Abdominal pain Gr 1 Nausea Gr 1 8 Gemcitabine 11 13
F 56 T4N1M0 4 56 6 40.8 Nausea Gr 2
Diarrhoea Gr 1 1 Pancreatico-duodenectomy 11 22
M 70 T3N1M0 4 56 4 39.8 Vomiting Gr 2 0 16 18
M 79 T3N1M0 4 56 6 39.2 Abdominal pain Gr 1
Gastric ulceration Gr 2 4 29 29
F 60 T4N1M0 9 50.4 5 39.9 Nausea Gr 3 0 Nab-Paclitaxel/ Gemcitabine 15 24
A PETCT scan was scheduled after completion of first line FOLFORINOX chemotherapy and after completion of HTCTRT to assess response and resectability according to the PERCIST criteria [22]. Paired scans were available in 8 of 9 patients. The PET scans after FOLFORINOX chemotherapy showed a metabolic partial remission (PR) in 6/8 patients and stable disease (SD) in 2/8 patients. A PETCT scan repeated 3 months after completion of HTCTRT showed that 4/8 patients achieved a metabolic complete response (CR), 1/8 a PR and 3/8 SD when compared with the post chemotherapy PETCT scan. Two tumours became resectable and the postoperative stages were ypT0 ypN0 (pCR) and ypT2 ypN0 (pPR). Five patients received between 1 and 12 cycles of additional FOLFORINOX chemotherapy and two patients subsequently received palliative gemcitabine chemotherapy at disease progression. As of 20th September 2020, two patients are alive and seven have died.
All nine patients (100%) were alive 1 year after commencing induction chemotherapy and five of nine patients (56%) were alive 2 years from the same time point. The median OS was 24 months (95% CI 21.2–26.8 mths) (Fig. 1a), which remained unchanged when the two patients with resected tumours were excluded. One of the two patients with a complete pathological response and a R0 resected tumour is still alive with no evidence of disease 34 months from start of induction chemotherapy, despite M1 disease (a solitary liver metastasis, later resected) at diagnosis. The second patient with M1 disease survived 1 year. Median radiological progression-free survival was 15 months (95% CI 6.2–23.7 mths) (Fig. 1b) and 1 year PFS was 64.8%. Most patients reported transient Grade 1–2 nausea and abdominal discomfort during HTCRT and one patient required antiemetics and hydration for grade 3 nausea (Table 1). The ascites in the above-mentioned patient disappeared within months after completion of treatment.Fig. 1 According to the Kaplan-Meier curves, median overall survival was 24 months (95% CI 21.2–26.8 mths) (Fig. 1a) and median progression-free survival was 15 months (95% CI 6.2–23.7 mths) (Fig. 1a).
4 Discussion
We report the results of nine consecutive patients treated with an intensified HTCTRT regimen designed for optimal biological interaction between all three therapeutic modalities. The median overall survival of 24 months reported here appears superior when compared with recent trials of photon-based chemoradiation.
Pancreatic cancer is notable for its resistance to photon radiotherapy, chemotherapy and targeted therapies. Chemoradiation has long been used in locally advanced pancreatic cancer in attempt to render tumours operable or achieve local control. The LAP07 study has called the radiation component into question however, as overall survival with gemcitabine-based chemoradiation to 54 Gy (15.2 months) was not superior to that observed with gemcitabine chemotherapy alone (16.5 months) [23]. A similar median OS of 15 months has recently been reported in the interim analysis of the CONKO-007 randomised trial of chemotherapy versus chemoradiotherapy in inoperable pancreatic cancer [3]. One clinical trial of photon chemoradiation compared with chemoradiation and hyperthermia has been published previously. Maluta et al. reported a comparative cohort trial of 68 patients treated with 3-D radiotherapy between 30 Gy in 10 fractions and 66 Gy in 33 fractions combined with gemcitabine alone or with oxaliplatin, cisplatin or 5-fluorouracil, with or without twice-weekly deep hyperthermia. The overall survival in the first group was 11 months and was 15 months in the hyperthermia group (p = 0.025) without additional toxicity, demonstrating feasibility and suggesting a modest but significant overall survival benefit from hyperthermia [15]. Of note, some of the patients received only a palliative dose of radiotherapy. Two small trials of gemcitabine and regional hyperthermia have been reported. In patients with LAPC and metastatic pancreatic cancer, median survival was 17.7 months in 6 patients with M0 disease [24] and 15 months was following sequential gemcitabine and cisplatin combined with hyperthermia [14].
The present study used intraduodenal temperature instead of intratumoral thermometric measurements. This pragmatic thermometric assessment was chosen to be safe and acceptable to the patients during the 6 weeks of treatment. A multisensor probe with 8 sensors (at 2 cm intervals) was placed in the C-loop of the duodenum prior to each weekly hyperthermia session. This provided information regarding the locoregional temperature in the heated volume. Invasive thermometry for intratumoral measurement would have been limited to one or few thermal sensors and would only represent the temperature adjacent to the tip of the probe. Our centre presently has no facilities for non-invasive thermometry using MRI. Moreover, non-invasive thermometry has challenges associated with pancreatic motion [6].
Investigations into alternative forms of irradiation with protons and carbon ions in LAPC have been recently published. 42 patients received proton beam irradiation combined with gemcitabine chemotherapy, 32 of whom also received hyperthermia. OS from the initial treatment was 84.5% at 1 year and 58.7% at 2 years with a median OS of 27.5 months and 2 patients (4%) became resectable [25]. In a trial of carbon ion therapy in 72 patients with LAPC, the majority received induction and concurrent gemcitabine chemotherapy, and OS rates were 73% at 1 year, and 46% at 2 years with a median OS of 21.5 months [26]. Both series report superior outcomes to photon CRT and the median OS are very similar to the HEATPAC series. Indeed it has been suggested that hyperthermia could modify the radiobiological properties of photons to resemble those of neutrons without additional toxicity [27] and that proton irradiation hyperthermia combined with would have the properties of high LET carbon ions [28].
When designing the HEATPAC protocol, multi-agent FOLFORINOX was chosen as the induction and additive chemotherapy due to the increased efficacy over gemcitabine in the palliative setting reported by Conroy et al. [18]. All nine tumours remained inoperable after neoadjuvant chemotherapy however and the chemoradiation with hyperthermia is the most therapeutically active component of the protocol. A Phase II trial with similar design recently reported a 60% R0 resection rate in patients with LAPC using 8 cycles of FOLFORINOX/losartan followed by 5 × 5 Gy proton therapy with capecitabine or 55.8 Gy photon radiotherapy with concurrent 5-fluorouracil or capecitabine. In the interim analysis of the CONKO-007 trial, median OS was significantly better (26.5 months) in patients with an R0 resection after neoadjuvant treatment than in non-operated patients (16.5 months) [3]. Patients in the non-surgical HEATPAC cohort had a similar median OS (24 months) to patients achieving an R0 resection in CONKO-007 and these data highlight the potential role of HTCRT as part of 'total neoadjuvant therapy' [29].
Immunotherapy is recognised as the fourth pillar of cancer therapy. Modulation of the tumor immune microenvironment, along with the other mechanistic effects of hyperthermia, make it a compelling area of active research in therapy-refractory tumours such as PDAC. A current European phase III trial (HEAT) will compare overall survival and progression-free survival following the addition of hyperthermia to gemcitabine or gemcitabine and cisplatin as adjuvant therapy following a R0 or R1 resection in patients with resectable pancreatic cancer.
The clinical outcomes of this selected patient cohort are provocative as the median OS of 24 months with HTCRT far exceeds the median OS of 15.2 months (95% CI, 13.9–17.3 months) with CRT reported in LAP07, and this despite two patients having M1 disease. This multimodality approach of triple sensitisation to achieve biological intensification of therapy has yielded very encouraging data but accrual to the HEATPAC protocol has unfortunately been limited by the low incidence of eligible cases in a small population and there only being one deep hyperthermia unit in Switzerland. Multicentre international cooperation is urgently required for adequate recruitment to the HEATPAC randomised trial to draw conclusions regarding efficacy.
5 Conclusions
Triple sensitisation with HTCRT was associated with promising feasibility, toxicity and efficacy in this small cohort of patients. Median overall and progression free survival exceeded those currently seen with gemcitabine-based CRT in LAPC.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The study is partly funded by the “Günter und Regine Kelm Stiftung,” and the “Hugo und Elsa Isler-Fonds,” Switzerland. | GEMCITABINE?BASED CHEMORADIATION | DrugDosageText | CC BY-NC-ND | 33598571 | 19,202,901 | 2021-03 |
What was the outcome of reaction 'Abdominal pain'? | The addition of deep hyperthermia to gemcitabine-based chemoradiation may achieve enhanced survival in unresectable locally advanced adenocarcinoma of the pancreas.
Driven by the current unsatisfactory outcomes for patients with locally advanced pancreatic cancer (LAPC), a biologically intensified clinical protocol was developed to explore the feasibility and efficacy of FOLFORINOX chemotherapy followed by deep hyperthermia concomitant with chemoradiation and subsequent FOLFORINOX chemotherapy in patients with LAPC.
Nine patients with LAPC were treated according to the HEATPAC Phase II trial protocol which consists of 4 cycles of FOLFORINOX chemotherapy followed by gemcitabine-based chemoradiation to 56 Gy combined with weekly deep hyperthermia and then a further 8 cycles of FOLFORINOX chemotherapy.
One grade three related toxicity was reported and two tumours became resectable. The median overall survival was 24 months and 1 year overall survival was 100%.
Intensification of chemoradiation with deep hyperthermia was feasible in nine consecutive patients with LAPC.
1 Introduction
The incidence and mortality of pancreatic ductal adenocarcinoma (PDAC) are similar and this highly fatal disease has a 5 year survival rate of only 5% [1]. 50% of patients have metastatic disease at diagnosis and 30% present with locally advanced non-metastatic but inoperable pancreatic cancer (LAPC) [2] which has a median overall survival (OS) of 15 months [3]. At presentation, 10–20% of cases qualify for surgical resection, which is the only curative treatment option. The high percentage of patients presenting with LAPC and the frequent microscopic incomplete resections provide a strong rationale for clinical research into increasing the efficacy of non-surgical therapies. In 2013, a comprehensive review and meta-analysis regarding neoadjuvant therapies in LAPC summarised the limited evidence that combination chemotherapy (CT) might induce resectability in up to 30%–40% of patients with LAPC [4]. Gemcitabine has long been the chemotherapeutic agent of choice [5] and chemoradiation (CRT) is the standard modality after induction chemotherapy in LAPC.
Clinical hyperthermia is a unique multifaceted, therapeutic modality that achieves cytotoxicity and radio- and chemosensitisation and is also an immunomodulator akin to in situ tumour vaccination [6]. Meta-analyses and network meta-analyses have confirmed the greater efficacy of thermoradiotherapy over radiotherapy and the lack of significant additional toxicity in various tumour entities [7], [8], [9], [10]. Gemcitabine is a proven radiosensitiser due to reduced radiotherapy-induced DNA repair, S phase cell cycle arrest and the triggering of apoptosis [11]. Furthermore, HT has been shown to sensitise the effects of gemcitabine at 43 °C. This has been best observed if gemcitabine is given 24 h after HT [12]. Hyperthermia increases the cytotoxicity of gemcitabine in human pancreatic cancer cell lines [12], [13] and thus a combination of HT, RT and gemcitabine would lead to triple sensitisation: thermal sensitisation of RT, thermal sensitisation of gemcitabine [14] and radiosensitisation by gemcitabine. A concurrent approach of gemcitabine, RT and HT (HTCRT) merits evaluation in LAPC and has been previously explored in a prospective single arm study reporting a median OS of 15 months and a 1 year OS of 67% [15].
Driven by the current unsatisfactory outcomes for patients with LAPC, a biologically intensified clinical protocol was developed to explore the feasibility and efficacy of FOLFORINOX chemotherapy followed by HTCRT with gemcitabine and additional FOLFORINOX chemotherapy in patients with LAPC.
2 Methods
Patients were treated according to the previously published ethics-approved protocol (HEATPAC Phase II trial, ClinicalTrials.gov: NCT02439593) [16] after the tumour was deemed inoperable [17] at a multidisciplinary tumour board. Between 06/2015 and 01/2019, nine patients with LAPC were identified and treated according to protocol. 7 of the 9 patients could not be included in the HEATPAC study as they either (a) were treated before the start of the HEATPAC study to check feasibility and logistics (n = 2), or (b) had been already started on pre-HTCTRT chemotherapy with FOLFIRINOX at other centres (n = 5) or (c) they did not fulfil the inclusion criterion of M0 disease (n = 2) due to suspicion of low volume metastases. Patients were commenced on 4 cycles of FOLFORINOX chemotherapy on a two weekly schedule [18]. CT, MRI or PETCT imaging was repeated four weeks after completion of chemotherapy and the resectability of the tumour was re-evaluated. In the event of persisting inoperability, patients received photon radiotherapy with 28 × 1.8 Gray (Gy) = 50.4 Gy to the clinical target volume, with a simultaneous integrated boost to the gross tumour volume and any involved regional lymph nodes to 56 Gy, delivered daily over 5.5 weeks with a VMAT technique combined with gemcitabine chemotherapy 400 mg/m2 weekly [16].
HT was delivered at Kantonsspital Aarau, Switzerland and regular quality assurance was carried out in accordance with European Society of Hyperthermia Oncology (ESHO) guidelines for clinical studies in regional deep HT [19], [20]. Deep HT was delivered with the BSD 2000 unit with the Sigma-60 or Sigma-Eye phased array applicator (M/s Pyrexar Medical, Salt Lake City, Utah, USA). To define the HT treatment volume, a planning CT was carried out in the HT treatment position on the HT planning support (hammock) adapted for CT. The tumor and the adjacent normal structures were contoured on these scans. The HT treatment planning target volume was based on the radiotherapy PTV/CTV and planned using the HT treatment planning Sigma HYPERPLAN software (M/s Dr. Sennewald Medizintechnik GmbH, Munich, Germany) by segmentation and creation of a grid model of the various body tissues according to their dielectric properties (e.g. tumor, intestine, abdominal organs, muscle, bone, fat) followed by simulation of the electric fields. Suitable power and steering parameters were used to generate a specific absorption rate distribution in the target volume using finite element modeling. A warm-up heating phase of 30 min followed by 60 min of HT treatment were applied.
Prior to each hyperthermia session, a multisensor (8 sensors) thermometric probe (FISO, FISO Technologies Inc. Quebec, Canada) was placed endoscopically in the C-loop of the duodenum. The position of the probes was checked under fluoroscopy and with a CT scan to ensure correct placement adjacent to the primary tumor. Direct intratumoral temperature measurements were not possible without undue risk to the patients, thus the temperatures recorded approximated those achieved in the tumor. Maximum power, ranging between 650 and 750 W (median: 700 W), was delivered according to the tolerance of the patient and temperature was continuously recorded during the heating session. Eight cycles of two weekly FOLFORINOX chemotherapy [18] were commenced four weeks later and imaging was performed three months after completion of therapy.
Response assessment: Response was assessed by comparing the pre-treatment tumor volume and metabolic activity with measurements taken 4 weeks after completion of radiotherapy.
Therapeutic response was assessed by PET-CT and MRI and contrast-enhanced CT in addition if available. Radiological response was evaluated as per the revised Response Evaluation Criteria in Solid Tumors (RECIST, Version 1.1) [21] and the metabolic response according to the PERCIST criteria [22].
Statistical analysis: Survival analysis was performed using Kaplan-Meier statistics. All survival estimates were computed from the first day of FOLFIRINOX chemotherapy. Progression-free survival represented the length of time during and after the treatment of disease, during which the patient had either complete, partial or stable response as defined in the “response assessment”. Progressive disease and death due to any cause irrespective of the disease status were considered as events for calculation of PFS. The overall survival period was computed from the first day of FOLFIRINOX until last follow-up or death. Death due to any cause was considered as an event for overall survival.
3 Results
Follow-up data were available for all nine patients and are summarised in Table 1. Seven patients received the planned four cycles of neoadjuvant FOLFORINOX, one received five and one received nine. All tumours were subsequently restaged and remained inoperable according to radiological criteria and discussion at a multidisciplinary team meeting. Nine patients received subsequent RT (eight to 56 Gy and one patient to 50.4 Gy) combined with gemcitabine and hyperthermia. The median temperature recorded on the endoscopic duodenal probe during delivery of hyperthermia was 39.9 °C (39.1–40.8 °C). The RT boost was omitted in one patient due to grade 3 nausea and vomiting. Another patient received only 2 cycles of gemcitabine and 2 sessions of hyperthermia due to rapidly increasing ascites of uncertain origin which resolved completely.Table 1 Patient demographics.
Gender Age TNM No. of cycles FOLFORINOX pre HTCTRT Total RT dose (Gy) Total no. of hyperthermia sessions Maximum Recorded endogastric hyperthermia (°C) Toxicity CTC AE v5.0 No. of cycles FOLFORINOX post HTCTRT Further therapy PFS from start of neoadj. chemo (mths) OS from start of neoadj. chemo (mths)
M 68 T3N1M0 4 56 2 39.9 Abdominal pain Gr 2 0 SBRT of lung metastases 4 34
M 77 T4N1M0 5 56 6 40.0 Nausea Gr 1
Diarrhoea Gr 1 4 Nab-Paclitaxel/Gemcitabine 12 17
M 81 T4N0M0 4 56 4 40.5 Abdominal pain Gr 1 8 21 24
M 44 T3N1M1 4 56 6 38.7 Vomiting Gr 1 2 Pancreatico-duodenectomy 29 30
F 58 T2N1M1 4 56 5 39.1 Abdominal pain Gr 1 Nausea Gr 1 8 Gemcitabine 11 13
F 56 T4N1M0 4 56 6 40.8 Nausea Gr 2
Diarrhoea Gr 1 1 Pancreatico-duodenectomy 11 22
M 70 T3N1M0 4 56 4 39.8 Vomiting Gr 2 0 16 18
M 79 T3N1M0 4 56 6 39.2 Abdominal pain Gr 1
Gastric ulceration Gr 2 4 29 29
F 60 T4N1M0 9 50.4 5 39.9 Nausea Gr 3 0 Nab-Paclitaxel/ Gemcitabine 15 24
A PETCT scan was scheduled after completion of first line FOLFORINOX chemotherapy and after completion of HTCTRT to assess response and resectability according to the PERCIST criteria [22]. Paired scans were available in 8 of 9 patients. The PET scans after FOLFORINOX chemotherapy showed a metabolic partial remission (PR) in 6/8 patients and stable disease (SD) in 2/8 patients. A PETCT scan repeated 3 months after completion of HTCTRT showed that 4/8 patients achieved a metabolic complete response (CR), 1/8 a PR and 3/8 SD when compared with the post chemotherapy PETCT scan. Two tumours became resectable and the postoperative stages were ypT0 ypN0 (pCR) and ypT2 ypN0 (pPR). Five patients received between 1 and 12 cycles of additional FOLFORINOX chemotherapy and two patients subsequently received palliative gemcitabine chemotherapy at disease progression. As of 20th September 2020, two patients are alive and seven have died.
All nine patients (100%) were alive 1 year after commencing induction chemotherapy and five of nine patients (56%) were alive 2 years from the same time point. The median OS was 24 months (95% CI 21.2–26.8 mths) (Fig. 1a), which remained unchanged when the two patients with resected tumours were excluded. One of the two patients with a complete pathological response and a R0 resected tumour is still alive with no evidence of disease 34 months from start of induction chemotherapy, despite M1 disease (a solitary liver metastasis, later resected) at diagnosis. The second patient with M1 disease survived 1 year. Median radiological progression-free survival was 15 months (95% CI 6.2–23.7 mths) (Fig. 1b) and 1 year PFS was 64.8%. Most patients reported transient Grade 1–2 nausea and abdominal discomfort during HTCRT and one patient required antiemetics and hydration for grade 3 nausea (Table 1). The ascites in the above-mentioned patient disappeared within months after completion of treatment.Fig. 1 According to the Kaplan-Meier curves, median overall survival was 24 months (95% CI 21.2–26.8 mths) (Fig. 1a) and median progression-free survival was 15 months (95% CI 6.2–23.7 mths) (Fig. 1a).
4 Discussion
We report the results of nine consecutive patients treated with an intensified HTCTRT regimen designed for optimal biological interaction between all three therapeutic modalities. The median overall survival of 24 months reported here appears superior when compared with recent trials of photon-based chemoradiation.
Pancreatic cancer is notable for its resistance to photon radiotherapy, chemotherapy and targeted therapies. Chemoradiation has long been used in locally advanced pancreatic cancer in attempt to render tumours operable or achieve local control. The LAP07 study has called the radiation component into question however, as overall survival with gemcitabine-based chemoradiation to 54 Gy (15.2 months) was not superior to that observed with gemcitabine chemotherapy alone (16.5 months) [23]. A similar median OS of 15 months has recently been reported in the interim analysis of the CONKO-007 randomised trial of chemotherapy versus chemoradiotherapy in inoperable pancreatic cancer [3]. One clinical trial of photon chemoradiation compared with chemoradiation and hyperthermia has been published previously. Maluta et al. reported a comparative cohort trial of 68 patients treated with 3-D radiotherapy between 30 Gy in 10 fractions and 66 Gy in 33 fractions combined with gemcitabine alone or with oxaliplatin, cisplatin or 5-fluorouracil, with or without twice-weekly deep hyperthermia. The overall survival in the first group was 11 months and was 15 months in the hyperthermia group (p = 0.025) without additional toxicity, demonstrating feasibility and suggesting a modest but significant overall survival benefit from hyperthermia [15]. Of note, some of the patients received only a palliative dose of radiotherapy. Two small trials of gemcitabine and regional hyperthermia have been reported. In patients with LAPC and metastatic pancreatic cancer, median survival was 17.7 months in 6 patients with M0 disease [24] and 15 months was following sequential gemcitabine and cisplatin combined with hyperthermia [14].
The present study used intraduodenal temperature instead of intratumoral thermometric measurements. This pragmatic thermometric assessment was chosen to be safe and acceptable to the patients during the 6 weeks of treatment. A multisensor probe with 8 sensors (at 2 cm intervals) was placed in the C-loop of the duodenum prior to each weekly hyperthermia session. This provided information regarding the locoregional temperature in the heated volume. Invasive thermometry for intratumoral measurement would have been limited to one or few thermal sensors and would only represent the temperature adjacent to the tip of the probe. Our centre presently has no facilities for non-invasive thermometry using MRI. Moreover, non-invasive thermometry has challenges associated with pancreatic motion [6].
Investigations into alternative forms of irradiation with protons and carbon ions in LAPC have been recently published. 42 patients received proton beam irradiation combined with gemcitabine chemotherapy, 32 of whom also received hyperthermia. OS from the initial treatment was 84.5% at 1 year and 58.7% at 2 years with a median OS of 27.5 months and 2 patients (4%) became resectable [25]. In a trial of carbon ion therapy in 72 patients with LAPC, the majority received induction and concurrent gemcitabine chemotherapy, and OS rates were 73% at 1 year, and 46% at 2 years with a median OS of 21.5 months [26]. Both series report superior outcomes to photon CRT and the median OS are very similar to the HEATPAC series. Indeed it has been suggested that hyperthermia could modify the radiobiological properties of photons to resemble those of neutrons without additional toxicity [27] and that proton irradiation hyperthermia combined with would have the properties of high LET carbon ions [28].
When designing the HEATPAC protocol, multi-agent FOLFORINOX was chosen as the induction and additive chemotherapy due to the increased efficacy over gemcitabine in the palliative setting reported by Conroy et al. [18]. All nine tumours remained inoperable after neoadjuvant chemotherapy however and the chemoradiation with hyperthermia is the most therapeutically active component of the protocol. A Phase II trial with similar design recently reported a 60% R0 resection rate in patients with LAPC using 8 cycles of FOLFORINOX/losartan followed by 5 × 5 Gy proton therapy with capecitabine or 55.8 Gy photon radiotherapy with concurrent 5-fluorouracil or capecitabine. In the interim analysis of the CONKO-007 trial, median OS was significantly better (26.5 months) in patients with an R0 resection after neoadjuvant treatment than in non-operated patients (16.5 months) [3]. Patients in the non-surgical HEATPAC cohort had a similar median OS (24 months) to patients achieving an R0 resection in CONKO-007 and these data highlight the potential role of HTCRT as part of 'total neoadjuvant therapy' [29].
Immunotherapy is recognised as the fourth pillar of cancer therapy. Modulation of the tumor immune microenvironment, along with the other mechanistic effects of hyperthermia, make it a compelling area of active research in therapy-refractory tumours such as PDAC. A current European phase III trial (HEAT) will compare overall survival and progression-free survival following the addition of hyperthermia to gemcitabine or gemcitabine and cisplatin as adjuvant therapy following a R0 or R1 resection in patients with resectable pancreatic cancer.
The clinical outcomes of this selected patient cohort are provocative as the median OS of 24 months with HTCRT far exceeds the median OS of 15.2 months (95% CI, 13.9–17.3 months) with CRT reported in LAP07, and this despite two patients having M1 disease. This multimodality approach of triple sensitisation to achieve biological intensification of therapy has yielded very encouraging data but accrual to the HEATPAC protocol has unfortunately been limited by the low incidence of eligible cases in a small population and there only being one deep hyperthermia unit in Switzerland. Multicentre international cooperation is urgently required for adequate recruitment to the HEATPAC randomised trial to draw conclusions regarding efficacy.
5 Conclusions
Triple sensitisation with HTCRT was associated with promising feasibility, toxicity and efficacy in this small cohort of patients. Median overall and progression free survival exceeded those currently seen with gemcitabine-based CRT in LAPC.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The study is partly funded by the “Günter und Regine Kelm Stiftung,” and the “Hugo und Elsa Isler-Fonds,” Switzerland. | Recovered | ReactionOutcome | CC BY-NC-ND | 33598571 | 19,202,901 | 2021-03 |
What was the outcome of reaction 'Gastric ulcer'? | The addition of deep hyperthermia to gemcitabine-based chemoradiation may achieve enhanced survival in unresectable locally advanced adenocarcinoma of the pancreas.
Driven by the current unsatisfactory outcomes for patients with locally advanced pancreatic cancer (LAPC), a biologically intensified clinical protocol was developed to explore the feasibility and efficacy of FOLFORINOX chemotherapy followed by deep hyperthermia concomitant with chemoradiation and subsequent FOLFORINOX chemotherapy in patients with LAPC.
Nine patients with LAPC were treated according to the HEATPAC Phase II trial protocol which consists of 4 cycles of FOLFORINOX chemotherapy followed by gemcitabine-based chemoradiation to 56 Gy combined with weekly deep hyperthermia and then a further 8 cycles of FOLFORINOX chemotherapy.
One grade three related toxicity was reported and two tumours became resectable. The median overall survival was 24 months and 1 year overall survival was 100%.
Intensification of chemoradiation with deep hyperthermia was feasible in nine consecutive patients with LAPC.
1 Introduction
The incidence and mortality of pancreatic ductal adenocarcinoma (PDAC) are similar and this highly fatal disease has a 5 year survival rate of only 5% [1]. 50% of patients have metastatic disease at diagnosis and 30% present with locally advanced non-metastatic but inoperable pancreatic cancer (LAPC) [2] which has a median overall survival (OS) of 15 months [3]. At presentation, 10–20% of cases qualify for surgical resection, which is the only curative treatment option. The high percentage of patients presenting with LAPC and the frequent microscopic incomplete resections provide a strong rationale for clinical research into increasing the efficacy of non-surgical therapies. In 2013, a comprehensive review and meta-analysis regarding neoadjuvant therapies in LAPC summarised the limited evidence that combination chemotherapy (CT) might induce resectability in up to 30%–40% of patients with LAPC [4]. Gemcitabine has long been the chemotherapeutic agent of choice [5] and chemoradiation (CRT) is the standard modality after induction chemotherapy in LAPC.
Clinical hyperthermia is a unique multifaceted, therapeutic modality that achieves cytotoxicity and radio- and chemosensitisation and is also an immunomodulator akin to in situ tumour vaccination [6]. Meta-analyses and network meta-analyses have confirmed the greater efficacy of thermoradiotherapy over radiotherapy and the lack of significant additional toxicity in various tumour entities [7], [8], [9], [10]. Gemcitabine is a proven radiosensitiser due to reduced radiotherapy-induced DNA repair, S phase cell cycle arrest and the triggering of apoptosis [11]. Furthermore, HT has been shown to sensitise the effects of gemcitabine at 43 °C. This has been best observed if gemcitabine is given 24 h after HT [12]. Hyperthermia increases the cytotoxicity of gemcitabine in human pancreatic cancer cell lines [12], [13] and thus a combination of HT, RT and gemcitabine would lead to triple sensitisation: thermal sensitisation of RT, thermal sensitisation of gemcitabine [14] and radiosensitisation by gemcitabine. A concurrent approach of gemcitabine, RT and HT (HTCRT) merits evaluation in LAPC and has been previously explored in a prospective single arm study reporting a median OS of 15 months and a 1 year OS of 67% [15].
Driven by the current unsatisfactory outcomes for patients with LAPC, a biologically intensified clinical protocol was developed to explore the feasibility and efficacy of FOLFORINOX chemotherapy followed by HTCRT with gemcitabine and additional FOLFORINOX chemotherapy in patients with LAPC.
2 Methods
Patients were treated according to the previously published ethics-approved protocol (HEATPAC Phase II trial, ClinicalTrials.gov: NCT02439593) [16] after the tumour was deemed inoperable [17] at a multidisciplinary tumour board. Between 06/2015 and 01/2019, nine patients with LAPC were identified and treated according to protocol. 7 of the 9 patients could not be included in the HEATPAC study as they either (a) were treated before the start of the HEATPAC study to check feasibility and logistics (n = 2), or (b) had been already started on pre-HTCTRT chemotherapy with FOLFIRINOX at other centres (n = 5) or (c) they did not fulfil the inclusion criterion of M0 disease (n = 2) due to suspicion of low volume metastases. Patients were commenced on 4 cycles of FOLFORINOX chemotherapy on a two weekly schedule [18]. CT, MRI or PETCT imaging was repeated four weeks after completion of chemotherapy and the resectability of the tumour was re-evaluated. In the event of persisting inoperability, patients received photon radiotherapy with 28 × 1.8 Gray (Gy) = 50.4 Gy to the clinical target volume, with a simultaneous integrated boost to the gross tumour volume and any involved regional lymph nodes to 56 Gy, delivered daily over 5.5 weeks with a VMAT technique combined with gemcitabine chemotherapy 400 mg/m2 weekly [16].
HT was delivered at Kantonsspital Aarau, Switzerland and regular quality assurance was carried out in accordance with European Society of Hyperthermia Oncology (ESHO) guidelines for clinical studies in regional deep HT [19], [20]. Deep HT was delivered with the BSD 2000 unit with the Sigma-60 or Sigma-Eye phased array applicator (M/s Pyrexar Medical, Salt Lake City, Utah, USA). To define the HT treatment volume, a planning CT was carried out in the HT treatment position on the HT planning support (hammock) adapted for CT. The tumor and the adjacent normal structures were contoured on these scans. The HT treatment planning target volume was based on the radiotherapy PTV/CTV and planned using the HT treatment planning Sigma HYPERPLAN software (M/s Dr. Sennewald Medizintechnik GmbH, Munich, Germany) by segmentation and creation of a grid model of the various body tissues according to their dielectric properties (e.g. tumor, intestine, abdominal organs, muscle, bone, fat) followed by simulation of the electric fields. Suitable power and steering parameters were used to generate a specific absorption rate distribution in the target volume using finite element modeling. A warm-up heating phase of 30 min followed by 60 min of HT treatment were applied.
Prior to each hyperthermia session, a multisensor (8 sensors) thermometric probe (FISO, FISO Technologies Inc. Quebec, Canada) was placed endoscopically in the C-loop of the duodenum. The position of the probes was checked under fluoroscopy and with a CT scan to ensure correct placement adjacent to the primary tumor. Direct intratumoral temperature measurements were not possible without undue risk to the patients, thus the temperatures recorded approximated those achieved in the tumor. Maximum power, ranging between 650 and 750 W (median: 700 W), was delivered according to the tolerance of the patient and temperature was continuously recorded during the heating session. Eight cycles of two weekly FOLFORINOX chemotherapy [18] were commenced four weeks later and imaging was performed three months after completion of therapy.
Response assessment: Response was assessed by comparing the pre-treatment tumor volume and metabolic activity with measurements taken 4 weeks after completion of radiotherapy.
Therapeutic response was assessed by PET-CT and MRI and contrast-enhanced CT in addition if available. Radiological response was evaluated as per the revised Response Evaluation Criteria in Solid Tumors (RECIST, Version 1.1) [21] and the metabolic response according to the PERCIST criteria [22].
Statistical analysis: Survival analysis was performed using Kaplan-Meier statistics. All survival estimates were computed from the first day of FOLFIRINOX chemotherapy. Progression-free survival represented the length of time during and after the treatment of disease, during which the patient had either complete, partial or stable response as defined in the “response assessment”. Progressive disease and death due to any cause irrespective of the disease status were considered as events for calculation of PFS. The overall survival period was computed from the first day of FOLFIRINOX until last follow-up or death. Death due to any cause was considered as an event for overall survival.
3 Results
Follow-up data were available for all nine patients and are summarised in Table 1. Seven patients received the planned four cycles of neoadjuvant FOLFORINOX, one received five and one received nine. All tumours were subsequently restaged and remained inoperable according to radiological criteria and discussion at a multidisciplinary team meeting. Nine patients received subsequent RT (eight to 56 Gy and one patient to 50.4 Gy) combined with gemcitabine and hyperthermia. The median temperature recorded on the endoscopic duodenal probe during delivery of hyperthermia was 39.9 °C (39.1–40.8 °C). The RT boost was omitted in one patient due to grade 3 nausea and vomiting. Another patient received only 2 cycles of gemcitabine and 2 sessions of hyperthermia due to rapidly increasing ascites of uncertain origin which resolved completely.Table 1 Patient demographics.
Gender Age TNM No. of cycles FOLFORINOX pre HTCTRT Total RT dose (Gy) Total no. of hyperthermia sessions Maximum Recorded endogastric hyperthermia (°C) Toxicity CTC AE v5.0 No. of cycles FOLFORINOX post HTCTRT Further therapy PFS from start of neoadj. chemo (mths) OS from start of neoadj. chemo (mths)
M 68 T3N1M0 4 56 2 39.9 Abdominal pain Gr 2 0 SBRT of lung metastases 4 34
M 77 T4N1M0 5 56 6 40.0 Nausea Gr 1
Diarrhoea Gr 1 4 Nab-Paclitaxel/Gemcitabine 12 17
M 81 T4N0M0 4 56 4 40.5 Abdominal pain Gr 1 8 21 24
M 44 T3N1M1 4 56 6 38.7 Vomiting Gr 1 2 Pancreatico-duodenectomy 29 30
F 58 T2N1M1 4 56 5 39.1 Abdominal pain Gr 1 Nausea Gr 1 8 Gemcitabine 11 13
F 56 T4N1M0 4 56 6 40.8 Nausea Gr 2
Diarrhoea Gr 1 1 Pancreatico-duodenectomy 11 22
M 70 T3N1M0 4 56 4 39.8 Vomiting Gr 2 0 16 18
M 79 T3N1M0 4 56 6 39.2 Abdominal pain Gr 1
Gastric ulceration Gr 2 4 29 29
F 60 T4N1M0 9 50.4 5 39.9 Nausea Gr 3 0 Nab-Paclitaxel/ Gemcitabine 15 24
A PETCT scan was scheduled after completion of first line FOLFORINOX chemotherapy and after completion of HTCTRT to assess response and resectability according to the PERCIST criteria [22]. Paired scans were available in 8 of 9 patients. The PET scans after FOLFORINOX chemotherapy showed a metabolic partial remission (PR) in 6/8 patients and stable disease (SD) in 2/8 patients. A PETCT scan repeated 3 months after completion of HTCTRT showed that 4/8 patients achieved a metabolic complete response (CR), 1/8 a PR and 3/8 SD when compared with the post chemotherapy PETCT scan. Two tumours became resectable and the postoperative stages were ypT0 ypN0 (pCR) and ypT2 ypN0 (pPR). Five patients received between 1 and 12 cycles of additional FOLFORINOX chemotherapy and two patients subsequently received palliative gemcitabine chemotherapy at disease progression. As of 20th September 2020, two patients are alive and seven have died.
All nine patients (100%) were alive 1 year after commencing induction chemotherapy and five of nine patients (56%) were alive 2 years from the same time point. The median OS was 24 months (95% CI 21.2–26.8 mths) (Fig. 1a), which remained unchanged when the two patients with resected tumours were excluded. One of the two patients with a complete pathological response and a R0 resected tumour is still alive with no evidence of disease 34 months from start of induction chemotherapy, despite M1 disease (a solitary liver metastasis, later resected) at diagnosis. The second patient with M1 disease survived 1 year. Median radiological progression-free survival was 15 months (95% CI 6.2–23.7 mths) (Fig. 1b) and 1 year PFS was 64.8%. Most patients reported transient Grade 1–2 nausea and abdominal discomfort during HTCRT and one patient required antiemetics and hydration for grade 3 nausea (Table 1). The ascites in the above-mentioned patient disappeared within months after completion of treatment.Fig. 1 According to the Kaplan-Meier curves, median overall survival was 24 months (95% CI 21.2–26.8 mths) (Fig. 1a) and median progression-free survival was 15 months (95% CI 6.2–23.7 mths) (Fig. 1a).
4 Discussion
We report the results of nine consecutive patients treated with an intensified HTCTRT regimen designed for optimal biological interaction between all three therapeutic modalities. The median overall survival of 24 months reported here appears superior when compared with recent trials of photon-based chemoradiation.
Pancreatic cancer is notable for its resistance to photon radiotherapy, chemotherapy and targeted therapies. Chemoradiation has long been used in locally advanced pancreatic cancer in attempt to render tumours operable or achieve local control. The LAP07 study has called the radiation component into question however, as overall survival with gemcitabine-based chemoradiation to 54 Gy (15.2 months) was not superior to that observed with gemcitabine chemotherapy alone (16.5 months) [23]. A similar median OS of 15 months has recently been reported in the interim analysis of the CONKO-007 randomised trial of chemotherapy versus chemoradiotherapy in inoperable pancreatic cancer [3]. One clinical trial of photon chemoradiation compared with chemoradiation and hyperthermia has been published previously. Maluta et al. reported a comparative cohort trial of 68 patients treated with 3-D radiotherapy between 30 Gy in 10 fractions and 66 Gy in 33 fractions combined with gemcitabine alone or with oxaliplatin, cisplatin or 5-fluorouracil, with or without twice-weekly deep hyperthermia. The overall survival in the first group was 11 months and was 15 months in the hyperthermia group (p = 0.025) without additional toxicity, demonstrating feasibility and suggesting a modest but significant overall survival benefit from hyperthermia [15]. Of note, some of the patients received only a palliative dose of radiotherapy. Two small trials of gemcitabine and regional hyperthermia have been reported. In patients with LAPC and metastatic pancreatic cancer, median survival was 17.7 months in 6 patients with M0 disease [24] and 15 months was following sequential gemcitabine and cisplatin combined with hyperthermia [14].
The present study used intraduodenal temperature instead of intratumoral thermometric measurements. This pragmatic thermometric assessment was chosen to be safe and acceptable to the patients during the 6 weeks of treatment. A multisensor probe with 8 sensors (at 2 cm intervals) was placed in the C-loop of the duodenum prior to each weekly hyperthermia session. This provided information regarding the locoregional temperature in the heated volume. Invasive thermometry for intratumoral measurement would have been limited to one or few thermal sensors and would only represent the temperature adjacent to the tip of the probe. Our centre presently has no facilities for non-invasive thermometry using MRI. Moreover, non-invasive thermometry has challenges associated with pancreatic motion [6].
Investigations into alternative forms of irradiation with protons and carbon ions in LAPC have been recently published. 42 patients received proton beam irradiation combined with gemcitabine chemotherapy, 32 of whom also received hyperthermia. OS from the initial treatment was 84.5% at 1 year and 58.7% at 2 years with a median OS of 27.5 months and 2 patients (4%) became resectable [25]. In a trial of carbon ion therapy in 72 patients with LAPC, the majority received induction and concurrent gemcitabine chemotherapy, and OS rates were 73% at 1 year, and 46% at 2 years with a median OS of 21.5 months [26]. Both series report superior outcomes to photon CRT and the median OS are very similar to the HEATPAC series. Indeed it has been suggested that hyperthermia could modify the radiobiological properties of photons to resemble those of neutrons without additional toxicity [27] and that proton irradiation hyperthermia combined with would have the properties of high LET carbon ions [28].
When designing the HEATPAC protocol, multi-agent FOLFORINOX was chosen as the induction and additive chemotherapy due to the increased efficacy over gemcitabine in the palliative setting reported by Conroy et al. [18]. All nine tumours remained inoperable after neoadjuvant chemotherapy however and the chemoradiation with hyperthermia is the most therapeutically active component of the protocol. A Phase II trial with similar design recently reported a 60% R0 resection rate in patients with LAPC using 8 cycles of FOLFORINOX/losartan followed by 5 × 5 Gy proton therapy with capecitabine or 55.8 Gy photon radiotherapy with concurrent 5-fluorouracil or capecitabine. In the interim analysis of the CONKO-007 trial, median OS was significantly better (26.5 months) in patients with an R0 resection after neoadjuvant treatment than in non-operated patients (16.5 months) [3]. Patients in the non-surgical HEATPAC cohort had a similar median OS (24 months) to patients achieving an R0 resection in CONKO-007 and these data highlight the potential role of HTCRT as part of 'total neoadjuvant therapy' [29].
Immunotherapy is recognised as the fourth pillar of cancer therapy. Modulation of the tumor immune microenvironment, along with the other mechanistic effects of hyperthermia, make it a compelling area of active research in therapy-refractory tumours such as PDAC. A current European phase III trial (HEAT) will compare overall survival and progression-free survival following the addition of hyperthermia to gemcitabine or gemcitabine and cisplatin as adjuvant therapy following a R0 or R1 resection in patients with resectable pancreatic cancer.
The clinical outcomes of this selected patient cohort are provocative as the median OS of 24 months with HTCRT far exceeds the median OS of 15.2 months (95% CI, 13.9–17.3 months) with CRT reported in LAP07, and this despite two patients having M1 disease. This multimodality approach of triple sensitisation to achieve biological intensification of therapy has yielded very encouraging data but accrual to the HEATPAC protocol has unfortunately been limited by the low incidence of eligible cases in a small population and there only being one deep hyperthermia unit in Switzerland. Multicentre international cooperation is urgently required for adequate recruitment to the HEATPAC randomised trial to draw conclusions regarding efficacy.
5 Conclusions
Triple sensitisation with HTCRT was associated with promising feasibility, toxicity and efficacy in this small cohort of patients. Median overall and progression free survival exceeded those currently seen with gemcitabine-based CRT in LAPC.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The study is partly funded by the “Günter und Regine Kelm Stiftung,” and the “Hugo und Elsa Isler-Fonds,” Switzerland. | Recovered | ReactionOutcome | CC BY-NC-ND | 33598571 | 19,202,901 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Aortitis'. | Granulocyte colony stimulating factor-associated aortitis evaluated via multiple imaging modalities including vascular echography: a case report.
Granulocyte colony stimulating factor (G-CSF) preparations are used for patients with granulocytopenia, especially to prevent febrile neutropenia. Arteritis has been recognized as a side effect of G-CSF treatment; however, there are no clear diagnostic criteria or treatment guidelines because not enough cases have been reported. Present case showed one of the diagnostic and treatment selection methods via multiple imaging modality including vascular echography.
A 52-year-old woman underwent chemotherapy for ovarian cancer and received G-CSF because of myelosuppression. The patient experienced high and remittent fever that persisted during treatment using antibiotics and acetaminophen. Enhanced computed tomography revealed thickening of the tissue around the aortic arch and abdominal aorta. Echography of the abdominal aorta revealed thickening of the wall and a hypoechoic region around the aorta. Gadolinium-enhanced magnetic resonance imaging and 18F-fludeoxyglucose positron emission tomography also revealed that the inflammation was localized to the lesion. A suspicion of G-CSF-associated aortitis was based on the patient's history and the exclusion of other diseases that might have caused the aortitis. Her condition rapidly improved after starting corticosteroid treatment.
The differential diagnosis in similar cases should consider immune diseases that cause large-vessel arteritis (Takayasu arteritis, giant cell arteritis, and another vasculitis), infection, drug-induced disease, and immunoglobulin G4-related disease. The use of different imaging modalities, including vascular echography, helped guide the diagnosis and follow-up. It is necessary to evaluate the patient's general condition before the selection of treatments.
Learning points
In patients with persistent fever and a history of granulocyte colony stimulating factor administration, aortitis should be considered in the differential diagnosis.
The arteritis localization and activity should be evaluated using multiple modalities (e.g. vascular echography, computed tomography, and magnetic resonance imaging) including neck to the pelvis to guide treatment.
The treatment including the necessity of corticosteroid therapy should be selected based on the general condition of the patients, considering that the patients are treated for cancer.
Introduction
Granulocyte colony-stimulating factor (G-CSF) preparations are used for chemotherapy-related granulocytopenia, especially to prevent febrile neutropenia. The G-CSF preparations bind to G-CSF receptors that are present on neutrophil progenitor cells in the bone marrow, which promote their differentiation into neutrophils. The clinical regimens include filgrastim, lenograstim, nartograstim, filgrastim biosimilars, and long-lasting pegylated preparations of filgrastim.1 The first report regarding G-CSF-associated aortitis was in 2004,2 and arteritis has been reported as a side effect of G-CSF treatment. However, there are no clear diagnostic criteria or treatment guidelines. Therefore, we report a case of G-CSF-associated aortitis that required careful exclusion of similar aortitis and multiple imaging modalities to support the diagnosis.
Timeline
One month before onset The 5th course of chemotherapy [paclitaxel 262 mg (180 mg/m2)/carboplatin 583 mg (target area under the concentration-time curve 6 mg min/mL)] was administered.
Two weeks before onset Myelosuppression was detected, and the granulocyte colony stimulating factor (G-CSF) was administered for the first time and continued for 3 days.
Ten days before onset The 6th course of chemotherapy was administered.
Three days before onset Myelosuppression was detected, and the G-CSF treatment was started and continued for 4 days.
Day 0 (onset) Last administration of G-CSF. The patient developed a high fever during the night.
Day 1 The patient visited an outpatient clinic and was prescribed acetaminophen and levofloxacin.
Day 4 The patient was admitted to the gynaecology department for a persistent high fever. Although the thickening around the aorta was suspected via computed tomography (CT), it was uncertain whether the inflammation was localized there, and the patient first received cefmetazole for suspected infection or febrile neutropenia.
Day 9 The antibiotic treatment was changed to piperacillin/tazobactam.
Day 16 The fever and inflammation did not improve completely. Aortitis was re-considered as a differential diagnosis of fever. An magnetic resonance imaging was performed to evaluate the aortitis.
Day 17 The patient was transferred to the cardiology department for treatment of the aortitis. Bone marrow testing was performed.
Day 23 Positron emission tomography revealed active inflammation of the aortic arch and abdominal aorta. Prednisolone (PSL) was started (50 mg/day, 1 mg/kg).
Day 24 The fever improved, and the temperature was maintained at <37.5°C.
Day 38 A CT examination revealed that the thickening around the aorta had improved. C-reactive protein concentration returned to normal.
Day 46 The PSL dose was gradually reduced.
Day 71 The patient was discharged (PSL 25 mg/day).
After 9 months The PSL dose was gradually reduced to 10 mg/day for 9 months.
After 1 year No episode of infection, and no recurrence of aortitis and cancer. The patient is almost free from the PSL.
Case presentation
A 52-year-old woman underwent six courses of post-operative chemotherapy (paclitaxel 262 mg/carboplatin 583 mg) for ovarian cancer. Myelosuppression was detected after the 5th and 6th chemotherapy courses, which prompted G-CSF treatment (filgrastim, 75 μg/day). The patient developed a high fever after the last G-CSF administration and was admitted 4 days later in the gynaecology department. Negative bacterial, fungal, and viral test results were observed, and a broad-spectrum antibiotic treatment did not completely improve her condition. Aortitis was suspected based on enhanced computed tomography (CT) findings, and she was referred to our cardiology department.
Her peripheral arterial oxygen saturation was 96% (room air), body temperature was 38.0˚C with remittent fever, blood pressure was 92/50 mmHg, and bilateral pulse was 70 beats/min. The head and neck had no bruit or tenderness, and the patient reported no visual deterioration or diplopia. Chest auscultation was clear, and cardiac auscultation revealed normal S1 and S2 with no S3 or murmurs. There were no abdominal abnormalities or notable skin lesions and swelling on the extremities. Her medical history included pulmonary embolism and deep vein thrombosis that had been controlled using anticoagulant medication.
Table 1 shows the patient’s laboratory findings on admission, which included an elevated C-reactive protein concentration (CRP). Although the white blood cell count (WBC) slightly elevated on admission, it gradually decreased to 1400/μL (normal range 3300–8600). Decreasing of the platelet counts and normocytic anaemia were also observed. Bone marrow tests showed that the three lineages of haematopoietic cells were retained, and there was no increase in blasts or morphological abnormalities.
Table 1 Laboratory findings on admission (Day 4)
WBC 8780/μL (3300–8600) MMP-3 103.8 ng/mL (17.3–59.7)
Neut 76.0% (41.8–75.0) ESR 1.0hr >140 mm/h (3.0–15.0)
Lymph 15.7% (18.5–48.7) sIL-2R 584 U/mL (140–394)
Mono 8.1% (2.2–7.9) Ferritin 883 ng/mL (10.0–120.0)
Eo 0.1% (0.4–8.7) STS Negative
RBC 2.14 × 104/μL (3.86–4.92) TPAb Negative
Hb 7.2 g/dL (11.6–14.8) TbIFN-γ Negative
HCT 22.2% (35.1–44.4) β-D glucan <2.50 pg/mL (−10.99)
Plt 7.0 × 104/μL (15.8–34.8) PCT 0.15 ng/mL (0.00–0.49)
MCV 103.7 fL (83.6–98.2) MPO-ANCA <1.0 U/mL (−3.4)
MCH 33.6 pg (27.5–33.2) PR3-ANCA <1.0 U/mL (−3.4)
MCHC 32.4% (31.7–35.3) IgA 240 mg/dL (93–393)
TP 7.0 g/dL (6.6–8.1) IgM 74 mg/dL (50–269)
Alb 3.5 g/dL (4.1–5.1) IgG 1468 mg/dL (861–1747)
UN 12.6 mg/dL (8.0–20.0) IgG4 21 mg/dL (−134)
Cr 0.80 mg/dL (0.46–0.79) C3 164 mg/dL (73–138)
eGFR 59 mL/min/1.73 m2 C4 31.8 mg/dL (11.0–31.0)
LDH 170 U/L (124–222) CH50 77.1 U/mL (30.0–53.0)
Na 140 mEq/L (138–145) RF 3 U/mL (0–14)
K 3.8 mEq/L (3.6–4.8) FANA Negative
Cl 107 mEq/L (101–108) APTT 29.9 sec (23.0–38.0)
CRP 19.39 mg/dL (0.00–0.14) PT-INR 1.15 (0.85–1.15)
Anti SS-A/Ro antibody, anti SS-B/La antibodies, anti Sm antibodies, anti-double strand-DNA antibodies, anti-RNP antibodies were all negative. ESR is the data of Day 24. Normal ranges are shown in brackets.
Alb, albumin; APTT, activated partial thromboplastin time; C3, complement component 3; C4, complement component 4; CH50, 50% haemolytic complement activity; Cl, chlorine; Cr, creatinine; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; Eo, eosinophil; ESR, erythrocyte sedimentation rate; FANA, fluorescent anti-nuclear antibodies; Hb, haemoglobin; HCT, haematocrit; Ig, immunoglobulin; K, potassium; Lymph, lymphocyte; MCH, mean corpuscular haemoglobin; MCHC, mean corpuscular haemoglobin concentration; MCV, mean corpuscular volume; MMP-3, matrix metalloproteinase-3; Mono, monocyte; MPO-ANCA, myeloperoxidase-anti-neutrophil cytoplasmic antibody; Na, sodium; Neut, neutrophil; PCT, procalcitonin; Plt, platelet; PR3-ANCA, serine proteinase3-anti-neutrophil cytoplasmic antibody; PT-INR, international normalized ratio of prothrombin time; RBC, red blood cell; RF, rheumatoid factor; sIL-2, soluble interleukin-2 receptor; STS, serologic test for syphilis; Tb-INF, tuberculosis interferon-gamma; TP, total protein; TPAb, treponema pallidum antibodies; UN, urea nitrogen; WBC, white blood cell.
Table 2 Previously reported cases
No Age Sex Year Nationality Background disease G-CSF Symptoms Lesions Glucocorticoid treatment
12 55 F 2004 France Stem cell donor Filgrastim Fever, abdominal and lumbar pain, vomiting Descending ao, abdominal ao yes
2 54 M 2009 US Lung cancer
a
Fever, epigastric tenderness Abdominal ao no
33 52 M 2016 Israel Healthy donor Filgrastim Weight loss, back pain, constipation Abdominal ao, iliac artery yes
4 78 F 2016 Japan Cyclic neutropenia Filgrastim Fever, head ache, jaw claudication, visual abnormality Temporal arteries yes
5 59 F 2017 Japan Lymphoma Pegfilgrastim Neck and chest pain, fever Carotid artery, subclavian artery, ao arch, descending ao yes
6 61 F 2017 Japan Ovarian cancer Lenograstim Fever Carotid artery no
74 67 F 2017 Japan Lung cancer Pegfilgrastim Malaise and fever Carotid artery, thoracic ao yes
8 61 F 2018 Japan Breast cancer Pegfilgrastim Neck and chest pain → fever Carotid artery, thoracic ao no
9 47 F 2018 Japan Ovarian cancer
a
Fever ao arch, descending ao yes
10 71 F 2019 Japan Endometrial cancer Pegfilgrastim Fever ao arch, descending ao yes
11 72 F 2019 Japan Lymphoma Pegfilgrastim Fever, chest pain ao arch no
12 62 F 2019 Japan Lymphoma Pegfilgrastim Fever, chest pain Descending ao yes
13 69 M 2019 Japan Lymphoma Pegfilgrastim Fever Subclavian artery unknown
14 77 F 2019 Japan Ovarian cancer
a
Fever Carotid artery, subclavian artery no
155 60 F 2019 Sweden Breast cancer Filgrastim Abdominal tenderness → fever Subclavian artery, ao arch, descending ao, abdominal ao yes
165 70 F 2019 Sweden Breast cancer
a
Syncope, diarrhoea, dehydration → fever Thoracic ao, brachiocephalic trunk yes
17 72 F 2019 Japan Breast cancer Pegfilgrastim Fever Descending ao no
186 43 F 2020 Japan Uterine cancer Pegfilgrastim Unknown Thoracic ao no
196 47 F 2020 Japan Uterine cancer Pegfilgrastim Unknown Thoracic ao no
206 74 F 2020 Japan Tongue cancer Pegfilgrastim Unknown Thoracic ao no
216 65 F 2020 Japan Pancreatic cancer Pegfilgrastim Fever, chest pain ao arch, abdominal ao no
227 66 F 2020 Japan Breast cancer Pegfilgrastim Fever, malaise, abdominal discomfort ao arch, abdominal ao yes
238 52 F 2020 Finland Breast cancer Filgrastim Fever, chest pain Aorta yes
248 62 F 2020 Finland Breast cancer Filgrastim, Pegfilgrastim Fever Aorta yes
258 70 F 2020 Finland Breast cancer Lipegfilgrastim Fever Aorta, supra-aortic vessels no
268 56 F 2020 Finland Breast cancer Lipegfilgrastim Fever, neck pain, jaw pain, malaise Carotid artery, thoracic ao yes
278 53 F 2020 Finland Breast cancer Pegfilgrastim Fever, sore throat, ear ache, dyspnoea, and chest pain Aorta yes
298 40 F 2020 Finland Breast cancer Lipegfilgrastim Fever, sore throat, chest and neck pain, malaise Carotid artery yes
ao, aorta or aortic; F, female; M, male.
The figures in square brackets refer to page numbers.
a Name of the G-CSF preparations were unknown, however these were used for several days.
Electrocardiography, echocardiography, and chest radiography revealed no abnormalities that could explain the fever. Echography of the abdominal aorta revealed aortic wall thickening and a hypoechoic region around the aorta (Figure 1). Furthermore, CT revealed an increase in the soft tissue surrounding the aortic arch and abdominal aorta (Figure 2A,B). Gadolinium-enhanced magnetic resonance imaging revealed thickening of the aortic wall and enhancement of the wall and perivascular tissue (Figure 3A), and uptake was observed during 18F-fludeoxyglucose positron emission tomography (Figure 3B). These imaging findings suggested active inflammation at the lesions.
Figure 1 Imaging findings via echography of the abdominal aorta. Echography of the abdominal aorta at the level of the coeliac artery bifurcation (left: long-axis image, right: short-axis image) revealed increased brightness and thickening of the vessel wall. There was a hypoechoic region surrounding the outside of the artery (arrow), and increased blood flow was not observed. Echography helped to distinguish some lesion features (e.g. for an abscess, a tumour, and an atheroma).
Figure 2 Imaging findings via enhanced computed tomography. (A) Enhanced computed tomography (CT) findings before chemotherapy. (B) The computed tomography findings after onset (chest: early phase, abdomen: plain, early, and delay phase), which revealed enhancement of the peri-aortic tissue from the aortic arch and the abdominal aorta (vs. the pre-chemotherapy findings). There was no wall thickening in the branches of the aorta, aortic stenosis, aneurism, or dissection. (C) Enhanced computed tomography after the treatment for aortitis. The thickening around the aorta had improved after 2 weeks.
Figure 3 Imaging findings via gadolinium-enhanced magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. (A) Gadolinium-enhanced T1-weighted image revealed thickening of the vessel wall at the aortic arch and the abdominal aorta at the diaphragm (arrow). (B) Fluorodeoxyglucose positron emission tomography (18F-FDG PET) revealed FDG uptake in the aortic arch and the abdominal aorta, with a standardized uptake value (SUV) of 2–3 like that in the liver (arrow).
The patient was transferred to the cardiology department, and G-CSF-associated aortitis was suggested based on her history and clinical course (Naranjo adverse drug reaction probability scale score 7; probable). On Day 23, she was exhausted because of the persistent fever and received prednisolone treatment (PSL, 50 mg/day), which promptly resolved her symptoms. Follow-up testing revealed improvement in her CRP concentration and erythrocyte sedimentation rate (Supplementary material online, Figure S1). After 2 weeks, CT revealed an improvement in the thickening around the aorta (Figure 2C). The PSL dose was gradually reduced. This treatment was marked by the absence of recurrence of the aortitis, cancer, and infection at her 1-year follow-up.
Discussion
This case involved a patient who presented with a significant fever. Aortitis was suspected via multiple imaging modalities, and the association with G-CSF treatment was suggested based on the patient’s history and exclusion of other diseases.
Clinical course in previous cases
A PubMed search revealed 28 reported cases involving arteritis associated with G-CSF treatment (Table 2). Most cases involved fever at the onset of disease, although other symptoms (e.g. abdominal tenderness, syncope) appeared before the fever in some cases.5 In this case, PSL was started because of a high fever and malaise; however, one-half of the reported cases resolved without corticosteroids.6 In the previous cases that involved corticosteroid treatment, three cases were administered high-dose treatments (e.g. pulse methylprednisolone),4,7 and six cases involved PSL doses starting at 30–60 mg/day with gradual tapering.3,5 Early reduction of the corticosteroid may be possible because G-CSF-associated arteritis may have a relatively good prognosis compared to other arteritis.7 Nevertheless, a case that involved aortic dissection highlighted the need for careful observation.4 Some cases with G-CSF re-administration had aortitis recurrence,6 and dose reduction or change of the anti-cancer drug were needed to avoid myelosuppression.
Differential diagnosis of aortitis
Takayasu arteritis and giant cell arteritis (GCA) are immune disorders that cause large-vessel arteritis. Takayasu arteritis onset is most common among women in their 20s, and the lesions are often continuous in the aorta and its primary branches. More than 90% of patients have lesions in the aortic arch, and 40% in the abdominal aorta.9 Onset of GCA is most common among women in their 60s to 70s, and lesions are typically detected in the branches of the carotid and vertebral arteries, and other large arteries may have lesions.10 Perivascular inflammation caused by IgG4-related diseases is found in the abdominal and iliac arteries, although lesions can be present in the thoracic aorta. These lesions tend to be detected in men in their sixties.11 Other differential diagnoses include infection (bacterial, syphilis, human immunodeficiency virus, and tuberculosis), drug-induced disease,12 malignancy,13 Behçet disease, Cogan syndrome, systemic lupus erythematosus, and anti-neutrophil cytoplasmic antibody-related vasculitis (Supplementary material online, Figure S2).14 The differential diagnosis needs to be performed based on the characteristics of the diseases in addition to the imaging evaluation.
Lesions and imaging
Previous reports of G-CSF-associated arteritis indicated that most lesions were detected in the thoracic aorta (68%), especially in the arch (29%) and descending aorta (29%). However, lesions can be detected in the abdominal aorta (21%), carotid artery (25%), and subclavian artery (14%) (Table 2). Most cases involved circumferential thickening of the peri-arterial tissue, which was detected via CT. Echography was useful in guiding the diagnosis in this case, although none of the previously English reported cases involved an abdominal aorta echography. Nevertheless, an echography was used to evaluate some lesions in the temporal and carotid arteries.8
Mechanism of aortitis
The pathological mechanisms underlying G-CSF-associated arteritis are unclear. Previous reports have speculated that arteritis is related to cytokines and complex immune reactions between anti-cancer agents and G-CSF.8 In aortitis after acute aortic dissection, G-CSF may act on the arterial adventitia and invading granulocytes, which results in inflammation.15 Nevertheless, this mechanism for G-CSF-associated arteritis remains speculative.
Conclusions
Chronic inflammation can lead to a reduced nutritional status and quality of life in cancer patients, which may influence their general condition and make them unable to continue chemotherapy. When cancer patients experience persistent fever after G-CSF treatment, it is necessary to make a differential diagnosis carefully and select treatments based on the patient’s general condition as well as the prognosis of arteries.
Patient perspective
The patient was mentally exhausted before treatment. Psychiatric support also improved her mental status, despite the high dose of PSL used.
Lead author biography
Graduated from Jichi Medical University School of Medicine, Japan and worked as a general physician. In 2016, conducted clinical studies on cardiovascular risk factors among young people at Shinshu University Graduate School of Medicine. Currently working in general cardiology and preventive medicine.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
ytaa503_Supplementary_Data Click here for additional data file.
Acknowledgements
The authors thank Prof. Yasunari Fujinaga and Dr Fumihito Ichinohe, Department of Radiology, Shinshu University School of Medicine, for guidance with the imaging. The authors thank the clinical team members of Department of Cardiovascular Medicine, Shinshu University School of Medicine; Dr Shusaku Maruyama, Dr Masafumi Kanai, and Ms. Junko Iguchi.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared. | CARBOPLATIN, FILGRASTIM, PACLITAXEL | DrugsGivenReaction | CC BY-NC | 33598604 | 20,059,561 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myelosuppression'. | Granulocyte colony stimulating factor-associated aortitis evaluated via multiple imaging modalities including vascular echography: a case report.
Granulocyte colony stimulating factor (G-CSF) preparations are used for patients with granulocytopenia, especially to prevent febrile neutropenia. Arteritis has been recognized as a side effect of G-CSF treatment; however, there are no clear diagnostic criteria or treatment guidelines because not enough cases have been reported. Present case showed one of the diagnostic and treatment selection methods via multiple imaging modality including vascular echography.
A 52-year-old woman underwent chemotherapy for ovarian cancer and received G-CSF because of myelosuppression. The patient experienced high and remittent fever that persisted during treatment using antibiotics and acetaminophen. Enhanced computed tomography revealed thickening of the tissue around the aortic arch and abdominal aorta. Echography of the abdominal aorta revealed thickening of the wall and a hypoechoic region around the aorta. Gadolinium-enhanced magnetic resonance imaging and 18F-fludeoxyglucose positron emission tomography also revealed that the inflammation was localized to the lesion. A suspicion of G-CSF-associated aortitis was based on the patient's history and the exclusion of other diseases that might have caused the aortitis. Her condition rapidly improved after starting corticosteroid treatment.
The differential diagnosis in similar cases should consider immune diseases that cause large-vessel arteritis (Takayasu arteritis, giant cell arteritis, and another vasculitis), infection, drug-induced disease, and immunoglobulin G4-related disease. The use of different imaging modalities, including vascular echography, helped guide the diagnosis and follow-up. It is necessary to evaluate the patient's general condition before the selection of treatments.
Learning points
In patients with persistent fever and a history of granulocyte colony stimulating factor administration, aortitis should be considered in the differential diagnosis.
The arteritis localization and activity should be evaluated using multiple modalities (e.g. vascular echography, computed tomography, and magnetic resonance imaging) including neck to the pelvis to guide treatment.
The treatment including the necessity of corticosteroid therapy should be selected based on the general condition of the patients, considering that the patients are treated for cancer.
Introduction
Granulocyte colony-stimulating factor (G-CSF) preparations are used for chemotherapy-related granulocytopenia, especially to prevent febrile neutropenia. The G-CSF preparations bind to G-CSF receptors that are present on neutrophil progenitor cells in the bone marrow, which promote their differentiation into neutrophils. The clinical regimens include filgrastim, lenograstim, nartograstim, filgrastim biosimilars, and long-lasting pegylated preparations of filgrastim.1 The first report regarding G-CSF-associated aortitis was in 2004,2 and arteritis has been reported as a side effect of G-CSF treatment. However, there are no clear diagnostic criteria or treatment guidelines. Therefore, we report a case of G-CSF-associated aortitis that required careful exclusion of similar aortitis and multiple imaging modalities to support the diagnosis.
Timeline
One month before onset The 5th course of chemotherapy [paclitaxel 262 mg (180 mg/m2)/carboplatin 583 mg (target area under the concentration-time curve 6 mg min/mL)] was administered.
Two weeks before onset Myelosuppression was detected, and the granulocyte colony stimulating factor (G-CSF) was administered for the first time and continued for 3 days.
Ten days before onset The 6th course of chemotherapy was administered.
Three days before onset Myelosuppression was detected, and the G-CSF treatment was started and continued for 4 days.
Day 0 (onset) Last administration of G-CSF. The patient developed a high fever during the night.
Day 1 The patient visited an outpatient clinic and was prescribed acetaminophen and levofloxacin.
Day 4 The patient was admitted to the gynaecology department for a persistent high fever. Although the thickening around the aorta was suspected via computed tomography (CT), it was uncertain whether the inflammation was localized there, and the patient first received cefmetazole for suspected infection or febrile neutropenia.
Day 9 The antibiotic treatment was changed to piperacillin/tazobactam.
Day 16 The fever and inflammation did not improve completely. Aortitis was re-considered as a differential diagnosis of fever. An magnetic resonance imaging was performed to evaluate the aortitis.
Day 17 The patient was transferred to the cardiology department for treatment of the aortitis. Bone marrow testing was performed.
Day 23 Positron emission tomography revealed active inflammation of the aortic arch and abdominal aorta. Prednisolone (PSL) was started (50 mg/day, 1 mg/kg).
Day 24 The fever improved, and the temperature was maintained at <37.5°C.
Day 38 A CT examination revealed that the thickening around the aorta had improved. C-reactive protein concentration returned to normal.
Day 46 The PSL dose was gradually reduced.
Day 71 The patient was discharged (PSL 25 mg/day).
After 9 months The PSL dose was gradually reduced to 10 mg/day for 9 months.
After 1 year No episode of infection, and no recurrence of aortitis and cancer. The patient is almost free from the PSL.
Case presentation
A 52-year-old woman underwent six courses of post-operative chemotherapy (paclitaxel 262 mg/carboplatin 583 mg) for ovarian cancer. Myelosuppression was detected after the 5th and 6th chemotherapy courses, which prompted G-CSF treatment (filgrastim, 75 μg/day). The patient developed a high fever after the last G-CSF administration and was admitted 4 days later in the gynaecology department. Negative bacterial, fungal, and viral test results were observed, and a broad-spectrum antibiotic treatment did not completely improve her condition. Aortitis was suspected based on enhanced computed tomography (CT) findings, and she was referred to our cardiology department.
Her peripheral arterial oxygen saturation was 96% (room air), body temperature was 38.0˚C with remittent fever, blood pressure was 92/50 mmHg, and bilateral pulse was 70 beats/min. The head and neck had no bruit or tenderness, and the patient reported no visual deterioration or diplopia. Chest auscultation was clear, and cardiac auscultation revealed normal S1 and S2 with no S3 or murmurs. There were no abdominal abnormalities or notable skin lesions and swelling on the extremities. Her medical history included pulmonary embolism and deep vein thrombosis that had been controlled using anticoagulant medication.
Table 1 shows the patient’s laboratory findings on admission, which included an elevated C-reactive protein concentration (CRP). Although the white blood cell count (WBC) slightly elevated on admission, it gradually decreased to 1400/μL (normal range 3300–8600). Decreasing of the platelet counts and normocytic anaemia were also observed. Bone marrow tests showed that the three lineages of haematopoietic cells were retained, and there was no increase in blasts or morphological abnormalities.
Table 1 Laboratory findings on admission (Day 4)
WBC 8780/μL (3300–8600) MMP-3 103.8 ng/mL (17.3–59.7)
Neut 76.0% (41.8–75.0) ESR 1.0hr >140 mm/h (3.0–15.0)
Lymph 15.7% (18.5–48.7) sIL-2R 584 U/mL (140–394)
Mono 8.1% (2.2–7.9) Ferritin 883 ng/mL (10.0–120.0)
Eo 0.1% (0.4–8.7) STS Negative
RBC 2.14 × 104/μL (3.86–4.92) TPAb Negative
Hb 7.2 g/dL (11.6–14.8) TbIFN-γ Negative
HCT 22.2% (35.1–44.4) β-D glucan <2.50 pg/mL (−10.99)
Plt 7.0 × 104/μL (15.8–34.8) PCT 0.15 ng/mL (0.00–0.49)
MCV 103.7 fL (83.6–98.2) MPO-ANCA <1.0 U/mL (−3.4)
MCH 33.6 pg (27.5–33.2) PR3-ANCA <1.0 U/mL (−3.4)
MCHC 32.4% (31.7–35.3) IgA 240 mg/dL (93–393)
TP 7.0 g/dL (6.6–8.1) IgM 74 mg/dL (50–269)
Alb 3.5 g/dL (4.1–5.1) IgG 1468 mg/dL (861–1747)
UN 12.6 mg/dL (8.0–20.0) IgG4 21 mg/dL (−134)
Cr 0.80 mg/dL (0.46–0.79) C3 164 mg/dL (73–138)
eGFR 59 mL/min/1.73 m2 C4 31.8 mg/dL (11.0–31.0)
LDH 170 U/L (124–222) CH50 77.1 U/mL (30.0–53.0)
Na 140 mEq/L (138–145) RF 3 U/mL (0–14)
K 3.8 mEq/L (3.6–4.8) FANA Negative
Cl 107 mEq/L (101–108) APTT 29.9 sec (23.0–38.0)
CRP 19.39 mg/dL (0.00–0.14) PT-INR 1.15 (0.85–1.15)
Anti SS-A/Ro antibody, anti SS-B/La antibodies, anti Sm antibodies, anti-double strand-DNA antibodies, anti-RNP antibodies were all negative. ESR is the data of Day 24. Normal ranges are shown in brackets.
Alb, albumin; APTT, activated partial thromboplastin time; C3, complement component 3; C4, complement component 4; CH50, 50% haemolytic complement activity; Cl, chlorine; Cr, creatinine; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; Eo, eosinophil; ESR, erythrocyte sedimentation rate; FANA, fluorescent anti-nuclear antibodies; Hb, haemoglobin; HCT, haematocrit; Ig, immunoglobulin; K, potassium; Lymph, lymphocyte; MCH, mean corpuscular haemoglobin; MCHC, mean corpuscular haemoglobin concentration; MCV, mean corpuscular volume; MMP-3, matrix metalloproteinase-3; Mono, monocyte; MPO-ANCA, myeloperoxidase-anti-neutrophil cytoplasmic antibody; Na, sodium; Neut, neutrophil; PCT, procalcitonin; Plt, platelet; PR3-ANCA, serine proteinase3-anti-neutrophil cytoplasmic antibody; PT-INR, international normalized ratio of prothrombin time; RBC, red blood cell; RF, rheumatoid factor; sIL-2, soluble interleukin-2 receptor; STS, serologic test for syphilis; Tb-INF, tuberculosis interferon-gamma; TP, total protein; TPAb, treponema pallidum antibodies; UN, urea nitrogen; WBC, white blood cell.
Table 2 Previously reported cases
No Age Sex Year Nationality Background disease G-CSF Symptoms Lesions Glucocorticoid treatment
12 55 F 2004 France Stem cell donor Filgrastim Fever, abdominal and lumbar pain, vomiting Descending ao, abdominal ao yes
2 54 M 2009 US Lung cancer
a
Fever, epigastric tenderness Abdominal ao no
33 52 M 2016 Israel Healthy donor Filgrastim Weight loss, back pain, constipation Abdominal ao, iliac artery yes
4 78 F 2016 Japan Cyclic neutropenia Filgrastim Fever, head ache, jaw claudication, visual abnormality Temporal arteries yes
5 59 F 2017 Japan Lymphoma Pegfilgrastim Neck and chest pain, fever Carotid artery, subclavian artery, ao arch, descending ao yes
6 61 F 2017 Japan Ovarian cancer Lenograstim Fever Carotid artery no
74 67 F 2017 Japan Lung cancer Pegfilgrastim Malaise and fever Carotid artery, thoracic ao yes
8 61 F 2018 Japan Breast cancer Pegfilgrastim Neck and chest pain → fever Carotid artery, thoracic ao no
9 47 F 2018 Japan Ovarian cancer
a
Fever ao arch, descending ao yes
10 71 F 2019 Japan Endometrial cancer Pegfilgrastim Fever ao arch, descending ao yes
11 72 F 2019 Japan Lymphoma Pegfilgrastim Fever, chest pain ao arch no
12 62 F 2019 Japan Lymphoma Pegfilgrastim Fever, chest pain Descending ao yes
13 69 M 2019 Japan Lymphoma Pegfilgrastim Fever Subclavian artery unknown
14 77 F 2019 Japan Ovarian cancer
a
Fever Carotid artery, subclavian artery no
155 60 F 2019 Sweden Breast cancer Filgrastim Abdominal tenderness → fever Subclavian artery, ao arch, descending ao, abdominal ao yes
165 70 F 2019 Sweden Breast cancer
a
Syncope, diarrhoea, dehydration → fever Thoracic ao, brachiocephalic trunk yes
17 72 F 2019 Japan Breast cancer Pegfilgrastim Fever Descending ao no
186 43 F 2020 Japan Uterine cancer Pegfilgrastim Unknown Thoracic ao no
196 47 F 2020 Japan Uterine cancer Pegfilgrastim Unknown Thoracic ao no
206 74 F 2020 Japan Tongue cancer Pegfilgrastim Unknown Thoracic ao no
216 65 F 2020 Japan Pancreatic cancer Pegfilgrastim Fever, chest pain ao arch, abdominal ao no
227 66 F 2020 Japan Breast cancer Pegfilgrastim Fever, malaise, abdominal discomfort ao arch, abdominal ao yes
238 52 F 2020 Finland Breast cancer Filgrastim Fever, chest pain Aorta yes
248 62 F 2020 Finland Breast cancer Filgrastim, Pegfilgrastim Fever Aorta yes
258 70 F 2020 Finland Breast cancer Lipegfilgrastim Fever Aorta, supra-aortic vessels no
268 56 F 2020 Finland Breast cancer Lipegfilgrastim Fever, neck pain, jaw pain, malaise Carotid artery, thoracic ao yes
278 53 F 2020 Finland Breast cancer Pegfilgrastim Fever, sore throat, ear ache, dyspnoea, and chest pain Aorta yes
298 40 F 2020 Finland Breast cancer Lipegfilgrastim Fever, sore throat, chest and neck pain, malaise Carotid artery yes
ao, aorta or aortic; F, female; M, male.
The figures in square brackets refer to page numbers.
a Name of the G-CSF preparations were unknown, however these were used for several days.
Electrocardiography, echocardiography, and chest radiography revealed no abnormalities that could explain the fever. Echography of the abdominal aorta revealed aortic wall thickening and a hypoechoic region around the aorta (Figure 1). Furthermore, CT revealed an increase in the soft tissue surrounding the aortic arch and abdominal aorta (Figure 2A,B). Gadolinium-enhanced magnetic resonance imaging revealed thickening of the aortic wall and enhancement of the wall and perivascular tissue (Figure 3A), and uptake was observed during 18F-fludeoxyglucose positron emission tomography (Figure 3B). These imaging findings suggested active inflammation at the lesions.
Figure 1 Imaging findings via echography of the abdominal aorta. Echography of the abdominal aorta at the level of the coeliac artery bifurcation (left: long-axis image, right: short-axis image) revealed increased brightness and thickening of the vessel wall. There was a hypoechoic region surrounding the outside of the artery (arrow), and increased blood flow was not observed. Echography helped to distinguish some lesion features (e.g. for an abscess, a tumour, and an atheroma).
Figure 2 Imaging findings via enhanced computed tomography. (A) Enhanced computed tomography (CT) findings before chemotherapy. (B) The computed tomography findings after onset (chest: early phase, abdomen: plain, early, and delay phase), which revealed enhancement of the peri-aortic tissue from the aortic arch and the abdominal aorta (vs. the pre-chemotherapy findings). There was no wall thickening in the branches of the aorta, aortic stenosis, aneurism, or dissection. (C) Enhanced computed tomography after the treatment for aortitis. The thickening around the aorta had improved after 2 weeks.
Figure 3 Imaging findings via gadolinium-enhanced magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. (A) Gadolinium-enhanced T1-weighted image revealed thickening of the vessel wall at the aortic arch and the abdominal aorta at the diaphragm (arrow). (B) Fluorodeoxyglucose positron emission tomography (18F-FDG PET) revealed FDG uptake in the aortic arch and the abdominal aorta, with a standardized uptake value (SUV) of 2–3 like that in the liver (arrow).
The patient was transferred to the cardiology department, and G-CSF-associated aortitis was suggested based on her history and clinical course (Naranjo adverse drug reaction probability scale score 7; probable). On Day 23, she was exhausted because of the persistent fever and received prednisolone treatment (PSL, 50 mg/day), which promptly resolved her symptoms. Follow-up testing revealed improvement in her CRP concentration and erythrocyte sedimentation rate (Supplementary material online, Figure S1). After 2 weeks, CT revealed an improvement in the thickening around the aorta (Figure 2C). The PSL dose was gradually reduced. This treatment was marked by the absence of recurrence of the aortitis, cancer, and infection at her 1-year follow-up.
Discussion
This case involved a patient who presented with a significant fever. Aortitis was suspected via multiple imaging modalities, and the association with G-CSF treatment was suggested based on the patient’s history and exclusion of other diseases.
Clinical course in previous cases
A PubMed search revealed 28 reported cases involving arteritis associated with G-CSF treatment (Table 2). Most cases involved fever at the onset of disease, although other symptoms (e.g. abdominal tenderness, syncope) appeared before the fever in some cases.5 In this case, PSL was started because of a high fever and malaise; however, one-half of the reported cases resolved without corticosteroids.6 In the previous cases that involved corticosteroid treatment, three cases were administered high-dose treatments (e.g. pulse methylprednisolone),4,7 and six cases involved PSL doses starting at 30–60 mg/day with gradual tapering.3,5 Early reduction of the corticosteroid may be possible because G-CSF-associated arteritis may have a relatively good prognosis compared to other arteritis.7 Nevertheless, a case that involved aortic dissection highlighted the need for careful observation.4 Some cases with G-CSF re-administration had aortitis recurrence,6 and dose reduction or change of the anti-cancer drug were needed to avoid myelosuppression.
Differential diagnosis of aortitis
Takayasu arteritis and giant cell arteritis (GCA) are immune disorders that cause large-vessel arteritis. Takayasu arteritis onset is most common among women in their 20s, and the lesions are often continuous in the aorta and its primary branches. More than 90% of patients have lesions in the aortic arch, and 40% in the abdominal aorta.9 Onset of GCA is most common among women in their 60s to 70s, and lesions are typically detected in the branches of the carotid and vertebral arteries, and other large arteries may have lesions.10 Perivascular inflammation caused by IgG4-related diseases is found in the abdominal and iliac arteries, although lesions can be present in the thoracic aorta. These lesions tend to be detected in men in their sixties.11 Other differential diagnoses include infection (bacterial, syphilis, human immunodeficiency virus, and tuberculosis), drug-induced disease,12 malignancy,13 Behçet disease, Cogan syndrome, systemic lupus erythematosus, and anti-neutrophil cytoplasmic antibody-related vasculitis (Supplementary material online, Figure S2).14 The differential diagnosis needs to be performed based on the characteristics of the diseases in addition to the imaging evaluation.
Lesions and imaging
Previous reports of G-CSF-associated arteritis indicated that most lesions were detected in the thoracic aorta (68%), especially in the arch (29%) and descending aorta (29%). However, lesions can be detected in the abdominal aorta (21%), carotid artery (25%), and subclavian artery (14%) (Table 2). Most cases involved circumferential thickening of the peri-arterial tissue, which was detected via CT. Echography was useful in guiding the diagnosis in this case, although none of the previously English reported cases involved an abdominal aorta echography. Nevertheless, an echography was used to evaluate some lesions in the temporal and carotid arteries.8
Mechanism of aortitis
The pathological mechanisms underlying G-CSF-associated arteritis are unclear. Previous reports have speculated that arteritis is related to cytokines and complex immune reactions between anti-cancer agents and G-CSF.8 In aortitis after acute aortic dissection, G-CSF may act on the arterial adventitia and invading granulocytes, which results in inflammation.15 Nevertheless, this mechanism for G-CSF-associated arteritis remains speculative.
Conclusions
Chronic inflammation can lead to a reduced nutritional status and quality of life in cancer patients, which may influence their general condition and make them unable to continue chemotherapy. When cancer patients experience persistent fever after G-CSF treatment, it is necessary to make a differential diagnosis carefully and select treatments based on the patient’s general condition as well as the prognosis of arteries.
Patient perspective
The patient was mentally exhausted before treatment. Psychiatric support also improved her mental status, despite the high dose of PSL used.
Lead author biography
Graduated from Jichi Medical University School of Medicine, Japan and worked as a general physician. In 2016, conducted clinical studies on cardiovascular risk factors among young people at Shinshu University Graduate School of Medicine. Currently working in general cardiology and preventive medicine.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
ytaa503_Supplementary_Data Click here for additional data file.
Acknowledgements
The authors thank Prof. Yasunari Fujinaga and Dr Fumihito Ichinohe, Department of Radiology, Shinshu University School of Medicine, for guidance with the imaging. The authors thank the clinical team members of Department of Cardiovascular Medicine, Shinshu University School of Medicine; Dr Shusaku Maruyama, Dr Masafumi Kanai, and Ms. Junko Iguchi.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared. | CARBOPLATIN, FILGRASTIM, PACLITAXEL | DrugsGivenReaction | CC BY-NC | 33598604 | 20,059,561 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Normocytic anaemia'. | Granulocyte colony stimulating factor-associated aortitis evaluated via multiple imaging modalities including vascular echography: a case report.
Granulocyte colony stimulating factor (G-CSF) preparations are used for patients with granulocytopenia, especially to prevent febrile neutropenia. Arteritis has been recognized as a side effect of G-CSF treatment; however, there are no clear diagnostic criteria or treatment guidelines because not enough cases have been reported. Present case showed one of the diagnostic and treatment selection methods via multiple imaging modality including vascular echography.
A 52-year-old woman underwent chemotherapy for ovarian cancer and received G-CSF because of myelosuppression. The patient experienced high and remittent fever that persisted during treatment using antibiotics and acetaminophen. Enhanced computed tomography revealed thickening of the tissue around the aortic arch and abdominal aorta. Echography of the abdominal aorta revealed thickening of the wall and a hypoechoic region around the aorta. Gadolinium-enhanced magnetic resonance imaging and 18F-fludeoxyglucose positron emission tomography also revealed that the inflammation was localized to the lesion. A suspicion of G-CSF-associated aortitis was based on the patient's history and the exclusion of other diseases that might have caused the aortitis. Her condition rapidly improved after starting corticosteroid treatment.
The differential diagnosis in similar cases should consider immune diseases that cause large-vessel arteritis (Takayasu arteritis, giant cell arteritis, and another vasculitis), infection, drug-induced disease, and immunoglobulin G4-related disease. The use of different imaging modalities, including vascular echography, helped guide the diagnosis and follow-up. It is necessary to evaluate the patient's general condition before the selection of treatments.
Learning points
In patients with persistent fever and a history of granulocyte colony stimulating factor administration, aortitis should be considered in the differential diagnosis.
The arteritis localization and activity should be evaluated using multiple modalities (e.g. vascular echography, computed tomography, and magnetic resonance imaging) including neck to the pelvis to guide treatment.
The treatment including the necessity of corticosteroid therapy should be selected based on the general condition of the patients, considering that the patients are treated for cancer.
Introduction
Granulocyte colony-stimulating factor (G-CSF) preparations are used for chemotherapy-related granulocytopenia, especially to prevent febrile neutropenia. The G-CSF preparations bind to G-CSF receptors that are present on neutrophil progenitor cells in the bone marrow, which promote their differentiation into neutrophils. The clinical regimens include filgrastim, lenograstim, nartograstim, filgrastim biosimilars, and long-lasting pegylated preparations of filgrastim.1 The first report regarding G-CSF-associated aortitis was in 2004,2 and arteritis has been reported as a side effect of G-CSF treatment. However, there are no clear diagnostic criteria or treatment guidelines. Therefore, we report a case of G-CSF-associated aortitis that required careful exclusion of similar aortitis and multiple imaging modalities to support the diagnosis.
Timeline
One month before onset The 5th course of chemotherapy [paclitaxel 262 mg (180 mg/m2)/carboplatin 583 mg (target area under the concentration-time curve 6 mg min/mL)] was administered.
Two weeks before onset Myelosuppression was detected, and the granulocyte colony stimulating factor (G-CSF) was administered for the first time and continued for 3 days.
Ten days before onset The 6th course of chemotherapy was administered.
Three days before onset Myelosuppression was detected, and the G-CSF treatment was started and continued for 4 days.
Day 0 (onset) Last administration of G-CSF. The patient developed a high fever during the night.
Day 1 The patient visited an outpatient clinic and was prescribed acetaminophen and levofloxacin.
Day 4 The patient was admitted to the gynaecology department for a persistent high fever. Although the thickening around the aorta was suspected via computed tomography (CT), it was uncertain whether the inflammation was localized there, and the patient first received cefmetazole for suspected infection or febrile neutropenia.
Day 9 The antibiotic treatment was changed to piperacillin/tazobactam.
Day 16 The fever and inflammation did not improve completely. Aortitis was re-considered as a differential diagnosis of fever. An magnetic resonance imaging was performed to evaluate the aortitis.
Day 17 The patient was transferred to the cardiology department for treatment of the aortitis. Bone marrow testing was performed.
Day 23 Positron emission tomography revealed active inflammation of the aortic arch and abdominal aorta. Prednisolone (PSL) was started (50 mg/day, 1 mg/kg).
Day 24 The fever improved, and the temperature was maintained at <37.5°C.
Day 38 A CT examination revealed that the thickening around the aorta had improved. C-reactive protein concentration returned to normal.
Day 46 The PSL dose was gradually reduced.
Day 71 The patient was discharged (PSL 25 mg/day).
After 9 months The PSL dose was gradually reduced to 10 mg/day for 9 months.
After 1 year No episode of infection, and no recurrence of aortitis and cancer. The patient is almost free from the PSL.
Case presentation
A 52-year-old woman underwent six courses of post-operative chemotherapy (paclitaxel 262 mg/carboplatin 583 mg) for ovarian cancer. Myelosuppression was detected after the 5th and 6th chemotherapy courses, which prompted G-CSF treatment (filgrastim, 75 μg/day). The patient developed a high fever after the last G-CSF administration and was admitted 4 days later in the gynaecology department. Negative bacterial, fungal, and viral test results were observed, and a broad-spectrum antibiotic treatment did not completely improve her condition. Aortitis was suspected based on enhanced computed tomography (CT) findings, and she was referred to our cardiology department.
Her peripheral arterial oxygen saturation was 96% (room air), body temperature was 38.0˚C with remittent fever, blood pressure was 92/50 mmHg, and bilateral pulse was 70 beats/min. The head and neck had no bruit or tenderness, and the patient reported no visual deterioration or diplopia. Chest auscultation was clear, and cardiac auscultation revealed normal S1 and S2 with no S3 or murmurs. There were no abdominal abnormalities or notable skin lesions and swelling on the extremities. Her medical history included pulmonary embolism and deep vein thrombosis that had been controlled using anticoagulant medication.
Table 1 shows the patient’s laboratory findings on admission, which included an elevated C-reactive protein concentration (CRP). Although the white blood cell count (WBC) slightly elevated on admission, it gradually decreased to 1400/μL (normal range 3300–8600). Decreasing of the platelet counts and normocytic anaemia were also observed. Bone marrow tests showed that the three lineages of haematopoietic cells were retained, and there was no increase in blasts or morphological abnormalities.
Table 1 Laboratory findings on admission (Day 4)
WBC 8780/μL (3300–8600) MMP-3 103.8 ng/mL (17.3–59.7)
Neut 76.0% (41.8–75.0) ESR 1.0hr >140 mm/h (3.0–15.0)
Lymph 15.7% (18.5–48.7) sIL-2R 584 U/mL (140–394)
Mono 8.1% (2.2–7.9) Ferritin 883 ng/mL (10.0–120.0)
Eo 0.1% (0.4–8.7) STS Negative
RBC 2.14 × 104/μL (3.86–4.92) TPAb Negative
Hb 7.2 g/dL (11.6–14.8) TbIFN-γ Negative
HCT 22.2% (35.1–44.4) β-D glucan <2.50 pg/mL (−10.99)
Plt 7.0 × 104/μL (15.8–34.8) PCT 0.15 ng/mL (0.00–0.49)
MCV 103.7 fL (83.6–98.2) MPO-ANCA <1.0 U/mL (−3.4)
MCH 33.6 pg (27.5–33.2) PR3-ANCA <1.0 U/mL (−3.4)
MCHC 32.4% (31.7–35.3) IgA 240 mg/dL (93–393)
TP 7.0 g/dL (6.6–8.1) IgM 74 mg/dL (50–269)
Alb 3.5 g/dL (4.1–5.1) IgG 1468 mg/dL (861–1747)
UN 12.6 mg/dL (8.0–20.0) IgG4 21 mg/dL (−134)
Cr 0.80 mg/dL (0.46–0.79) C3 164 mg/dL (73–138)
eGFR 59 mL/min/1.73 m2 C4 31.8 mg/dL (11.0–31.0)
LDH 170 U/L (124–222) CH50 77.1 U/mL (30.0–53.0)
Na 140 mEq/L (138–145) RF 3 U/mL (0–14)
K 3.8 mEq/L (3.6–4.8) FANA Negative
Cl 107 mEq/L (101–108) APTT 29.9 sec (23.0–38.0)
CRP 19.39 mg/dL (0.00–0.14) PT-INR 1.15 (0.85–1.15)
Anti SS-A/Ro antibody, anti SS-B/La antibodies, anti Sm antibodies, anti-double strand-DNA antibodies, anti-RNP antibodies were all negative. ESR is the data of Day 24. Normal ranges are shown in brackets.
Alb, albumin; APTT, activated partial thromboplastin time; C3, complement component 3; C4, complement component 4; CH50, 50% haemolytic complement activity; Cl, chlorine; Cr, creatinine; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; Eo, eosinophil; ESR, erythrocyte sedimentation rate; FANA, fluorescent anti-nuclear antibodies; Hb, haemoglobin; HCT, haematocrit; Ig, immunoglobulin; K, potassium; Lymph, lymphocyte; MCH, mean corpuscular haemoglobin; MCHC, mean corpuscular haemoglobin concentration; MCV, mean corpuscular volume; MMP-3, matrix metalloproteinase-3; Mono, monocyte; MPO-ANCA, myeloperoxidase-anti-neutrophil cytoplasmic antibody; Na, sodium; Neut, neutrophil; PCT, procalcitonin; Plt, platelet; PR3-ANCA, serine proteinase3-anti-neutrophil cytoplasmic antibody; PT-INR, international normalized ratio of prothrombin time; RBC, red blood cell; RF, rheumatoid factor; sIL-2, soluble interleukin-2 receptor; STS, serologic test for syphilis; Tb-INF, tuberculosis interferon-gamma; TP, total protein; TPAb, treponema pallidum antibodies; UN, urea nitrogen; WBC, white blood cell.
Table 2 Previously reported cases
No Age Sex Year Nationality Background disease G-CSF Symptoms Lesions Glucocorticoid treatment
12 55 F 2004 France Stem cell donor Filgrastim Fever, abdominal and lumbar pain, vomiting Descending ao, abdominal ao yes
2 54 M 2009 US Lung cancer
a
Fever, epigastric tenderness Abdominal ao no
33 52 M 2016 Israel Healthy donor Filgrastim Weight loss, back pain, constipation Abdominal ao, iliac artery yes
4 78 F 2016 Japan Cyclic neutropenia Filgrastim Fever, head ache, jaw claudication, visual abnormality Temporal arteries yes
5 59 F 2017 Japan Lymphoma Pegfilgrastim Neck and chest pain, fever Carotid artery, subclavian artery, ao arch, descending ao yes
6 61 F 2017 Japan Ovarian cancer Lenograstim Fever Carotid artery no
74 67 F 2017 Japan Lung cancer Pegfilgrastim Malaise and fever Carotid artery, thoracic ao yes
8 61 F 2018 Japan Breast cancer Pegfilgrastim Neck and chest pain → fever Carotid artery, thoracic ao no
9 47 F 2018 Japan Ovarian cancer
a
Fever ao arch, descending ao yes
10 71 F 2019 Japan Endometrial cancer Pegfilgrastim Fever ao arch, descending ao yes
11 72 F 2019 Japan Lymphoma Pegfilgrastim Fever, chest pain ao arch no
12 62 F 2019 Japan Lymphoma Pegfilgrastim Fever, chest pain Descending ao yes
13 69 M 2019 Japan Lymphoma Pegfilgrastim Fever Subclavian artery unknown
14 77 F 2019 Japan Ovarian cancer
a
Fever Carotid artery, subclavian artery no
155 60 F 2019 Sweden Breast cancer Filgrastim Abdominal tenderness → fever Subclavian artery, ao arch, descending ao, abdominal ao yes
165 70 F 2019 Sweden Breast cancer
a
Syncope, diarrhoea, dehydration → fever Thoracic ao, brachiocephalic trunk yes
17 72 F 2019 Japan Breast cancer Pegfilgrastim Fever Descending ao no
186 43 F 2020 Japan Uterine cancer Pegfilgrastim Unknown Thoracic ao no
196 47 F 2020 Japan Uterine cancer Pegfilgrastim Unknown Thoracic ao no
206 74 F 2020 Japan Tongue cancer Pegfilgrastim Unknown Thoracic ao no
216 65 F 2020 Japan Pancreatic cancer Pegfilgrastim Fever, chest pain ao arch, abdominal ao no
227 66 F 2020 Japan Breast cancer Pegfilgrastim Fever, malaise, abdominal discomfort ao arch, abdominal ao yes
238 52 F 2020 Finland Breast cancer Filgrastim Fever, chest pain Aorta yes
248 62 F 2020 Finland Breast cancer Filgrastim, Pegfilgrastim Fever Aorta yes
258 70 F 2020 Finland Breast cancer Lipegfilgrastim Fever Aorta, supra-aortic vessels no
268 56 F 2020 Finland Breast cancer Lipegfilgrastim Fever, neck pain, jaw pain, malaise Carotid artery, thoracic ao yes
278 53 F 2020 Finland Breast cancer Pegfilgrastim Fever, sore throat, ear ache, dyspnoea, and chest pain Aorta yes
298 40 F 2020 Finland Breast cancer Lipegfilgrastim Fever, sore throat, chest and neck pain, malaise Carotid artery yes
ao, aorta or aortic; F, female; M, male.
The figures in square brackets refer to page numbers.
a Name of the G-CSF preparations were unknown, however these were used for several days.
Electrocardiography, echocardiography, and chest radiography revealed no abnormalities that could explain the fever. Echography of the abdominal aorta revealed aortic wall thickening and a hypoechoic region around the aorta (Figure 1). Furthermore, CT revealed an increase in the soft tissue surrounding the aortic arch and abdominal aorta (Figure 2A,B). Gadolinium-enhanced magnetic resonance imaging revealed thickening of the aortic wall and enhancement of the wall and perivascular tissue (Figure 3A), and uptake was observed during 18F-fludeoxyglucose positron emission tomography (Figure 3B). These imaging findings suggested active inflammation at the lesions.
Figure 1 Imaging findings via echography of the abdominal aorta. Echography of the abdominal aorta at the level of the coeliac artery bifurcation (left: long-axis image, right: short-axis image) revealed increased brightness and thickening of the vessel wall. There was a hypoechoic region surrounding the outside of the artery (arrow), and increased blood flow was not observed. Echography helped to distinguish some lesion features (e.g. for an abscess, a tumour, and an atheroma).
Figure 2 Imaging findings via enhanced computed tomography. (A) Enhanced computed tomography (CT) findings before chemotherapy. (B) The computed tomography findings after onset (chest: early phase, abdomen: plain, early, and delay phase), which revealed enhancement of the peri-aortic tissue from the aortic arch and the abdominal aorta (vs. the pre-chemotherapy findings). There was no wall thickening in the branches of the aorta, aortic stenosis, aneurism, or dissection. (C) Enhanced computed tomography after the treatment for aortitis. The thickening around the aorta had improved after 2 weeks.
Figure 3 Imaging findings via gadolinium-enhanced magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. (A) Gadolinium-enhanced T1-weighted image revealed thickening of the vessel wall at the aortic arch and the abdominal aorta at the diaphragm (arrow). (B) Fluorodeoxyglucose positron emission tomography (18F-FDG PET) revealed FDG uptake in the aortic arch and the abdominal aorta, with a standardized uptake value (SUV) of 2–3 like that in the liver (arrow).
The patient was transferred to the cardiology department, and G-CSF-associated aortitis was suggested based on her history and clinical course (Naranjo adverse drug reaction probability scale score 7; probable). On Day 23, she was exhausted because of the persistent fever and received prednisolone treatment (PSL, 50 mg/day), which promptly resolved her symptoms. Follow-up testing revealed improvement in her CRP concentration and erythrocyte sedimentation rate (Supplementary material online, Figure S1). After 2 weeks, CT revealed an improvement in the thickening around the aorta (Figure 2C). The PSL dose was gradually reduced. This treatment was marked by the absence of recurrence of the aortitis, cancer, and infection at her 1-year follow-up.
Discussion
This case involved a patient who presented with a significant fever. Aortitis was suspected via multiple imaging modalities, and the association with G-CSF treatment was suggested based on the patient’s history and exclusion of other diseases.
Clinical course in previous cases
A PubMed search revealed 28 reported cases involving arteritis associated with G-CSF treatment (Table 2). Most cases involved fever at the onset of disease, although other symptoms (e.g. abdominal tenderness, syncope) appeared before the fever in some cases.5 In this case, PSL was started because of a high fever and malaise; however, one-half of the reported cases resolved without corticosteroids.6 In the previous cases that involved corticosteroid treatment, three cases were administered high-dose treatments (e.g. pulse methylprednisolone),4,7 and six cases involved PSL doses starting at 30–60 mg/day with gradual tapering.3,5 Early reduction of the corticosteroid may be possible because G-CSF-associated arteritis may have a relatively good prognosis compared to other arteritis.7 Nevertheless, a case that involved aortic dissection highlighted the need for careful observation.4 Some cases with G-CSF re-administration had aortitis recurrence,6 and dose reduction or change of the anti-cancer drug were needed to avoid myelosuppression.
Differential diagnosis of aortitis
Takayasu arteritis and giant cell arteritis (GCA) are immune disorders that cause large-vessel arteritis. Takayasu arteritis onset is most common among women in their 20s, and the lesions are often continuous in the aorta and its primary branches. More than 90% of patients have lesions in the aortic arch, and 40% in the abdominal aorta.9 Onset of GCA is most common among women in their 60s to 70s, and lesions are typically detected in the branches of the carotid and vertebral arteries, and other large arteries may have lesions.10 Perivascular inflammation caused by IgG4-related diseases is found in the abdominal and iliac arteries, although lesions can be present in the thoracic aorta. These lesions tend to be detected in men in their sixties.11 Other differential diagnoses include infection (bacterial, syphilis, human immunodeficiency virus, and tuberculosis), drug-induced disease,12 malignancy,13 Behçet disease, Cogan syndrome, systemic lupus erythematosus, and anti-neutrophil cytoplasmic antibody-related vasculitis (Supplementary material online, Figure S2).14 The differential diagnosis needs to be performed based on the characteristics of the diseases in addition to the imaging evaluation.
Lesions and imaging
Previous reports of G-CSF-associated arteritis indicated that most lesions were detected in the thoracic aorta (68%), especially in the arch (29%) and descending aorta (29%). However, lesions can be detected in the abdominal aorta (21%), carotid artery (25%), and subclavian artery (14%) (Table 2). Most cases involved circumferential thickening of the peri-arterial tissue, which was detected via CT. Echography was useful in guiding the diagnosis in this case, although none of the previously English reported cases involved an abdominal aorta echography. Nevertheless, an echography was used to evaluate some lesions in the temporal and carotid arteries.8
Mechanism of aortitis
The pathological mechanisms underlying G-CSF-associated arteritis are unclear. Previous reports have speculated that arteritis is related to cytokines and complex immune reactions between anti-cancer agents and G-CSF.8 In aortitis after acute aortic dissection, G-CSF may act on the arterial adventitia and invading granulocytes, which results in inflammation.15 Nevertheless, this mechanism for G-CSF-associated arteritis remains speculative.
Conclusions
Chronic inflammation can lead to a reduced nutritional status and quality of life in cancer patients, which may influence their general condition and make them unable to continue chemotherapy. When cancer patients experience persistent fever after G-CSF treatment, it is necessary to make a differential diagnosis carefully and select treatments based on the patient’s general condition as well as the prognosis of arteries.
Patient perspective
The patient was mentally exhausted before treatment. Psychiatric support also improved her mental status, despite the high dose of PSL used.
Lead author biography
Graduated from Jichi Medical University School of Medicine, Japan and worked as a general physician. In 2016, conducted clinical studies on cardiovascular risk factors among young people at Shinshu University Graduate School of Medicine. Currently working in general cardiology and preventive medicine.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
ytaa503_Supplementary_Data Click here for additional data file.
Acknowledgements
The authors thank Prof. Yasunari Fujinaga and Dr Fumihito Ichinohe, Department of Radiology, Shinshu University School of Medicine, for guidance with the imaging. The authors thank the clinical team members of Department of Cardiovascular Medicine, Shinshu University School of Medicine; Dr Shusaku Maruyama, Dr Masafumi Kanai, and Ms. Junko Iguchi.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared. | CARBOPLATIN, FILGRASTIM, PACLITAXEL | DrugsGivenReaction | CC BY-NC | 33598604 | 20,059,561 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Platelet count decreased'. | Granulocyte colony stimulating factor-associated aortitis evaluated via multiple imaging modalities including vascular echography: a case report.
Granulocyte colony stimulating factor (G-CSF) preparations are used for patients with granulocytopenia, especially to prevent febrile neutropenia. Arteritis has been recognized as a side effect of G-CSF treatment; however, there are no clear diagnostic criteria or treatment guidelines because not enough cases have been reported. Present case showed one of the diagnostic and treatment selection methods via multiple imaging modality including vascular echography.
A 52-year-old woman underwent chemotherapy for ovarian cancer and received G-CSF because of myelosuppression. The patient experienced high and remittent fever that persisted during treatment using antibiotics and acetaminophen. Enhanced computed tomography revealed thickening of the tissue around the aortic arch and abdominal aorta. Echography of the abdominal aorta revealed thickening of the wall and a hypoechoic region around the aorta. Gadolinium-enhanced magnetic resonance imaging and 18F-fludeoxyglucose positron emission tomography also revealed that the inflammation was localized to the lesion. A suspicion of G-CSF-associated aortitis was based on the patient's history and the exclusion of other diseases that might have caused the aortitis. Her condition rapidly improved after starting corticosteroid treatment.
The differential diagnosis in similar cases should consider immune diseases that cause large-vessel arteritis (Takayasu arteritis, giant cell arteritis, and another vasculitis), infection, drug-induced disease, and immunoglobulin G4-related disease. The use of different imaging modalities, including vascular echography, helped guide the diagnosis and follow-up. It is necessary to evaluate the patient's general condition before the selection of treatments.
Learning points
In patients with persistent fever and a history of granulocyte colony stimulating factor administration, aortitis should be considered in the differential diagnosis.
The arteritis localization and activity should be evaluated using multiple modalities (e.g. vascular echography, computed tomography, and magnetic resonance imaging) including neck to the pelvis to guide treatment.
The treatment including the necessity of corticosteroid therapy should be selected based on the general condition of the patients, considering that the patients are treated for cancer.
Introduction
Granulocyte colony-stimulating factor (G-CSF) preparations are used for chemotherapy-related granulocytopenia, especially to prevent febrile neutropenia. The G-CSF preparations bind to G-CSF receptors that are present on neutrophil progenitor cells in the bone marrow, which promote their differentiation into neutrophils. The clinical regimens include filgrastim, lenograstim, nartograstim, filgrastim biosimilars, and long-lasting pegylated preparations of filgrastim.1 The first report regarding G-CSF-associated aortitis was in 2004,2 and arteritis has been reported as a side effect of G-CSF treatment. However, there are no clear diagnostic criteria or treatment guidelines. Therefore, we report a case of G-CSF-associated aortitis that required careful exclusion of similar aortitis and multiple imaging modalities to support the diagnosis.
Timeline
One month before onset The 5th course of chemotherapy [paclitaxel 262 mg (180 mg/m2)/carboplatin 583 mg (target area under the concentration-time curve 6 mg min/mL)] was administered.
Two weeks before onset Myelosuppression was detected, and the granulocyte colony stimulating factor (G-CSF) was administered for the first time and continued for 3 days.
Ten days before onset The 6th course of chemotherapy was administered.
Three days before onset Myelosuppression was detected, and the G-CSF treatment was started and continued for 4 days.
Day 0 (onset) Last administration of G-CSF. The patient developed a high fever during the night.
Day 1 The patient visited an outpatient clinic and was prescribed acetaminophen and levofloxacin.
Day 4 The patient was admitted to the gynaecology department for a persistent high fever. Although the thickening around the aorta was suspected via computed tomography (CT), it was uncertain whether the inflammation was localized there, and the patient first received cefmetazole for suspected infection or febrile neutropenia.
Day 9 The antibiotic treatment was changed to piperacillin/tazobactam.
Day 16 The fever and inflammation did not improve completely. Aortitis was re-considered as a differential diagnosis of fever. An magnetic resonance imaging was performed to evaluate the aortitis.
Day 17 The patient was transferred to the cardiology department for treatment of the aortitis. Bone marrow testing was performed.
Day 23 Positron emission tomography revealed active inflammation of the aortic arch and abdominal aorta. Prednisolone (PSL) was started (50 mg/day, 1 mg/kg).
Day 24 The fever improved, and the temperature was maintained at <37.5°C.
Day 38 A CT examination revealed that the thickening around the aorta had improved. C-reactive protein concentration returned to normal.
Day 46 The PSL dose was gradually reduced.
Day 71 The patient was discharged (PSL 25 mg/day).
After 9 months The PSL dose was gradually reduced to 10 mg/day for 9 months.
After 1 year No episode of infection, and no recurrence of aortitis and cancer. The patient is almost free from the PSL.
Case presentation
A 52-year-old woman underwent six courses of post-operative chemotherapy (paclitaxel 262 mg/carboplatin 583 mg) for ovarian cancer. Myelosuppression was detected after the 5th and 6th chemotherapy courses, which prompted G-CSF treatment (filgrastim, 75 μg/day). The patient developed a high fever after the last G-CSF administration and was admitted 4 days later in the gynaecology department. Negative bacterial, fungal, and viral test results were observed, and a broad-spectrum antibiotic treatment did not completely improve her condition. Aortitis was suspected based on enhanced computed tomography (CT) findings, and she was referred to our cardiology department.
Her peripheral arterial oxygen saturation was 96% (room air), body temperature was 38.0˚C with remittent fever, blood pressure was 92/50 mmHg, and bilateral pulse was 70 beats/min. The head and neck had no bruit or tenderness, and the patient reported no visual deterioration or diplopia. Chest auscultation was clear, and cardiac auscultation revealed normal S1 and S2 with no S3 or murmurs. There were no abdominal abnormalities or notable skin lesions and swelling on the extremities. Her medical history included pulmonary embolism and deep vein thrombosis that had been controlled using anticoagulant medication.
Table 1 shows the patient’s laboratory findings on admission, which included an elevated C-reactive protein concentration (CRP). Although the white blood cell count (WBC) slightly elevated on admission, it gradually decreased to 1400/μL (normal range 3300–8600). Decreasing of the platelet counts and normocytic anaemia were also observed. Bone marrow tests showed that the three lineages of haematopoietic cells were retained, and there was no increase in blasts or morphological abnormalities.
Table 1 Laboratory findings on admission (Day 4)
WBC 8780/μL (3300–8600) MMP-3 103.8 ng/mL (17.3–59.7)
Neut 76.0% (41.8–75.0) ESR 1.0hr >140 mm/h (3.0–15.0)
Lymph 15.7% (18.5–48.7) sIL-2R 584 U/mL (140–394)
Mono 8.1% (2.2–7.9) Ferritin 883 ng/mL (10.0–120.0)
Eo 0.1% (0.4–8.7) STS Negative
RBC 2.14 × 104/μL (3.86–4.92) TPAb Negative
Hb 7.2 g/dL (11.6–14.8) TbIFN-γ Negative
HCT 22.2% (35.1–44.4) β-D glucan <2.50 pg/mL (−10.99)
Plt 7.0 × 104/μL (15.8–34.8) PCT 0.15 ng/mL (0.00–0.49)
MCV 103.7 fL (83.6–98.2) MPO-ANCA <1.0 U/mL (−3.4)
MCH 33.6 pg (27.5–33.2) PR3-ANCA <1.0 U/mL (−3.4)
MCHC 32.4% (31.7–35.3) IgA 240 mg/dL (93–393)
TP 7.0 g/dL (6.6–8.1) IgM 74 mg/dL (50–269)
Alb 3.5 g/dL (4.1–5.1) IgG 1468 mg/dL (861–1747)
UN 12.6 mg/dL (8.0–20.0) IgG4 21 mg/dL (−134)
Cr 0.80 mg/dL (0.46–0.79) C3 164 mg/dL (73–138)
eGFR 59 mL/min/1.73 m2 C4 31.8 mg/dL (11.0–31.0)
LDH 170 U/L (124–222) CH50 77.1 U/mL (30.0–53.0)
Na 140 mEq/L (138–145) RF 3 U/mL (0–14)
K 3.8 mEq/L (3.6–4.8) FANA Negative
Cl 107 mEq/L (101–108) APTT 29.9 sec (23.0–38.0)
CRP 19.39 mg/dL (0.00–0.14) PT-INR 1.15 (0.85–1.15)
Anti SS-A/Ro antibody, anti SS-B/La antibodies, anti Sm antibodies, anti-double strand-DNA antibodies, anti-RNP antibodies were all negative. ESR is the data of Day 24. Normal ranges are shown in brackets.
Alb, albumin; APTT, activated partial thromboplastin time; C3, complement component 3; C4, complement component 4; CH50, 50% haemolytic complement activity; Cl, chlorine; Cr, creatinine; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; Eo, eosinophil; ESR, erythrocyte sedimentation rate; FANA, fluorescent anti-nuclear antibodies; Hb, haemoglobin; HCT, haematocrit; Ig, immunoglobulin; K, potassium; Lymph, lymphocyte; MCH, mean corpuscular haemoglobin; MCHC, mean corpuscular haemoglobin concentration; MCV, mean corpuscular volume; MMP-3, matrix metalloproteinase-3; Mono, monocyte; MPO-ANCA, myeloperoxidase-anti-neutrophil cytoplasmic antibody; Na, sodium; Neut, neutrophil; PCT, procalcitonin; Plt, platelet; PR3-ANCA, serine proteinase3-anti-neutrophil cytoplasmic antibody; PT-INR, international normalized ratio of prothrombin time; RBC, red blood cell; RF, rheumatoid factor; sIL-2, soluble interleukin-2 receptor; STS, serologic test for syphilis; Tb-INF, tuberculosis interferon-gamma; TP, total protein; TPAb, treponema pallidum antibodies; UN, urea nitrogen; WBC, white blood cell.
Table 2 Previously reported cases
No Age Sex Year Nationality Background disease G-CSF Symptoms Lesions Glucocorticoid treatment
12 55 F 2004 France Stem cell donor Filgrastim Fever, abdominal and lumbar pain, vomiting Descending ao, abdominal ao yes
2 54 M 2009 US Lung cancer
a
Fever, epigastric tenderness Abdominal ao no
33 52 M 2016 Israel Healthy donor Filgrastim Weight loss, back pain, constipation Abdominal ao, iliac artery yes
4 78 F 2016 Japan Cyclic neutropenia Filgrastim Fever, head ache, jaw claudication, visual abnormality Temporal arteries yes
5 59 F 2017 Japan Lymphoma Pegfilgrastim Neck and chest pain, fever Carotid artery, subclavian artery, ao arch, descending ao yes
6 61 F 2017 Japan Ovarian cancer Lenograstim Fever Carotid artery no
74 67 F 2017 Japan Lung cancer Pegfilgrastim Malaise and fever Carotid artery, thoracic ao yes
8 61 F 2018 Japan Breast cancer Pegfilgrastim Neck and chest pain → fever Carotid artery, thoracic ao no
9 47 F 2018 Japan Ovarian cancer
a
Fever ao arch, descending ao yes
10 71 F 2019 Japan Endometrial cancer Pegfilgrastim Fever ao arch, descending ao yes
11 72 F 2019 Japan Lymphoma Pegfilgrastim Fever, chest pain ao arch no
12 62 F 2019 Japan Lymphoma Pegfilgrastim Fever, chest pain Descending ao yes
13 69 M 2019 Japan Lymphoma Pegfilgrastim Fever Subclavian artery unknown
14 77 F 2019 Japan Ovarian cancer
a
Fever Carotid artery, subclavian artery no
155 60 F 2019 Sweden Breast cancer Filgrastim Abdominal tenderness → fever Subclavian artery, ao arch, descending ao, abdominal ao yes
165 70 F 2019 Sweden Breast cancer
a
Syncope, diarrhoea, dehydration → fever Thoracic ao, brachiocephalic trunk yes
17 72 F 2019 Japan Breast cancer Pegfilgrastim Fever Descending ao no
186 43 F 2020 Japan Uterine cancer Pegfilgrastim Unknown Thoracic ao no
196 47 F 2020 Japan Uterine cancer Pegfilgrastim Unknown Thoracic ao no
206 74 F 2020 Japan Tongue cancer Pegfilgrastim Unknown Thoracic ao no
216 65 F 2020 Japan Pancreatic cancer Pegfilgrastim Fever, chest pain ao arch, abdominal ao no
227 66 F 2020 Japan Breast cancer Pegfilgrastim Fever, malaise, abdominal discomfort ao arch, abdominal ao yes
238 52 F 2020 Finland Breast cancer Filgrastim Fever, chest pain Aorta yes
248 62 F 2020 Finland Breast cancer Filgrastim, Pegfilgrastim Fever Aorta yes
258 70 F 2020 Finland Breast cancer Lipegfilgrastim Fever Aorta, supra-aortic vessels no
268 56 F 2020 Finland Breast cancer Lipegfilgrastim Fever, neck pain, jaw pain, malaise Carotid artery, thoracic ao yes
278 53 F 2020 Finland Breast cancer Pegfilgrastim Fever, sore throat, ear ache, dyspnoea, and chest pain Aorta yes
298 40 F 2020 Finland Breast cancer Lipegfilgrastim Fever, sore throat, chest and neck pain, malaise Carotid artery yes
ao, aorta or aortic; F, female; M, male.
The figures in square brackets refer to page numbers.
a Name of the G-CSF preparations were unknown, however these were used for several days.
Electrocardiography, echocardiography, and chest radiography revealed no abnormalities that could explain the fever. Echography of the abdominal aorta revealed aortic wall thickening and a hypoechoic region around the aorta (Figure 1). Furthermore, CT revealed an increase in the soft tissue surrounding the aortic arch and abdominal aorta (Figure 2A,B). Gadolinium-enhanced magnetic resonance imaging revealed thickening of the aortic wall and enhancement of the wall and perivascular tissue (Figure 3A), and uptake was observed during 18F-fludeoxyglucose positron emission tomography (Figure 3B). These imaging findings suggested active inflammation at the lesions.
Figure 1 Imaging findings via echography of the abdominal aorta. Echography of the abdominal aorta at the level of the coeliac artery bifurcation (left: long-axis image, right: short-axis image) revealed increased brightness and thickening of the vessel wall. There was a hypoechoic region surrounding the outside of the artery (arrow), and increased blood flow was not observed. Echography helped to distinguish some lesion features (e.g. for an abscess, a tumour, and an atheroma).
Figure 2 Imaging findings via enhanced computed tomography. (A) Enhanced computed tomography (CT) findings before chemotherapy. (B) The computed tomography findings after onset (chest: early phase, abdomen: plain, early, and delay phase), which revealed enhancement of the peri-aortic tissue from the aortic arch and the abdominal aorta (vs. the pre-chemotherapy findings). There was no wall thickening in the branches of the aorta, aortic stenosis, aneurism, or dissection. (C) Enhanced computed tomography after the treatment for aortitis. The thickening around the aorta had improved after 2 weeks.
Figure 3 Imaging findings via gadolinium-enhanced magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. (A) Gadolinium-enhanced T1-weighted image revealed thickening of the vessel wall at the aortic arch and the abdominal aorta at the diaphragm (arrow). (B) Fluorodeoxyglucose positron emission tomography (18F-FDG PET) revealed FDG uptake in the aortic arch and the abdominal aorta, with a standardized uptake value (SUV) of 2–3 like that in the liver (arrow).
The patient was transferred to the cardiology department, and G-CSF-associated aortitis was suggested based on her history and clinical course (Naranjo adverse drug reaction probability scale score 7; probable). On Day 23, she was exhausted because of the persistent fever and received prednisolone treatment (PSL, 50 mg/day), which promptly resolved her symptoms. Follow-up testing revealed improvement in her CRP concentration and erythrocyte sedimentation rate (Supplementary material online, Figure S1). After 2 weeks, CT revealed an improvement in the thickening around the aorta (Figure 2C). The PSL dose was gradually reduced. This treatment was marked by the absence of recurrence of the aortitis, cancer, and infection at her 1-year follow-up.
Discussion
This case involved a patient who presented with a significant fever. Aortitis was suspected via multiple imaging modalities, and the association with G-CSF treatment was suggested based on the patient’s history and exclusion of other diseases.
Clinical course in previous cases
A PubMed search revealed 28 reported cases involving arteritis associated with G-CSF treatment (Table 2). Most cases involved fever at the onset of disease, although other symptoms (e.g. abdominal tenderness, syncope) appeared before the fever in some cases.5 In this case, PSL was started because of a high fever and malaise; however, one-half of the reported cases resolved without corticosteroids.6 In the previous cases that involved corticosteroid treatment, three cases were administered high-dose treatments (e.g. pulse methylprednisolone),4,7 and six cases involved PSL doses starting at 30–60 mg/day with gradual tapering.3,5 Early reduction of the corticosteroid may be possible because G-CSF-associated arteritis may have a relatively good prognosis compared to other arteritis.7 Nevertheless, a case that involved aortic dissection highlighted the need for careful observation.4 Some cases with G-CSF re-administration had aortitis recurrence,6 and dose reduction or change of the anti-cancer drug were needed to avoid myelosuppression.
Differential diagnosis of aortitis
Takayasu arteritis and giant cell arteritis (GCA) are immune disorders that cause large-vessel arteritis. Takayasu arteritis onset is most common among women in their 20s, and the lesions are often continuous in the aorta and its primary branches. More than 90% of patients have lesions in the aortic arch, and 40% in the abdominal aorta.9 Onset of GCA is most common among women in their 60s to 70s, and lesions are typically detected in the branches of the carotid and vertebral arteries, and other large arteries may have lesions.10 Perivascular inflammation caused by IgG4-related diseases is found in the abdominal and iliac arteries, although lesions can be present in the thoracic aorta. These lesions tend to be detected in men in their sixties.11 Other differential diagnoses include infection (bacterial, syphilis, human immunodeficiency virus, and tuberculosis), drug-induced disease,12 malignancy,13 Behçet disease, Cogan syndrome, systemic lupus erythematosus, and anti-neutrophil cytoplasmic antibody-related vasculitis (Supplementary material online, Figure S2).14 The differential diagnosis needs to be performed based on the characteristics of the diseases in addition to the imaging evaluation.
Lesions and imaging
Previous reports of G-CSF-associated arteritis indicated that most lesions were detected in the thoracic aorta (68%), especially in the arch (29%) and descending aorta (29%). However, lesions can be detected in the abdominal aorta (21%), carotid artery (25%), and subclavian artery (14%) (Table 2). Most cases involved circumferential thickening of the peri-arterial tissue, which was detected via CT. Echography was useful in guiding the diagnosis in this case, although none of the previously English reported cases involved an abdominal aorta echography. Nevertheless, an echography was used to evaluate some lesions in the temporal and carotid arteries.8
Mechanism of aortitis
The pathological mechanisms underlying G-CSF-associated arteritis are unclear. Previous reports have speculated that arteritis is related to cytokines and complex immune reactions between anti-cancer agents and G-CSF.8 In aortitis after acute aortic dissection, G-CSF may act on the arterial adventitia and invading granulocytes, which results in inflammation.15 Nevertheless, this mechanism for G-CSF-associated arteritis remains speculative.
Conclusions
Chronic inflammation can lead to a reduced nutritional status and quality of life in cancer patients, which may influence their general condition and make them unable to continue chemotherapy. When cancer patients experience persistent fever after G-CSF treatment, it is necessary to make a differential diagnosis carefully and select treatments based on the patient’s general condition as well as the prognosis of arteries.
Patient perspective
The patient was mentally exhausted before treatment. Psychiatric support also improved her mental status, despite the high dose of PSL used.
Lead author biography
Graduated from Jichi Medical University School of Medicine, Japan and worked as a general physician. In 2016, conducted clinical studies on cardiovascular risk factors among young people at Shinshu University Graduate School of Medicine. Currently working in general cardiology and preventive medicine.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
ytaa503_Supplementary_Data Click here for additional data file.
Acknowledgements
The authors thank Prof. Yasunari Fujinaga and Dr Fumihito Ichinohe, Department of Radiology, Shinshu University School of Medicine, for guidance with the imaging. The authors thank the clinical team members of Department of Cardiovascular Medicine, Shinshu University School of Medicine; Dr Shusaku Maruyama, Dr Masafumi Kanai, and Ms. Junko Iguchi.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared. | CARBOPLATIN, FILGRASTIM, PACLITAXEL | DrugsGivenReaction | CC BY-NC | 33598604 | 20,059,561 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'White blood cell count decreased'. | Granulocyte colony stimulating factor-associated aortitis evaluated via multiple imaging modalities including vascular echography: a case report.
Granulocyte colony stimulating factor (G-CSF) preparations are used for patients with granulocytopenia, especially to prevent febrile neutropenia. Arteritis has been recognized as a side effect of G-CSF treatment; however, there are no clear diagnostic criteria or treatment guidelines because not enough cases have been reported. Present case showed one of the diagnostic and treatment selection methods via multiple imaging modality including vascular echography.
A 52-year-old woman underwent chemotherapy for ovarian cancer and received G-CSF because of myelosuppression. The patient experienced high and remittent fever that persisted during treatment using antibiotics and acetaminophen. Enhanced computed tomography revealed thickening of the tissue around the aortic arch and abdominal aorta. Echography of the abdominal aorta revealed thickening of the wall and a hypoechoic region around the aorta. Gadolinium-enhanced magnetic resonance imaging and 18F-fludeoxyglucose positron emission tomography also revealed that the inflammation was localized to the lesion. A suspicion of G-CSF-associated aortitis was based on the patient's history and the exclusion of other diseases that might have caused the aortitis. Her condition rapidly improved after starting corticosteroid treatment.
The differential diagnosis in similar cases should consider immune diseases that cause large-vessel arteritis (Takayasu arteritis, giant cell arteritis, and another vasculitis), infection, drug-induced disease, and immunoglobulin G4-related disease. The use of different imaging modalities, including vascular echography, helped guide the diagnosis and follow-up. It is necessary to evaluate the patient's general condition before the selection of treatments.
Learning points
In patients with persistent fever and a history of granulocyte colony stimulating factor administration, aortitis should be considered in the differential diagnosis.
The arteritis localization and activity should be evaluated using multiple modalities (e.g. vascular echography, computed tomography, and magnetic resonance imaging) including neck to the pelvis to guide treatment.
The treatment including the necessity of corticosteroid therapy should be selected based on the general condition of the patients, considering that the patients are treated for cancer.
Introduction
Granulocyte colony-stimulating factor (G-CSF) preparations are used for chemotherapy-related granulocytopenia, especially to prevent febrile neutropenia. The G-CSF preparations bind to G-CSF receptors that are present on neutrophil progenitor cells in the bone marrow, which promote their differentiation into neutrophils. The clinical regimens include filgrastim, lenograstim, nartograstim, filgrastim biosimilars, and long-lasting pegylated preparations of filgrastim.1 The first report regarding G-CSF-associated aortitis was in 2004,2 and arteritis has been reported as a side effect of G-CSF treatment. However, there are no clear diagnostic criteria or treatment guidelines. Therefore, we report a case of G-CSF-associated aortitis that required careful exclusion of similar aortitis and multiple imaging modalities to support the diagnosis.
Timeline
One month before onset The 5th course of chemotherapy [paclitaxel 262 mg (180 mg/m2)/carboplatin 583 mg (target area under the concentration-time curve 6 mg min/mL)] was administered.
Two weeks before onset Myelosuppression was detected, and the granulocyte colony stimulating factor (G-CSF) was administered for the first time and continued for 3 days.
Ten days before onset The 6th course of chemotherapy was administered.
Three days before onset Myelosuppression was detected, and the G-CSF treatment was started and continued for 4 days.
Day 0 (onset) Last administration of G-CSF. The patient developed a high fever during the night.
Day 1 The patient visited an outpatient clinic and was prescribed acetaminophen and levofloxacin.
Day 4 The patient was admitted to the gynaecology department for a persistent high fever. Although the thickening around the aorta was suspected via computed tomography (CT), it was uncertain whether the inflammation was localized there, and the patient first received cefmetazole for suspected infection or febrile neutropenia.
Day 9 The antibiotic treatment was changed to piperacillin/tazobactam.
Day 16 The fever and inflammation did not improve completely. Aortitis was re-considered as a differential diagnosis of fever. An magnetic resonance imaging was performed to evaluate the aortitis.
Day 17 The patient was transferred to the cardiology department for treatment of the aortitis. Bone marrow testing was performed.
Day 23 Positron emission tomography revealed active inflammation of the aortic arch and abdominal aorta. Prednisolone (PSL) was started (50 mg/day, 1 mg/kg).
Day 24 The fever improved, and the temperature was maintained at <37.5°C.
Day 38 A CT examination revealed that the thickening around the aorta had improved. C-reactive protein concentration returned to normal.
Day 46 The PSL dose was gradually reduced.
Day 71 The patient was discharged (PSL 25 mg/day).
After 9 months The PSL dose was gradually reduced to 10 mg/day for 9 months.
After 1 year No episode of infection, and no recurrence of aortitis and cancer. The patient is almost free from the PSL.
Case presentation
A 52-year-old woman underwent six courses of post-operative chemotherapy (paclitaxel 262 mg/carboplatin 583 mg) for ovarian cancer. Myelosuppression was detected after the 5th and 6th chemotherapy courses, which prompted G-CSF treatment (filgrastim, 75 μg/day). The patient developed a high fever after the last G-CSF administration and was admitted 4 days later in the gynaecology department. Negative bacterial, fungal, and viral test results were observed, and a broad-spectrum antibiotic treatment did not completely improve her condition. Aortitis was suspected based on enhanced computed tomography (CT) findings, and she was referred to our cardiology department.
Her peripheral arterial oxygen saturation was 96% (room air), body temperature was 38.0˚C with remittent fever, blood pressure was 92/50 mmHg, and bilateral pulse was 70 beats/min. The head and neck had no bruit or tenderness, and the patient reported no visual deterioration or diplopia. Chest auscultation was clear, and cardiac auscultation revealed normal S1 and S2 with no S3 or murmurs. There were no abdominal abnormalities or notable skin lesions and swelling on the extremities. Her medical history included pulmonary embolism and deep vein thrombosis that had been controlled using anticoagulant medication.
Table 1 shows the patient’s laboratory findings on admission, which included an elevated C-reactive protein concentration (CRP). Although the white blood cell count (WBC) slightly elevated on admission, it gradually decreased to 1400/μL (normal range 3300–8600). Decreasing of the platelet counts and normocytic anaemia were also observed. Bone marrow tests showed that the three lineages of haematopoietic cells were retained, and there was no increase in blasts or morphological abnormalities.
Table 1 Laboratory findings on admission (Day 4)
WBC 8780/μL (3300–8600) MMP-3 103.8 ng/mL (17.3–59.7)
Neut 76.0% (41.8–75.0) ESR 1.0hr >140 mm/h (3.0–15.0)
Lymph 15.7% (18.5–48.7) sIL-2R 584 U/mL (140–394)
Mono 8.1% (2.2–7.9) Ferritin 883 ng/mL (10.0–120.0)
Eo 0.1% (0.4–8.7) STS Negative
RBC 2.14 × 104/μL (3.86–4.92) TPAb Negative
Hb 7.2 g/dL (11.6–14.8) TbIFN-γ Negative
HCT 22.2% (35.1–44.4) β-D glucan <2.50 pg/mL (−10.99)
Plt 7.0 × 104/μL (15.8–34.8) PCT 0.15 ng/mL (0.00–0.49)
MCV 103.7 fL (83.6–98.2) MPO-ANCA <1.0 U/mL (−3.4)
MCH 33.6 pg (27.5–33.2) PR3-ANCA <1.0 U/mL (−3.4)
MCHC 32.4% (31.7–35.3) IgA 240 mg/dL (93–393)
TP 7.0 g/dL (6.6–8.1) IgM 74 mg/dL (50–269)
Alb 3.5 g/dL (4.1–5.1) IgG 1468 mg/dL (861–1747)
UN 12.6 mg/dL (8.0–20.0) IgG4 21 mg/dL (−134)
Cr 0.80 mg/dL (0.46–0.79) C3 164 mg/dL (73–138)
eGFR 59 mL/min/1.73 m2 C4 31.8 mg/dL (11.0–31.0)
LDH 170 U/L (124–222) CH50 77.1 U/mL (30.0–53.0)
Na 140 mEq/L (138–145) RF 3 U/mL (0–14)
K 3.8 mEq/L (3.6–4.8) FANA Negative
Cl 107 mEq/L (101–108) APTT 29.9 sec (23.0–38.0)
CRP 19.39 mg/dL (0.00–0.14) PT-INR 1.15 (0.85–1.15)
Anti SS-A/Ro antibody, anti SS-B/La antibodies, anti Sm antibodies, anti-double strand-DNA antibodies, anti-RNP antibodies were all negative. ESR is the data of Day 24. Normal ranges are shown in brackets.
Alb, albumin; APTT, activated partial thromboplastin time; C3, complement component 3; C4, complement component 4; CH50, 50% haemolytic complement activity; Cl, chlorine; Cr, creatinine; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; Eo, eosinophil; ESR, erythrocyte sedimentation rate; FANA, fluorescent anti-nuclear antibodies; Hb, haemoglobin; HCT, haematocrit; Ig, immunoglobulin; K, potassium; Lymph, lymphocyte; MCH, mean corpuscular haemoglobin; MCHC, mean corpuscular haemoglobin concentration; MCV, mean corpuscular volume; MMP-3, matrix metalloproteinase-3; Mono, monocyte; MPO-ANCA, myeloperoxidase-anti-neutrophil cytoplasmic antibody; Na, sodium; Neut, neutrophil; PCT, procalcitonin; Plt, platelet; PR3-ANCA, serine proteinase3-anti-neutrophil cytoplasmic antibody; PT-INR, international normalized ratio of prothrombin time; RBC, red blood cell; RF, rheumatoid factor; sIL-2, soluble interleukin-2 receptor; STS, serologic test for syphilis; Tb-INF, tuberculosis interferon-gamma; TP, total protein; TPAb, treponema pallidum antibodies; UN, urea nitrogen; WBC, white blood cell.
Table 2 Previously reported cases
No Age Sex Year Nationality Background disease G-CSF Symptoms Lesions Glucocorticoid treatment
12 55 F 2004 France Stem cell donor Filgrastim Fever, abdominal and lumbar pain, vomiting Descending ao, abdominal ao yes
2 54 M 2009 US Lung cancer
a
Fever, epigastric tenderness Abdominal ao no
33 52 M 2016 Israel Healthy donor Filgrastim Weight loss, back pain, constipation Abdominal ao, iliac artery yes
4 78 F 2016 Japan Cyclic neutropenia Filgrastim Fever, head ache, jaw claudication, visual abnormality Temporal arteries yes
5 59 F 2017 Japan Lymphoma Pegfilgrastim Neck and chest pain, fever Carotid artery, subclavian artery, ao arch, descending ao yes
6 61 F 2017 Japan Ovarian cancer Lenograstim Fever Carotid artery no
74 67 F 2017 Japan Lung cancer Pegfilgrastim Malaise and fever Carotid artery, thoracic ao yes
8 61 F 2018 Japan Breast cancer Pegfilgrastim Neck and chest pain → fever Carotid artery, thoracic ao no
9 47 F 2018 Japan Ovarian cancer
a
Fever ao arch, descending ao yes
10 71 F 2019 Japan Endometrial cancer Pegfilgrastim Fever ao arch, descending ao yes
11 72 F 2019 Japan Lymphoma Pegfilgrastim Fever, chest pain ao arch no
12 62 F 2019 Japan Lymphoma Pegfilgrastim Fever, chest pain Descending ao yes
13 69 M 2019 Japan Lymphoma Pegfilgrastim Fever Subclavian artery unknown
14 77 F 2019 Japan Ovarian cancer
a
Fever Carotid artery, subclavian artery no
155 60 F 2019 Sweden Breast cancer Filgrastim Abdominal tenderness → fever Subclavian artery, ao arch, descending ao, abdominal ao yes
165 70 F 2019 Sweden Breast cancer
a
Syncope, diarrhoea, dehydration → fever Thoracic ao, brachiocephalic trunk yes
17 72 F 2019 Japan Breast cancer Pegfilgrastim Fever Descending ao no
186 43 F 2020 Japan Uterine cancer Pegfilgrastim Unknown Thoracic ao no
196 47 F 2020 Japan Uterine cancer Pegfilgrastim Unknown Thoracic ao no
206 74 F 2020 Japan Tongue cancer Pegfilgrastim Unknown Thoracic ao no
216 65 F 2020 Japan Pancreatic cancer Pegfilgrastim Fever, chest pain ao arch, abdominal ao no
227 66 F 2020 Japan Breast cancer Pegfilgrastim Fever, malaise, abdominal discomfort ao arch, abdominal ao yes
238 52 F 2020 Finland Breast cancer Filgrastim Fever, chest pain Aorta yes
248 62 F 2020 Finland Breast cancer Filgrastim, Pegfilgrastim Fever Aorta yes
258 70 F 2020 Finland Breast cancer Lipegfilgrastim Fever Aorta, supra-aortic vessels no
268 56 F 2020 Finland Breast cancer Lipegfilgrastim Fever, neck pain, jaw pain, malaise Carotid artery, thoracic ao yes
278 53 F 2020 Finland Breast cancer Pegfilgrastim Fever, sore throat, ear ache, dyspnoea, and chest pain Aorta yes
298 40 F 2020 Finland Breast cancer Lipegfilgrastim Fever, sore throat, chest and neck pain, malaise Carotid artery yes
ao, aorta or aortic; F, female; M, male.
The figures in square brackets refer to page numbers.
a Name of the G-CSF preparations were unknown, however these were used for several days.
Electrocardiography, echocardiography, and chest radiography revealed no abnormalities that could explain the fever. Echography of the abdominal aorta revealed aortic wall thickening and a hypoechoic region around the aorta (Figure 1). Furthermore, CT revealed an increase in the soft tissue surrounding the aortic arch and abdominal aorta (Figure 2A,B). Gadolinium-enhanced magnetic resonance imaging revealed thickening of the aortic wall and enhancement of the wall and perivascular tissue (Figure 3A), and uptake was observed during 18F-fludeoxyglucose positron emission tomography (Figure 3B). These imaging findings suggested active inflammation at the lesions.
Figure 1 Imaging findings via echography of the abdominal aorta. Echography of the abdominal aorta at the level of the coeliac artery bifurcation (left: long-axis image, right: short-axis image) revealed increased brightness and thickening of the vessel wall. There was a hypoechoic region surrounding the outside of the artery (arrow), and increased blood flow was not observed. Echography helped to distinguish some lesion features (e.g. for an abscess, a tumour, and an atheroma).
Figure 2 Imaging findings via enhanced computed tomography. (A) Enhanced computed tomography (CT) findings before chemotherapy. (B) The computed tomography findings after onset (chest: early phase, abdomen: plain, early, and delay phase), which revealed enhancement of the peri-aortic tissue from the aortic arch and the abdominal aorta (vs. the pre-chemotherapy findings). There was no wall thickening in the branches of the aorta, aortic stenosis, aneurism, or dissection. (C) Enhanced computed tomography after the treatment for aortitis. The thickening around the aorta had improved after 2 weeks.
Figure 3 Imaging findings via gadolinium-enhanced magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. (A) Gadolinium-enhanced T1-weighted image revealed thickening of the vessel wall at the aortic arch and the abdominal aorta at the diaphragm (arrow). (B) Fluorodeoxyglucose positron emission tomography (18F-FDG PET) revealed FDG uptake in the aortic arch and the abdominal aorta, with a standardized uptake value (SUV) of 2–3 like that in the liver (arrow).
The patient was transferred to the cardiology department, and G-CSF-associated aortitis was suggested based on her history and clinical course (Naranjo adverse drug reaction probability scale score 7; probable). On Day 23, she was exhausted because of the persistent fever and received prednisolone treatment (PSL, 50 mg/day), which promptly resolved her symptoms. Follow-up testing revealed improvement in her CRP concentration and erythrocyte sedimentation rate (Supplementary material online, Figure S1). After 2 weeks, CT revealed an improvement in the thickening around the aorta (Figure 2C). The PSL dose was gradually reduced. This treatment was marked by the absence of recurrence of the aortitis, cancer, and infection at her 1-year follow-up.
Discussion
This case involved a patient who presented with a significant fever. Aortitis was suspected via multiple imaging modalities, and the association with G-CSF treatment was suggested based on the patient’s history and exclusion of other diseases.
Clinical course in previous cases
A PubMed search revealed 28 reported cases involving arteritis associated with G-CSF treatment (Table 2). Most cases involved fever at the onset of disease, although other symptoms (e.g. abdominal tenderness, syncope) appeared before the fever in some cases.5 In this case, PSL was started because of a high fever and malaise; however, one-half of the reported cases resolved without corticosteroids.6 In the previous cases that involved corticosteroid treatment, three cases were administered high-dose treatments (e.g. pulse methylprednisolone),4,7 and six cases involved PSL doses starting at 30–60 mg/day with gradual tapering.3,5 Early reduction of the corticosteroid may be possible because G-CSF-associated arteritis may have a relatively good prognosis compared to other arteritis.7 Nevertheless, a case that involved aortic dissection highlighted the need for careful observation.4 Some cases with G-CSF re-administration had aortitis recurrence,6 and dose reduction or change of the anti-cancer drug were needed to avoid myelosuppression.
Differential diagnosis of aortitis
Takayasu arteritis and giant cell arteritis (GCA) are immune disorders that cause large-vessel arteritis. Takayasu arteritis onset is most common among women in their 20s, and the lesions are often continuous in the aorta and its primary branches. More than 90% of patients have lesions in the aortic arch, and 40% in the abdominal aorta.9 Onset of GCA is most common among women in their 60s to 70s, and lesions are typically detected in the branches of the carotid and vertebral arteries, and other large arteries may have lesions.10 Perivascular inflammation caused by IgG4-related diseases is found in the abdominal and iliac arteries, although lesions can be present in the thoracic aorta. These lesions tend to be detected in men in their sixties.11 Other differential diagnoses include infection (bacterial, syphilis, human immunodeficiency virus, and tuberculosis), drug-induced disease,12 malignancy,13 Behçet disease, Cogan syndrome, systemic lupus erythematosus, and anti-neutrophil cytoplasmic antibody-related vasculitis (Supplementary material online, Figure S2).14 The differential diagnosis needs to be performed based on the characteristics of the diseases in addition to the imaging evaluation.
Lesions and imaging
Previous reports of G-CSF-associated arteritis indicated that most lesions were detected in the thoracic aorta (68%), especially in the arch (29%) and descending aorta (29%). However, lesions can be detected in the abdominal aorta (21%), carotid artery (25%), and subclavian artery (14%) (Table 2). Most cases involved circumferential thickening of the peri-arterial tissue, which was detected via CT. Echography was useful in guiding the diagnosis in this case, although none of the previously English reported cases involved an abdominal aorta echography. Nevertheless, an echography was used to evaluate some lesions in the temporal and carotid arteries.8
Mechanism of aortitis
The pathological mechanisms underlying G-CSF-associated arteritis are unclear. Previous reports have speculated that arteritis is related to cytokines and complex immune reactions between anti-cancer agents and G-CSF.8 In aortitis after acute aortic dissection, G-CSF may act on the arterial adventitia and invading granulocytes, which results in inflammation.15 Nevertheless, this mechanism for G-CSF-associated arteritis remains speculative.
Conclusions
Chronic inflammation can lead to a reduced nutritional status and quality of life in cancer patients, which may influence their general condition and make them unable to continue chemotherapy. When cancer patients experience persistent fever after G-CSF treatment, it is necessary to make a differential diagnosis carefully and select treatments based on the patient’s general condition as well as the prognosis of arteries.
Patient perspective
The patient was mentally exhausted before treatment. Psychiatric support also improved her mental status, despite the high dose of PSL used.
Lead author biography
Graduated from Jichi Medical University School of Medicine, Japan and worked as a general physician. In 2016, conducted clinical studies on cardiovascular risk factors among young people at Shinshu University Graduate School of Medicine. Currently working in general cardiology and preventive medicine.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
ytaa503_Supplementary_Data Click here for additional data file.
Acknowledgements
The authors thank Prof. Yasunari Fujinaga and Dr Fumihito Ichinohe, Department of Radiology, Shinshu University School of Medicine, for guidance with the imaging. The authors thank the clinical team members of Department of Cardiovascular Medicine, Shinshu University School of Medicine; Dr Shusaku Maruyama, Dr Masafumi Kanai, and Ms. Junko Iguchi.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared. | CARBOPLATIN, FILGRASTIM, PACLITAXEL | DrugsGivenReaction | CC BY-NC | 33598604 | 20,059,561 | 2021-02 |
What was the dosage of drug 'CARBOPLATIN'? | Granulocyte colony stimulating factor-associated aortitis evaluated via multiple imaging modalities including vascular echography: a case report.
Granulocyte colony stimulating factor (G-CSF) preparations are used for patients with granulocytopenia, especially to prevent febrile neutropenia. Arteritis has been recognized as a side effect of G-CSF treatment; however, there are no clear diagnostic criteria or treatment guidelines because not enough cases have been reported. Present case showed one of the diagnostic and treatment selection methods via multiple imaging modality including vascular echography.
A 52-year-old woman underwent chemotherapy for ovarian cancer and received G-CSF because of myelosuppression. The patient experienced high and remittent fever that persisted during treatment using antibiotics and acetaminophen. Enhanced computed tomography revealed thickening of the tissue around the aortic arch and abdominal aorta. Echography of the abdominal aorta revealed thickening of the wall and a hypoechoic region around the aorta. Gadolinium-enhanced magnetic resonance imaging and 18F-fludeoxyglucose positron emission tomography also revealed that the inflammation was localized to the lesion. A suspicion of G-CSF-associated aortitis was based on the patient's history and the exclusion of other diseases that might have caused the aortitis. Her condition rapidly improved after starting corticosteroid treatment.
The differential diagnosis in similar cases should consider immune diseases that cause large-vessel arteritis (Takayasu arteritis, giant cell arteritis, and another vasculitis), infection, drug-induced disease, and immunoglobulin G4-related disease. The use of different imaging modalities, including vascular echography, helped guide the diagnosis and follow-up. It is necessary to evaluate the patient's general condition before the selection of treatments.
Learning points
In patients with persistent fever and a history of granulocyte colony stimulating factor administration, aortitis should be considered in the differential diagnosis.
The arteritis localization and activity should be evaluated using multiple modalities (e.g. vascular echography, computed tomography, and magnetic resonance imaging) including neck to the pelvis to guide treatment.
The treatment including the necessity of corticosteroid therapy should be selected based on the general condition of the patients, considering that the patients are treated for cancer.
Introduction
Granulocyte colony-stimulating factor (G-CSF) preparations are used for chemotherapy-related granulocytopenia, especially to prevent febrile neutropenia. The G-CSF preparations bind to G-CSF receptors that are present on neutrophil progenitor cells in the bone marrow, which promote their differentiation into neutrophils. The clinical regimens include filgrastim, lenograstim, nartograstim, filgrastim biosimilars, and long-lasting pegylated preparations of filgrastim.1 The first report regarding G-CSF-associated aortitis was in 2004,2 and arteritis has been reported as a side effect of G-CSF treatment. However, there are no clear diagnostic criteria or treatment guidelines. Therefore, we report a case of G-CSF-associated aortitis that required careful exclusion of similar aortitis and multiple imaging modalities to support the diagnosis.
Timeline
One month before onset The 5th course of chemotherapy [paclitaxel 262 mg (180 mg/m2)/carboplatin 583 mg (target area under the concentration-time curve 6 mg min/mL)] was administered.
Two weeks before onset Myelosuppression was detected, and the granulocyte colony stimulating factor (G-CSF) was administered for the first time and continued for 3 days.
Ten days before onset The 6th course of chemotherapy was administered.
Three days before onset Myelosuppression was detected, and the G-CSF treatment was started and continued for 4 days.
Day 0 (onset) Last administration of G-CSF. The patient developed a high fever during the night.
Day 1 The patient visited an outpatient clinic and was prescribed acetaminophen and levofloxacin.
Day 4 The patient was admitted to the gynaecology department for a persistent high fever. Although the thickening around the aorta was suspected via computed tomography (CT), it was uncertain whether the inflammation was localized there, and the patient first received cefmetazole for suspected infection or febrile neutropenia.
Day 9 The antibiotic treatment was changed to piperacillin/tazobactam.
Day 16 The fever and inflammation did not improve completely. Aortitis was re-considered as a differential diagnosis of fever. An magnetic resonance imaging was performed to evaluate the aortitis.
Day 17 The patient was transferred to the cardiology department for treatment of the aortitis. Bone marrow testing was performed.
Day 23 Positron emission tomography revealed active inflammation of the aortic arch and abdominal aorta. Prednisolone (PSL) was started (50 mg/day, 1 mg/kg).
Day 24 The fever improved, and the temperature was maintained at <37.5°C.
Day 38 A CT examination revealed that the thickening around the aorta had improved. C-reactive protein concentration returned to normal.
Day 46 The PSL dose was gradually reduced.
Day 71 The patient was discharged (PSL 25 mg/day).
After 9 months The PSL dose was gradually reduced to 10 mg/day for 9 months.
After 1 year No episode of infection, and no recurrence of aortitis and cancer. The patient is almost free from the PSL.
Case presentation
A 52-year-old woman underwent six courses of post-operative chemotherapy (paclitaxel 262 mg/carboplatin 583 mg) for ovarian cancer. Myelosuppression was detected after the 5th and 6th chemotherapy courses, which prompted G-CSF treatment (filgrastim, 75 μg/day). The patient developed a high fever after the last G-CSF administration and was admitted 4 days later in the gynaecology department. Negative bacterial, fungal, and viral test results were observed, and a broad-spectrum antibiotic treatment did not completely improve her condition. Aortitis was suspected based on enhanced computed tomography (CT) findings, and she was referred to our cardiology department.
Her peripheral arterial oxygen saturation was 96% (room air), body temperature was 38.0˚C with remittent fever, blood pressure was 92/50 mmHg, and bilateral pulse was 70 beats/min. The head and neck had no bruit or tenderness, and the patient reported no visual deterioration or diplopia. Chest auscultation was clear, and cardiac auscultation revealed normal S1 and S2 with no S3 or murmurs. There were no abdominal abnormalities or notable skin lesions and swelling on the extremities. Her medical history included pulmonary embolism and deep vein thrombosis that had been controlled using anticoagulant medication.
Table 1 shows the patient’s laboratory findings on admission, which included an elevated C-reactive protein concentration (CRP). Although the white blood cell count (WBC) slightly elevated on admission, it gradually decreased to 1400/μL (normal range 3300–8600). Decreasing of the platelet counts and normocytic anaemia were also observed. Bone marrow tests showed that the three lineages of haematopoietic cells were retained, and there was no increase in blasts or morphological abnormalities.
Table 1 Laboratory findings on admission (Day 4)
WBC 8780/μL (3300–8600) MMP-3 103.8 ng/mL (17.3–59.7)
Neut 76.0% (41.8–75.0) ESR 1.0hr >140 mm/h (3.0–15.0)
Lymph 15.7% (18.5–48.7) sIL-2R 584 U/mL (140–394)
Mono 8.1% (2.2–7.9) Ferritin 883 ng/mL (10.0–120.0)
Eo 0.1% (0.4–8.7) STS Negative
RBC 2.14 × 104/μL (3.86–4.92) TPAb Negative
Hb 7.2 g/dL (11.6–14.8) TbIFN-γ Negative
HCT 22.2% (35.1–44.4) β-D glucan <2.50 pg/mL (−10.99)
Plt 7.0 × 104/μL (15.8–34.8) PCT 0.15 ng/mL (0.00–0.49)
MCV 103.7 fL (83.6–98.2) MPO-ANCA <1.0 U/mL (−3.4)
MCH 33.6 pg (27.5–33.2) PR3-ANCA <1.0 U/mL (−3.4)
MCHC 32.4% (31.7–35.3) IgA 240 mg/dL (93–393)
TP 7.0 g/dL (6.6–8.1) IgM 74 mg/dL (50–269)
Alb 3.5 g/dL (4.1–5.1) IgG 1468 mg/dL (861–1747)
UN 12.6 mg/dL (8.0–20.0) IgG4 21 mg/dL (−134)
Cr 0.80 mg/dL (0.46–0.79) C3 164 mg/dL (73–138)
eGFR 59 mL/min/1.73 m2 C4 31.8 mg/dL (11.0–31.0)
LDH 170 U/L (124–222) CH50 77.1 U/mL (30.0–53.0)
Na 140 mEq/L (138–145) RF 3 U/mL (0–14)
K 3.8 mEq/L (3.6–4.8) FANA Negative
Cl 107 mEq/L (101–108) APTT 29.9 sec (23.0–38.0)
CRP 19.39 mg/dL (0.00–0.14) PT-INR 1.15 (0.85–1.15)
Anti SS-A/Ro antibody, anti SS-B/La antibodies, anti Sm antibodies, anti-double strand-DNA antibodies, anti-RNP antibodies were all negative. ESR is the data of Day 24. Normal ranges are shown in brackets.
Alb, albumin; APTT, activated partial thromboplastin time; C3, complement component 3; C4, complement component 4; CH50, 50% haemolytic complement activity; Cl, chlorine; Cr, creatinine; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; Eo, eosinophil; ESR, erythrocyte sedimentation rate; FANA, fluorescent anti-nuclear antibodies; Hb, haemoglobin; HCT, haematocrit; Ig, immunoglobulin; K, potassium; Lymph, lymphocyte; MCH, mean corpuscular haemoglobin; MCHC, mean corpuscular haemoglobin concentration; MCV, mean corpuscular volume; MMP-3, matrix metalloproteinase-3; Mono, monocyte; MPO-ANCA, myeloperoxidase-anti-neutrophil cytoplasmic antibody; Na, sodium; Neut, neutrophil; PCT, procalcitonin; Plt, platelet; PR3-ANCA, serine proteinase3-anti-neutrophil cytoplasmic antibody; PT-INR, international normalized ratio of prothrombin time; RBC, red blood cell; RF, rheumatoid factor; sIL-2, soluble interleukin-2 receptor; STS, serologic test for syphilis; Tb-INF, tuberculosis interferon-gamma; TP, total protein; TPAb, treponema pallidum antibodies; UN, urea nitrogen; WBC, white blood cell.
Table 2 Previously reported cases
No Age Sex Year Nationality Background disease G-CSF Symptoms Lesions Glucocorticoid treatment
12 55 F 2004 France Stem cell donor Filgrastim Fever, abdominal and lumbar pain, vomiting Descending ao, abdominal ao yes
2 54 M 2009 US Lung cancer
a
Fever, epigastric tenderness Abdominal ao no
33 52 M 2016 Israel Healthy donor Filgrastim Weight loss, back pain, constipation Abdominal ao, iliac artery yes
4 78 F 2016 Japan Cyclic neutropenia Filgrastim Fever, head ache, jaw claudication, visual abnormality Temporal arteries yes
5 59 F 2017 Japan Lymphoma Pegfilgrastim Neck and chest pain, fever Carotid artery, subclavian artery, ao arch, descending ao yes
6 61 F 2017 Japan Ovarian cancer Lenograstim Fever Carotid artery no
74 67 F 2017 Japan Lung cancer Pegfilgrastim Malaise and fever Carotid artery, thoracic ao yes
8 61 F 2018 Japan Breast cancer Pegfilgrastim Neck and chest pain → fever Carotid artery, thoracic ao no
9 47 F 2018 Japan Ovarian cancer
a
Fever ao arch, descending ao yes
10 71 F 2019 Japan Endometrial cancer Pegfilgrastim Fever ao arch, descending ao yes
11 72 F 2019 Japan Lymphoma Pegfilgrastim Fever, chest pain ao arch no
12 62 F 2019 Japan Lymphoma Pegfilgrastim Fever, chest pain Descending ao yes
13 69 M 2019 Japan Lymphoma Pegfilgrastim Fever Subclavian artery unknown
14 77 F 2019 Japan Ovarian cancer
a
Fever Carotid artery, subclavian artery no
155 60 F 2019 Sweden Breast cancer Filgrastim Abdominal tenderness → fever Subclavian artery, ao arch, descending ao, abdominal ao yes
165 70 F 2019 Sweden Breast cancer
a
Syncope, diarrhoea, dehydration → fever Thoracic ao, brachiocephalic trunk yes
17 72 F 2019 Japan Breast cancer Pegfilgrastim Fever Descending ao no
186 43 F 2020 Japan Uterine cancer Pegfilgrastim Unknown Thoracic ao no
196 47 F 2020 Japan Uterine cancer Pegfilgrastim Unknown Thoracic ao no
206 74 F 2020 Japan Tongue cancer Pegfilgrastim Unknown Thoracic ao no
216 65 F 2020 Japan Pancreatic cancer Pegfilgrastim Fever, chest pain ao arch, abdominal ao no
227 66 F 2020 Japan Breast cancer Pegfilgrastim Fever, malaise, abdominal discomfort ao arch, abdominal ao yes
238 52 F 2020 Finland Breast cancer Filgrastim Fever, chest pain Aorta yes
248 62 F 2020 Finland Breast cancer Filgrastim, Pegfilgrastim Fever Aorta yes
258 70 F 2020 Finland Breast cancer Lipegfilgrastim Fever Aorta, supra-aortic vessels no
268 56 F 2020 Finland Breast cancer Lipegfilgrastim Fever, neck pain, jaw pain, malaise Carotid artery, thoracic ao yes
278 53 F 2020 Finland Breast cancer Pegfilgrastim Fever, sore throat, ear ache, dyspnoea, and chest pain Aorta yes
298 40 F 2020 Finland Breast cancer Lipegfilgrastim Fever, sore throat, chest and neck pain, malaise Carotid artery yes
ao, aorta or aortic; F, female; M, male.
The figures in square brackets refer to page numbers.
a Name of the G-CSF preparations were unknown, however these were used for several days.
Electrocardiography, echocardiography, and chest radiography revealed no abnormalities that could explain the fever. Echography of the abdominal aorta revealed aortic wall thickening and a hypoechoic region around the aorta (Figure 1). Furthermore, CT revealed an increase in the soft tissue surrounding the aortic arch and abdominal aorta (Figure 2A,B). Gadolinium-enhanced magnetic resonance imaging revealed thickening of the aortic wall and enhancement of the wall and perivascular tissue (Figure 3A), and uptake was observed during 18F-fludeoxyglucose positron emission tomography (Figure 3B). These imaging findings suggested active inflammation at the lesions.
Figure 1 Imaging findings via echography of the abdominal aorta. Echography of the abdominal aorta at the level of the coeliac artery bifurcation (left: long-axis image, right: short-axis image) revealed increased brightness and thickening of the vessel wall. There was a hypoechoic region surrounding the outside of the artery (arrow), and increased blood flow was not observed. Echography helped to distinguish some lesion features (e.g. for an abscess, a tumour, and an atheroma).
Figure 2 Imaging findings via enhanced computed tomography. (A) Enhanced computed tomography (CT) findings before chemotherapy. (B) The computed tomography findings after onset (chest: early phase, abdomen: plain, early, and delay phase), which revealed enhancement of the peri-aortic tissue from the aortic arch and the abdominal aorta (vs. the pre-chemotherapy findings). There was no wall thickening in the branches of the aorta, aortic stenosis, aneurism, or dissection. (C) Enhanced computed tomography after the treatment for aortitis. The thickening around the aorta had improved after 2 weeks.
Figure 3 Imaging findings via gadolinium-enhanced magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. (A) Gadolinium-enhanced T1-weighted image revealed thickening of the vessel wall at the aortic arch and the abdominal aorta at the diaphragm (arrow). (B) Fluorodeoxyglucose positron emission tomography (18F-FDG PET) revealed FDG uptake in the aortic arch and the abdominal aorta, with a standardized uptake value (SUV) of 2–3 like that in the liver (arrow).
The patient was transferred to the cardiology department, and G-CSF-associated aortitis was suggested based on her history and clinical course (Naranjo adverse drug reaction probability scale score 7; probable). On Day 23, she was exhausted because of the persistent fever and received prednisolone treatment (PSL, 50 mg/day), which promptly resolved her symptoms. Follow-up testing revealed improvement in her CRP concentration and erythrocyte sedimentation rate (Supplementary material online, Figure S1). After 2 weeks, CT revealed an improvement in the thickening around the aorta (Figure 2C). The PSL dose was gradually reduced. This treatment was marked by the absence of recurrence of the aortitis, cancer, and infection at her 1-year follow-up.
Discussion
This case involved a patient who presented with a significant fever. Aortitis was suspected via multiple imaging modalities, and the association with G-CSF treatment was suggested based on the patient’s history and exclusion of other diseases.
Clinical course in previous cases
A PubMed search revealed 28 reported cases involving arteritis associated with G-CSF treatment (Table 2). Most cases involved fever at the onset of disease, although other symptoms (e.g. abdominal tenderness, syncope) appeared before the fever in some cases.5 In this case, PSL was started because of a high fever and malaise; however, one-half of the reported cases resolved without corticosteroids.6 In the previous cases that involved corticosteroid treatment, three cases were administered high-dose treatments (e.g. pulse methylprednisolone),4,7 and six cases involved PSL doses starting at 30–60 mg/day with gradual tapering.3,5 Early reduction of the corticosteroid may be possible because G-CSF-associated arteritis may have a relatively good prognosis compared to other arteritis.7 Nevertheless, a case that involved aortic dissection highlighted the need for careful observation.4 Some cases with G-CSF re-administration had aortitis recurrence,6 and dose reduction or change of the anti-cancer drug were needed to avoid myelosuppression.
Differential diagnosis of aortitis
Takayasu arteritis and giant cell arteritis (GCA) are immune disorders that cause large-vessel arteritis. Takayasu arteritis onset is most common among women in their 20s, and the lesions are often continuous in the aorta and its primary branches. More than 90% of patients have lesions in the aortic arch, and 40% in the abdominal aorta.9 Onset of GCA is most common among women in their 60s to 70s, and lesions are typically detected in the branches of the carotid and vertebral arteries, and other large arteries may have lesions.10 Perivascular inflammation caused by IgG4-related diseases is found in the abdominal and iliac arteries, although lesions can be present in the thoracic aorta. These lesions tend to be detected in men in their sixties.11 Other differential diagnoses include infection (bacterial, syphilis, human immunodeficiency virus, and tuberculosis), drug-induced disease,12 malignancy,13 Behçet disease, Cogan syndrome, systemic lupus erythematosus, and anti-neutrophil cytoplasmic antibody-related vasculitis (Supplementary material online, Figure S2).14 The differential diagnosis needs to be performed based on the characteristics of the diseases in addition to the imaging evaluation.
Lesions and imaging
Previous reports of G-CSF-associated arteritis indicated that most lesions were detected in the thoracic aorta (68%), especially in the arch (29%) and descending aorta (29%). However, lesions can be detected in the abdominal aorta (21%), carotid artery (25%), and subclavian artery (14%) (Table 2). Most cases involved circumferential thickening of the peri-arterial tissue, which was detected via CT. Echography was useful in guiding the diagnosis in this case, although none of the previously English reported cases involved an abdominal aorta echography. Nevertheless, an echography was used to evaluate some lesions in the temporal and carotid arteries.8
Mechanism of aortitis
The pathological mechanisms underlying G-CSF-associated arteritis are unclear. Previous reports have speculated that arteritis is related to cytokines and complex immune reactions between anti-cancer agents and G-CSF.8 In aortitis after acute aortic dissection, G-CSF may act on the arterial adventitia and invading granulocytes, which results in inflammation.15 Nevertheless, this mechanism for G-CSF-associated arteritis remains speculative.
Conclusions
Chronic inflammation can lead to a reduced nutritional status and quality of life in cancer patients, which may influence their general condition and make them unable to continue chemotherapy. When cancer patients experience persistent fever after G-CSF treatment, it is necessary to make a differential diagnosis carefully and select treatments based on the patient’s general condition as well as the prognosis of arteries.
Patient perspective
The patient was mentally exhausted before treatment. Psychiatric support also improved her mental status, despite the high dose of PSL used.
Lead author biography
Graduated from Jichi Medical University School of Medicine, Japan and worked as a general physician. In 2016, conducted clinical studies on cardiovascular risk factors among young people at Shinshu University Graduate School of Medicine. Currently working in general cardiology and preventive medicine.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
ytaa503_Supplementary_Data Click here for additional data file.
Acknowledgements
The authors thank Prof. Yasunari Fujinaga and Dr Fumihito Ichinohe, Department of Radiology, Shinshu University School of Medicine, for guidance with the imaging. The authors thank the clinical team members of Department of Cardiovascular Medicine, Shinshu University School of Medicine; Dr Shusaku Maruyama, Dr Masafumi Kanai, and Ms. Junko Iguchi.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared. | 583 MG (TARGET AREA UNDER THE CONCENTRATION- TIME CURVE 6 MG MIN/ML) | DrugDosageText | CC BY-NC | 33598604 | 20,059,561 | 2021-02 |
What was the outcome of reaction 'Aortitis'? | Granulocyte colony stimulating factor-associated aortitis evaluated via multiple imaging modalities including vascular echography: a case report.
Granulocyte colony stimulating factor (G-CSF) preparations are used for patients with granulocytopenia, especially to prevent febrile neutropenia. Arteritis has been recognized as a side effect of G-CSF treatment; however, there are no clear diagnostic criteria or treatment guidelines because not enough cases have been reported. Present case showed one of the diagnostic and treatment selection methods via multiple imaging modality including vascular echography.
A 52-year-old woman underwent chemotherapy for ovarian cancer and received G-CSF because of myelosuppression. The patient experienced high and remittent fever that persisted during treatment using antibiotics and acetaminophen. Enhanced computed tomography revealed thickening of the tissue around the aortic arch and abdominal aorta. Echography of the abdominal aorta revealed thickening of the wall and a hypoechoic region around the aorta. Gadolinium-enhanced magnetic resonance imaging and 18F-fludeoxyglucose positron emission tomography also revealed that the inflammation was localized to the lesion. A suspicion of G-CSF-associated aortitis was based on the patient's history and the exclusion of other diseases that might have caused the aortitis. Her condition rapidly improved after starting corticosteroid treatment.
The differential diagnosis in similar cases should consider immune diseases that cause large-vessel arteritis (Takayasu arteritis, giant cell arteritis, and another vasculitis), infection, drug-induced disease, and immunoglobulin G4-related disease. The use of different imaging modalities, including vascular echography, helped guide the diagnosis and follow-up. It is necessary to evaluate the patient's general condition before the selection of treatments.
Learning points
In patients with persistent fever and a history of granulocyte colony stimulating factor administration, aortitis should be considered in the differential diagnosis.
The arteritis localization and activity should be evaluated using multiple modalities (e.g. vascular echography, computed tomography, and magnetic resonance imaging) including neck to the pelvis to guide treatment.
The treatment including the necessity of corticosteroid therapy should be selected based on the general condition of the patients, considering that the patients are treated for cancer.
Introduction
Granulocyte colony-stimulating factor (G-CSF) preparations are used for chemotherapy-related granulocytopenia, especially to prevent febrile neutropenia. The G-CSF preparations bind to G-CSF receptors that are present on neutrophil progenitor cells in the bone marrow, which promote their differentiation into neutrophils. The clinical regimens include filgrastim, lenograstim, nartograstim, filgrastim biosimilars, and long-lasting pegylated preparations of filgrastim.1 The first report regarding G-CSF-associated aortitis was in 2004,2 and arteritis has been reported as a side effect of G-CSF treatment. However, there are no clear diagnostic criteria or treatment guidelines. Therefore, we report a case of G-CSF-associated aortitis that required careful exclusion of similar aortitis and multiple imaging modalities to support the diagnosis.
Timeline
One month before onset The 5th course of chemotherapy [paclitaxel 262 mg (180 mg/m2)/carboplatin 583 mg (target area under the concentration-time curve 6 mg min/mL)] was administered.
Two weeks before onset Myelosuppression was detected, and the granulocyte colony stimulating factor (G-CSF) was administered for the first time and continued for 3 days.
Ten days before onset The 6th course of chemotherapy was administered.
Three days before onset Myelosuppression was detected, and the G-CSF treatment was started and continued for 4 days.
Day 0 (onset) Last administration of G-CSF. The patient developed a high fever during the night.
Day 1 The patient visited an outpatient clinic and was prescribed acetaminophen and levofloxacin.
Day 4 The patient was admitted to the gynaecology department for a persistent high fever. Although the thickening around the aorta was suspected via computed tomography (CT), it was uncertain whether the inflammation was localized there, and the patient first received cefmetazole for suspected infection or febrile neutropenia.
Day 9 The antibiotic treatment was changed to piperacillin/tazobactam.
Day 16 The fever and inflammation did not improve completely. Aortitis was re-considered as a differential diagnosis of fever. An magnetic resonance imaging was performed to evaluate the aortitis.
Day 17 The patient was transferred to the cardiology department for treatment of the aortitis. Bone marrow testing was performed.
Day 23 Positron emission tomography revealed active inflammation of the aortic arch and abdominal aorta. Prednisolone (PSL) was started (50 mg/day, 1 mg/kg).
Day 24 The fever improved, and the temperature was maintained at <37.5°C.
Day 38 A CT examination revealed that the thickening around the aorta had improved. C-reactive protein concentration returned to normal.
Day 46 The PSL dose was gradually reduced.
Day 71 The patient was discharged (PSL 25 mg/day).
After 9 months The PSL dose was gradually reduced to 10 mg/day for 9 months.
After 1 year No episode of infection, and no recurrence of aortitis and cancer. The patient is almost free from the PSL.
Case presentation
A 52-year-old woman underwent six courses of post-operative chemotherapy (paclitaxel 262 mg/carboplatin 583 mg) for ovarian cancer. Myelosuppression was detected after the 5th and 6th chemotherapy courses, which prompted G-CSF treatment (filgrastim, 75 μg/day). The patient developed a high fever after the last G-CSF administration and was admitted 4 days later in the gynaecology department. Negative bacterial, fungal, and viral test results were observed, and a broad-spectrum antibiotic treatment did not completely improve her condition. Aortitis was suspected based on enhanced computed tomography (CT) findings, and she was referred to our cardiology department.
Her peripheral arterial oxygen saturation was 96% (room air), body temperature was 38.0˚C with remittent fever, blood pressure was 92/50 mmHg, and bilateral pulse was 70 beats/min. The head and neck had no bruit or tenderness, and the patient reported no visual deterioration or diplopia. Chest auscultation was clear, and cardiac auscultation revealed normal S1 and S2 with no S3 or murmurs. There were no abdominal abnormalities or notable skin lesions and swelling on the extremities. Her medical history included pulmonary embolism and deep vein thrombosis that had been controlled using anticoagulant medication.
Table 1 shows the patient’s laboratory findings on admission, which included an elevated C-reactive protein concentration (CRP). Although the white blood cell count (WBC) slightly elevated on admission, it gradually decreased to 1400/μL (normal range 3300–8600). Decreasing of the platelet counts and normocytic anaemia were also observed. Bone marrow tests showed that the three lineages of haematopoietic cells were retained, and there was no increase in blasts or morphological abnormalities.
Table 1 Laboratory findings on admission (Day 4)
WBC 8780/μL (3300–8600) MMP-3 103.8 ng/mL (17.3–59.7)
Neut 76.0% (41.8–75.0) ESR 1.0hr >140 mm/h (3.0–15.0)
Lymph 15.7% (18.5–48.7) sIL-2R 584 U/mL (140–394)
Mono 8.1% (2.2–7.9) Ferritin 883 ng/mL (10.0–120.0)
Eo 0.1% (0.4–8.7) STS Negative
RBC 2.14 × 104/μL (3.86–4.92) TPAb Negative
Hb 7.2 g/dL (11.6–14.8) TbIFN-γ Negative
HCT 22.2% (35.1–44.4) β-D glucan <2.50 pg/mL (−10.99)
Plt 7.0 × 104/μL (15.8–34.8) PCT 0.15 ng/mL (0.00–0.49)
MCV 103.7 fL (83.6–98.2) MPO-ANCA <1.0 U/mL (−3.4)
MCH 33.6 pg (27.5–33.2) PR3-ANCA <1.0 U/mL (−3.4)
MCHC 32.4% (31.7–35.3) IgA 240 mg/dL (93–393)
TP 7.0 g/dL (6.6–8.1) IgM 74 mg/dL (50–269)
Alb 3.5 g/dL (4.1–5.1) IgG 1468 mg/dL (861–1747)
UN 12.6 mg/dL (8.0–20.0) IgG4 21 mg/dL (−134)
Cr 0.80 mg/dL (0.46–0.79) C3 164 mg/dL (73–138)
eGFR 59 mL/min/1.73 m2 C4 31.8 mg/dL (11.0–31.0)
LDH 170 U/L (124–222) CH50 77.1 U/mL (30.0–53.0)
Na 140 mEq/L (138–145) RF 3 U/mL (0–14)
K 3.8 mEq/L (3.6–4.8) FANA Negative
Cl 107 mEq/L (101–108) APTT 29.9 sec (23.0–38.0)
CRP 19.39 mg/dL (0.00–0.14) PT-INR 1.15 (0.85–1.15)
Anti SS-A/Ro antibody, anti SS-B/La antibodies, anti Sm antibodies, anti-double strand-DNA antibodies, anti-RNP antibodies were all negative. ESR is the data of Day 24. Normal ranges are shown in brackets.
Alb, albumin; APTT, activated partial thromboplastin time; C3, complement component 3; C4, complement component 4; CH50, 50% haemolytic complement activity; Cl, chlorine; Cr, creatinine; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; Eo, eosinophil; ESR, erythrocyte sedimentation rate; FANA, fluorescent anti-nuclear antibodies; Hb, haemoglobin; HCT, haematocrit; Ig, immunoglobulin; K, potassium; Lymph, lymphocyte; MCH, mean corpuscular haemoglobin; MCHC, mean corpuscular haemoglobin concentration; MCV, mean corpuscular volume; MMP-3, matrix metalloproteinase-3; Mono, monocyte; MPO-ANCA, myeloperoxidase-anti-neutrophil cytoplasmic antibody; Na, sodium; Neut, neutrophil; PCT, procalcitonin; Plt, platelet; PR3-ANCA, serine proteinase3-anti-neutrophil cytoplasmic antibody; PT-INR, international normalized ratio of prothrombin time; RBC, red blood cell; RF, rheumatoid factor; sIL-2, soluble interleukin-2 receptor; STS, serologic test for syphilis; Tb-INF, tuberculosis interferon-gamma; TP, total protein; TPAb, treponema pallidum antibodies; UN, urea nitrogen; WBC, white blood cell.
Table 2 Previously reported cases
No Age Sex Year Nationality Background disease G-CSF Symptoms Lesions Glucocorticoid treatment
12 55 F 2004 France Stem cell donor Filgrastim Fever, abdominal and lumbar pain, vomiting Descending ao, abdominal ao yes
2 54 M 2009 US Lung cancer
a
Fever, epigastric tenderness Abdominal ao no
33 52 M 2016 Israel Healthy donor Filgrastim Weight loss, back pain, constipation Abdominal ao, iliac artery yes
4 78 F 2016 Japan Cyclic neutropenia Filgrastim Fever, head ache, jaw claudication, visual abnormality Temporal arteries yes
5 59 F 2017 Japan Lymphoma Pegfilgrastim Neck and chest pain, fever Carotid artery, subclavian artery, ao arch, descending ao yes
6 61 F 2017 Japan Ovarian cancer Lenograstim Fever Carotid artery no
74 67 F 2017 Japan Lung cancer Pegfilgrastim Malaise and fever Carotid artery, thoracic ao yes
8 61 F 2018 Japan Breast cancer Pegfilgrastim Neck and chest pain → fever Carotid artery, thoracic ao no
9 47 F 2018 Japan Ovarian cancer
a
Fever ao arch, descending ao yes
10 71 F 2019 Japan Endometrial cancer Pegfilgrastim Fever ao arch, descending ao yes
11 72 F 2019 Japan Lymphoma Pegfilgrastim Fever, chest pain ao arch no
12 62 F 2019 Japan Lymphoma Pegfilgrastim Fever, chest pain Descending ao yes
13 69 M 2019 Japan Lymphoma Pegfilgrastim Fever Subclavian artery unknown
14 77 F 2019 Japan Ovarian cancer
a
Fever Carotid artery, subclavian artery no
155 60 F 2019 Sweden Breast cancer Filgrastim Abdominal tenderness → fever Subclavian artery, ao arch, descending ao, abdominal ao yes
165 70 F 2019 Sweden Breast cancer
a
Syncope, diarrhoea, dehydration → fever Thoracic ao, brachiocephalic trunk yes
17 72 F 2019 Japan Breast cancer Pegfilgrastim Fever Descending ao no
186 43 F 2020 Japan Uterine cancer Pegfilgrastim Unknown Thoracic ao no
196 47 F 2020 Japan Uterine cancer Pegfilgrastim Unknown Thoracic ao no
206 74 F 2020 Japan Tongue cancer Pegfilgrastim Unknown Thoracic ao no
216 65 F 2020 Japan Pancreatic cancer Pegfilgrastim Fever, chest pain ao arch, abdominal ao no
227 66 F 2020 Japan Breast cancer Pegfilgrastim Fever, malaise, abdominal discomfort ao arch, abdominal ao yes
238 52 F 2020 Finland Breast cancer Filgrastim Fever, chest pain Aorta yes
248 62 F 2020 Finland Breast cancer Filgrastim, Pegfilgrastim Fever Aorta yes
258 70 F 2020 Finland Breast cancer Lipegfilgrastim Fever Aorta, supra-aortic vessels no
268 56 F 2020 Finland Breast cancer Lipegfilgrastim Fever, neck pain, jaw pain, malaise Carotid artery, thoracic ao yes
278 53 F 2020 Finland Breast cancer Pegfilgrastim Fever, sore throat, ear ache, dyspnoea, and chest pain Aorta yes
298 40 F 2020 Finland Breast cancer Lipegfilgrastim Fever, sore throat, chest and neck pain, malaise Carotid artery yes
ao, aorta or aortic; F, female; M, male.
The figures in square brackets refer to page numbers.
a Name of the G-CSF preparations were unknown, however these were used for several days.
Electrocardiography, echocardiography, and chest radiography revealed no abnormalities that could explain the fever. Echography of the abdominal aorta revealed aortic wall thickening and a hypoechoic region around the aorta (Figure 1). Furthermore, CT revealed an increase in the soft tissue surrounding the aortic arch and abdominal aorta (Figure 2A,B). Gadolinium-enhanced magnetic resonance imaging revealed thickening of the aortic wall and enhancement of the wall and perivascular tissue (Figure 3A), and uptake was observed during 18F-fludeoxyglucose positron emission tomography (Figure 3B). These imaging findings suggested active inflammation at the lesions.
Figure 1 Imaging findings via echography of the abdominal aorta. Echography of the abdominal aorta at the level of the coeliac artery bifurcation (left: long-axis image, right: short-axis image) revealed increased brightness and thickening of the vessel wall. There was a hypoechoic region surrounding the outside of the artery (arrow), and increased blood flow was not observed. Echography helped to distinguish some lesion features (e.g. for an abscess, a tumour, and an atheroma).
Figure 2 Imaging findings via enhanced computed tomography. (A) Enhanced computed tomography (CT) findings before chemotherapy. (B) The computed tomography findings after onset (chest: early phase, abdomen: plain, early, and delay phase), which revealed enhancement of the peri-aortic tissue from the aortic arch and the abdominal aorta (vs. the pre-chemotherapy findings). There was no wall thickening in the branches of the aorta, aortic stenosis, aneurism, or dissection. (C) Enhanced computed tomography after the treatment for aortitis. The thickening around the aorta had improved after 2 weeks.
Figure 3 Imaging findings via gadolinium-enhanced magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. (A) Gadolinium-enhanced T1-weighted image revealed thickening of the vessel wall at the aortic arch and the abdominal aorta at the diaphragm (arrow). (B) Fluorodeoxyglucose positron emission tomography (18F-FDG PET) revealed FDG uptake in the aortic arch and the abdominal aorta, with a standardized uptake value (SUV) of 2–3 like that in the liver (arrow).
The patient was transferred to the cardiology department, and G-CSF-associated aortitis was suggested based on her history and clinical course (Naranjo adverse drug reaction probability scale score 7; probable). On Day 23, she was exhausted because of the persistent fever and received prednisolone treatment (PSL, 50 mg/day), which promptly resolved her symptoms. Follow-up testing revealed improvement in her CRP concentration and erythrocyte sedimentation rate (Supplementary material online, Figure S1). After 2 weeks, CT revealed an improvement in the thickening around the aorta (Figure 2C). The PSL dose was gradually reduced. This treatment was marked by the absence of recurrence of the aortitis, cancer, and infection at her 1-year follow-up.
Discussion
This case involved a patient who presented with a significant fever. Aortitis was suspected via multiple imaging modalities, and the association with G-CSF treatment was suggested based on the patient’s history and exclusion of other diseases.
Clinical course in previous cases
A PubMed search revealed 28 reported cases involving arteritis associated with G-CSF treatment (Table 2). Most cases involved fever at the onset of disease, although other symptoms (e.g. abdominal tenderness, syncope) appeared before the fever in some cases.5 In this case, PSL was started because of a high fever and malaise; however, one-half of the reported cases resolved without corticosteroids.6 In the previous cases that involved corticosteroid treatment, three cases were administered high-dose treatments (e.g. pulse methylprednisolone),4,7 and six cases involved PSL doses starting at 30–60 mg/day with gradual tapering.3,5 Early reduction of the corticosteroid may be possible because G-CSF-associated arteritis may have a relatively good prognosis compared to other arteritis.7 Nevertheless, a case that involved aortic dissection highlighted the need for careful observation.4 Some cases with G-CSF re-administration had aortitis recurrence,6 and dose reduction or change of the anti-cancer drug were needed to avoid myelosuppression.
Differential diagnosis of aortitis
Takayasu arteritis and giant cell arteritis (GCA) are immune disorders that cause large-vessel arteritis. Takayasu arteritis onset is most common among women in their 20s, and the lesions are often continuous in the aorta and its primary branches. More than 90% of patients have lesions in the aortic arch, and 40% in the abdominal aorta.9 Onset of GCA is most common among women in their 60s to 70s, and lesions are typically detected in the branches of the carotid and vertebral arteries, and other large arteries may have lesions.10 Perivascular inflammation caused by IgG4-related diseases is found in the abdominal and iliac arteries, although lesions can be present in the thoracic aorta. These lesions tend to be detected in men in their sixties.11 Other differential diagnoses include infection (bacterial, syphilis, human immunodeficiency virus, and tuberculosis), drug-induced disease,12 malignancy,13 Behçet disease, Cogan syndrome, systemic lupus erythematosus, and anti-neutrophil cytoplasmic antibody-related vasculitis (Supplementary material online, Figure S2).14 The differential diagnosis needs to be performed based on the characteristics of the diseases in addition to the imaging evaluation.
Lesions and imaging
Previous reports of G-CSF-associated arteritis indicated that most lesions were detected in the thoracic aorta (68%), especially in the arch (29%) and descending aorta (29%). However, lesions can be detected in the abdominal aorta (21%), carotid artery (25%), and subclavian artery (14%) (Table 2). Most cases involved circumferential thickening of the peri-arterial tissue, which was detected via CT. Echography was useful in guiding the diagnosis in this case, although none of the previously English reported cases involved an abdominal aorta echography. Nevertheless, an echography was used to evaluate some lesions in the temporal and carotid arteries.8
Mechanism of aortitis
The pathological mechanisms underlying G-CSF-associated arteritis are unclear. Previous reports have speculated that arteritis is related to cytokines and complex immune reactions between anti-cancer agents and G-CSF.8 In aortitis after acute aortic dissection, G-CSF may act on the arterial adventitia and invading granulocytes, which results in inflammation.15 Nevertheless, this mechanism for G-CSF-associated arteritis remains speculative.
Conclusions
Chronic inflammation can lead to a reduced nutritional status and quality of life in cancer patients, which may influence their general condition and make them unable to continue chemotherapy. When cancer patients experience persistent fever after G-CSF treatment, it is necessary to make a differential diagnosis carefully and select treatments based on the patient’s general condition as well as the prognosis of arteries.
Patient perspective
The patient was mentally exhausted before treatment. Psychiatric support also improved her mental status, despite the high dose of PSL used.
Lead author biography
Graduated from Jichi Medical University School of Medicine, Japan and worked as a general physician. In 2016, conducted clinical studies on cardiovascular risk factors among young people at Shinshu University Graduate School of Medicine. Currently working in general cardiology and preventive medicine.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
ytaa503_Supplementary_Data Click here for additional data file.
Acknowledgements
The authors thank Prof. Yasunari Fujinaga and Dr Fumihito Ichinohe, Department of Radiology, Shinshu University School of Medicine, for guidance with the imaging. The authors thank the clinical team members of Department of Cardiovascular Medicine, Shinshu University School of Medicine; Dr Shusaku Maruyama, Dr Masafumi Kanai, and Ms. Junko Iguchi.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared. | Recovered | ReactionOutcome | CC BY-NC | 33598604 | 20,059,561 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac ventricular thrombosis'. | 'The bubble heart': an unusual natural history told by multimodality imaging- a case report.
Intracardiac thrombosis is a relatively common pathological condition. Often, it is diagnosed at echocardiography during the subacute or chronic phase. In the very acute phase, tissue composition can make thrombus appearance very different from that usually seen. Fresh thrombosis has been previously found also in peripartum cardiomyopathy (PPC), but with imaging features different from our case.
A 27-year-old woman was referred to our hospital for PPC, with echocardiographic finding of intraventricular masses, resembling big bubbles. Cardiac magnetic resonance (CMR) allowed definitively diagnosing intracardiac 'very acute' thrombosis, which is rarely detected.
Our case provides a practical lesson about management of an unusual presentation of a common problem. When early echocardiography does not allow making a certain diagnosis, CMR can be helpful and decisive, due to its unique ability to provide characterization of intracardiac masses.
Learning points
Fresh thrombi can show a cystic appearance, with echo-lucent centre and hyperechoic boundaries.
They appear hypoperfused at the first pass sequences and look very dark in early enhancement sequences.
Fresh thrombi appear hyperintense in T1 and T2-weighted sequences, depending on presence of oxyhaemoglobin and slowly flowing blood.
Introduction
Intracardiac thrombosis is reported in up to 53% of peripartum cardiomyopathy (PPC), due to the peculiar hypercoagulability state.1 Early certain diagnosis allows promptly starting anticoagulation therapy, but during the very acute phase it can be challenging, because of the unusual appearance of thrombi as ‘bubbles’ or ‘cysts’, as compared to the more widely codified features of high or mid-echo-density masses.2 Indeed, very acute fresh thrombosis may appear at echocardiography as mass with a relatively echo-lucent centre and hyperechoic boundaries between fluid and more organized regions.3 Its diagnosis may be confirmed by cardiac magnetic resonance (CMR).4
Timeline
Delivery after a normal pregnancy
8 weeks after delivery Onset and worsening of dyspnoea
Admission, Day 0 The patient was breathless with pulmonary and peripheral congestion. Blood pressure, heart rate, and respiratory rate were 100/70 mmHg, 130 b.p.m., and 20 breaths per minute, respectively
Echocardiography showed severe left ventricular dilation and contractile dysfunction, with several masses with a soft consistency, a smooth surface, a central core of reduced echogenicity, and a hyperechogenic thin cap
Day 1 Cardiac magnetic resonance allowed to diagnose intracardiac fresh thrombosis
Therapy with intravenous heparin was started
Day 8 Echocardiography showed solid and fixed thrombi
Contrast-enhanced computed tomography confirmed the huge intraventricular thrombosis and excluded concomitant pulmonary thromboembolism
Warfarin therapy was started
Day 15 No sign of thrombus was identifiable at echocardiography
Day 20 Urgent transplant due to absence of contractile improvement and onset of ventricular arrhythmias
Case presentation
A 27-year-old woman, with no previous cardiovascular events, but a family history of dilated cardiomyopathy (DCM), was referred to our intensive care unit 2 months after delivery from her first pregnancy, due to onset of worsening dyspnoea. The patient was not taking any medication before admission, since her previous medical history was unremarkable and delivery was uneventful. She started experiencing breathlessness about 6 weeks after delivery. After started, breathlessness rapidly worsened in 2 weeks, so she was hospitalized. On admission, she appeared breathless, with diffuse pulmonary rales and bilateral legs oedema. Although central venous pressure was not measured, the patient had distended jugular veins, thus suggesting high venous pressure. Blood pressure was 100/70 mmHg, heart rate was 130 beats per minute, and respiratory rate was 20 breaths per minute.
A twelve-lead electrocardiogram showed sinus tachycardia, with two ventricular ectopies, low amplitude of R wave in anterior precordial leads, and low amplitude of QRS in peripheral leads. Chest X-ray demonstrated bilateral pleural effusion and pulmonary interstitial oedema. High-sensitivity troponin I was slightly increased (0.09 ng/mL, normal value < 0.04) and NT-pro-B-type natriuretic peptide was 1973 pg/mL (normal value < 450). Mild elevation of white blood cell count and mild anaemia were also found, without any abnormality in renal and liver functions. Intravenous infusion of furosemide (240 mg per day) and spironolactone (200 mg once daily) were promptly started. A transthoracic echocardiography showed severely dilated and globally hypokinetic left ventricle, with ejection fraction 11% and thinned walls. A significant dilation of both atria together with mild enlargement and hypokinesia of the right ventricle and moderate tricuspid and mitral regurgitations were also found. Moreover, an unusual finding was detected within left ventricular (LV) cavity: the sub-endocardial border of left ventricle seemed entirely covered, from mid-cavity to apex, by several masses, resembling big bubbles. They looked regular, of soft consistency, with a smooth surface and hyperechogenic thin cap with a central core, which appeared with low echogenicity at 3D and mainly 2D echocardiography (Figure 1). No blood flowing inside them was identified by colour Doppler mode, so that non-compaction cardiomyopathy could be excluded. Neither deformation imaging was performed, nor contrast echocardiography for LV opacification, which would have helped with the diagnosis, as the patient was thought to be in a critical condition and ultrasound contrast agent administration was not deemed safe.
A CMR, performed the day after echocardiography, confirmed the severe LV dilatation with global hypokinesia and severe depression of both left and right ventricular systolic function. Endoluminal material was present in the LV chamber, along the subendocardial layer: it obliterated completely the apex, spreading along the septal, inferior and anterior wall and the LV outflow tract and appeared lobulated, hypointense, ‘floating’ in the cine sequences (Figure 2A–C). These masses were lobulated, with smooth regular surface, hyper intense in both T1 (Figure 2D–F) and T2 (Figure 2G–I)-weighted sequences (with fat suppression), hypo intense during the first pass (Figure 3A–C) and both in the early (Figure 3D–F) and delayed enhancement sequences. Material with the same signal characteristics was also seen in the left atrial appendage that was almost completely obliterated (Figure 3E). No areas of subendocardial or intramural delayed enhancement suggestive of fibrosis were found. The signal characteristics of the material adhering to the LV and left atrial appendage was similar to that commonly found in early haemorrhage and led to diagnose massive very acute thrombosis in DCM.
Administration of unfractioned heparin (intravenous bolus of 5000 UI followed by continuous infusion of 20 000–40 000 UI per day), based on activated partial thromboplastin time (APTT), in addiction to diuretics, bisoprolol 1.25 mg once daily and ramipril 2.5 mg once daily, was introduced. Although APTT was maintained at 1.5–2.0-fold of the control level, about 1 week after CMR and the beginning of heparin therapy, echocardiography showed an unexpected change of intracardiac masses: in spite of being reduced, they appeared markedly increased in dimension, cone-shaped and hyperechogenic with enhanced consistency, thus fulfilling echocardiographic criteria of solid and fixed thrombi (Figure 4A–C). Contrast-enhanced computed tomography, performed in the same day of latter echocardiography, confirmed the presence of hypodense material, mainly in the LV apex, suggestive of huge intraventricular thrombosis and excluded concomitant pulmonary thromboembolism (Figure 5). Thus, the patient started warfarin 5 mg once daily in addition to unfractioned heparin, by maintaining an APTT constantly at two-fold of the normal level. Contemporarily, as central and peripheral congestion was resolved, de-escalation of diuretic therapy up to oral dose of furosemide 25 mg three times a day was done. Then, unfractioned heparin was stopped when international normalized ratio reached 2.5.
One week later, no sign of thrombosis was identifiable any more at echocardiography (Figure 4D). However, the patient could not be discharged at home, due to onset of frequent ventricular arrhythmias, which were treated by intravenous continuous infusion of magnesium sulfate (10 g per day) and amiodarone (900 mg per day). Inotropes, such as dobutamine, which would have been useful to increase LV contractility, were avoided due to risk of worsen ventricular arrhythmia. Similarly, bromocriptine treatment, which would have been useful in our patient because of high rate of full LV recovery reported, could not be administered due to its prothrombotic effect.
About 15 days after starting medical therapy, LV dysfunction persisted associated to electrical instability, so that defibrillator implantation was firstly considered, but, as she was young, heart transplantation was also prematurely proposed. After brief screening, on Day 18th, the patient was urgently transferred to the referring transplant centre in another hospital. Bridge therapy to transplant, such as LV assist device, was planned, while only titration of bisoprolol up to 1.25 mg b.i.d. could be attempted. Further escalation of heart failure therapy could not be realized, due to prohibitive arterial pressure values. Neprilysin inhibitor was not approved for treatment at the time of patient hospitalization. In the meanwhile, ventricular arrhythmias became more and more frequent and sustained. Thanks to prompt availability of donor, no bridge therapy was actually needed, and the patient was urgently transplanted. No histopathological examination was done on the diseased heart, in order to confirm imaging findings. Unfortunately, we only knew that transplantation was successful, but patient follow-up was missed in our hospital and no other clinical data were available.
Figure 1 Two-dimensional (A) and three-dimensional (B) transthoracic echocardiographic images in four-chamber view. Intraventricular apical masses (arrows) look like bubbles or cysts.
Figure 2 Cardiac magnetic resonance images, in horizontal (A) and vertical (B) long-axis views and in short-axis view (C) by cine Steady State Free Precession sequence. Multislice images in short-axis view from basal (D, G) to apical (F, I), by T1- (D–F) and T2- (G–I) weighted sequences, showing hyperintense signal.
Figure 3 Cardiac magnetic resonance short axis images, from basal (A) to apical (C) levels, during first pass perfusion sequence (A-C), displaying the absence of contrast uptake. Early enhancement sequence images in horizontal (D) and vertical (E) long-axis and in short-axis views (F), showing the hypointense signal of the masses. Trombus in left atrial appendage is marked by (*).
Figure 4 Trans-oesophageal (A, B) and transthoracic (C) echocardiographic images 1 week after starting unfractioned heparin showing changed masses. At discharge (D), disappearance of masses can be seen.
Figure 5 Axial images by computed tomography, acquired at two different levels (A, B) after administration of iodinated contrast agent. Hypodense masses without contrast uptake can be seen filling left ventricular cavity.
Discussion
Subacute or chronic intraventricular thrombi appear, at echocardiography, as solid, hyperechogenic masses, which can be irregular, layered, immobile, and broad-based, located mainly where blood flow slows down. In a previous report of PPC,5 ‘fresh’ thrombi were described as shaggy, irregular, non-laminar, and disappeared after 4 days of intravenous heparin. Besides echo-density and size, a strain rate ≥1 s−1 has been proposed to distinguish ‘fresh’ from old thrombosis.6 Deformation imaging was not used at the time of first echocardiographic examination in our case, as thrombotic nature of the masses was not sure, and their appearance could be in keeping with cysts. Moreover, in our patient, in the time interval previously defined for ‘fresh’ thrombosis,6 thrombi rapidly evolved from the very acute to the sub-acute phases: whether it is associated to changes in strain rate values is not known. CMR remains the gold standard in tissue characterization of cardiac masses. In cine sequences, thrombi typically appear as filling defects, mobile or attached to the endocardium; they are very dark both in early and delayed enhancement sequences and are usually hypo-perfused at the first pass. In the Spin-Echo T1 and T2-weighted sequences, acute and sub-acute thrombi can be hyperintense, due to red blood cell lysis and accumulation of paramagnetic compounds such as deoxyhaemoglobin and methaemoglobin, while chronic thrombi become isointense or hypointense due to the progressive replacement by fibrous tissue.4 Although hyperintensity on T2-weighted images is also typical of tumour masses,4 hyperintensity in T1-weighted sequences and strong hypo-intensity at early and delayed enhancement sequences (with an inversion time ≥442 ms required to define thrombi with the best diagnostic accuracy) has a decisive role in establishing the thrombotic nature.7
Such an extensive left ventricle very acute thrombosis has never been reported before at CMR. It is likely that, in our patient, diuretic therapy used to treat heart failure, together with hypercoagulable state usually persisting for 6 weeks after delivery, might have worsened haemoconcentration, thus favouring the thrombus evolution, despite heparin administration. Thus, diuretics and hemoconcentration could have counterbalanced anticoagulant effect of unfractioned heparin. Previous reports do not strictly fit our findings, which uniquely detected the very early phase of thrombi evolution.
Conclusions
In the very acute phase, LV fresh thrombosis may resemble cyst or bubble, with echocardiographic appearance very different from that usually seen, and therapeutic management may be challenging in hypercoagulability states and hemoconcentration. Specific imaging features reveal diagnosis and may tell the natural history of LV thrombosis throughout different stages.
Lead author biography
Dr Gabriella Locorotondo graduated in Medicine and Surgery in 2007 and specialized in Cardiology in 2012. She currently practices transthoracic and transoesophageal echocardiography and has skills in myocardial contrast echocardiography, stress echo, coronary reserve, 3D, and strain. Dr Locorotondo is certified for second level competence in cardiac magnetic resonance imaging and has got a certification of competence for percutaneous treatment of valve heart disease. She has published research articles and book chapter about echocardiography, myocardial contrast echocardiography, and cardiac magnetic resonance, including participation in the EACVI textbook of echocardiography.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
ytaa533_Supplementary_Data Click here for additional data file.
Acknowledgements
We thank Dr R. Marano for support in CMR reporting, Prof. A.G. Rebuzzi and Prof. F. Crea for approving the manuscript.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared. | FUROSEMIDE, SPIRONOLACTONE | DrugsGivenReaction | CC BY-NC | 33598615 | 20,050,868 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | 'The bubble heart': an unusual natural history told by multimodality imaging- a case report.
Intracardiac thrombosis is a relatively common pathological condition. Often, it is diagnosed at echocardiography during the subacute or chronic phase. In the very acute phase, tissue composition can make thrombus appearance very different from that usually seen. Fresh thrombosis has been previously found also in peripartum cardiomyopathy (PPC), but with imaging features different from our case.
A 27-year-old woman was referred to our hospital for PPC, with echocardiographic finding of intraventricular masses, resembling big bubbles. Cardiac magnetic resonance (CMR) allowed definitively diagnosing intracardiac 'very acute' thrombosis, which is rarely detected.
Our case provides a practical lesson about management of an unusual presentation of a common problem. When early echocardiography does not allow making a certain diagnosis, CMR can be helpful and decisive, due to its unique ability to provide characterization of intracardiac masses.
Learning points
Fresh thrombi can show a cystic appearance, with echo-lucent centre and hyperechoic boundaries.
They appear hypoperfused at the first pass sequences and look very dark in early enhancement sequences.
Fresh thrombi appear hyperintense in T1 and T2-weighted sequences, depending on presence of oxyhaemoglobin and slowly flowing blood.
Introduction
Intracardiac thrombosis is reported in up to 53% of peripartum cardiomyopathy (PPC), due to the peculiar hypercoagulability state.1 Early certain diagnosis allows promptly starting anticoagulation therapy, but during the very acute phase it can be challenging, because of the unusual appearance of thrombi as ‘bubbles’ or ‘cysts’, as compared to the more widely codified features of high or mid-echo-density masses.2 Indeed, very acute fresh thrombosis may appear at echocardiography as mass with a relatively echo-lucent centre and hyperechoic boundaries between fluid and more organized regions.3 Its diagnosis may be confirmed by cardiac magnetic resonance (CMR).4
Timeline
Delivery after a normal pregnancy
8 weeks after delivery Onset and worsening of dyspnoea
Admission, Day 0 The patient was breathless with pulmonary and peripheral congestion. Blood pressure, heart rate, and respiratory rate were 100/70 mmHg, 130 b.p.m., and 20 breaths per minute, respectively
Echocardiography showed severe left ventricular dilation and contractile dysfunction, with several masses with a soft consistency, a smooth surface, a central core of reduced echogenicity, and a hyperechogenic thin cap
Day 1 Cardiac magnetic resonance allowed to diagnose intracardiac fresh thrombosis
Therapy with intravenous heparin was started
Day 8 Echocardiography showed solid and fixed thrombi
Contrast-enhanced computed tomography confirmed the huge intraventricular thrombosis and excluded concomitant pulmonary thromboembolism
Warfarin therapy was started
Day 15 No sign of thrombus was identifiable at echocardiography
Day 20 Urgent transplant due to absence of contractile improvement and onset of ventricular arrhythmias
Case presentation
A 27-year-old woman, with no previous cardiovascular events, but a family history of dilated cardiomyopathy (DCM), was referred to our intensive care unit 2 months after delivery from her first pregnancy, due to onset of worsening dyspnoea. The patient was not taking any medication before admission, since her previous medical history was unremarkable and delivery was uneventful. She started experiencing breathlessness about 6 weeks after delivery. After started, breathlessness rapidly worsened in 2 weeks, so she was hospitalized. On admission, she appeared breathless, with diffuse pulmonary rales and bilateral legs oedema. Although central venous pressure was not measured, the patient had distended jugular veins, thus suggesting high venous pressure. Blood pressure was 100/70 mmHg, heart rate was 130 beats per minute, and respiratory rate was 20 breaths per minute.
A twelve-lead electrocardiogram showed sinus tachycardia, with two ventricular ectopies, low amplitude of R wave in anterior precordial leads, and low amplitude of QRS in peripheral leads. Chest X-ray demonstrated bilateral pleural effusion and pulmonary interstitial oedema. High-sensitivity troponin I was slightly increased (0.09 ng/mL, normal value < 0.04) and NT-pro-B-type natriuretic peptide was 1973 pg/mL (normal value < 450). Mild elevation of white blood cell count and mild anaemia were also found, without any abnormality in renal and liver functions. Intravenous infusion of furosemide (240 mg per day) and spironolactone (200 mg once daily) were promptly started. A transthoracic echocardiography showed severely dilated and globally hypokinetic left ventricle, with ejection fraction 11% and thinned walls. A significant dilation of both atria together with mild enlargement and hypokinesia of the right ventricle and moderate tricuspid and mitral regurgitations were also found. Moreover, an unusual finding was detected within left ventricular (LV) cavity: the sub-endocardial border of left ventricle seemed entirely covered, from mid-cavity to apex, by several masses, resembling big bubbles. They looked regular, of soft consistency, with a smooth surface and hyperechogenic thin cap with a central core, which appeared with low echogenicity at 3D and mainly 2D echocardiography (Figure 1). No blood flowing inside them was identified by colour Doppler mode, so that non-compaction cardiomyopathy could be excluded. Neither deformation imaging was performed, nor contrast echocardiography for LV opacification, which would have helped with the diagnosis, as the patient was thought to be in a critical condition and ultrasound contrast agent administration was not deemed safe.
A CMR, performed the day after echocardiography, confirmed the severe LV dilatation with global hypokinesia and severe depression of both left and right ventricular systolic function. Endoluminal material was present in the LV chamber, along the subendocardial layer: it obliterated completely the apex, spreading along the septal, inferior and anterior wall and the LV outflow tract and appeared lobulated, hypointense, ‘floating’ in the cine sequences (Figure 2A–C). These masses were lobulated, with smooth regular surface, hyper intense in both T1 (Figure 2D–F) and T2 (Figure 2G–I)-weighted sequences (with fat suppression), hypo intense during the first pass (Figure 3A–C) and both in the early (Figure 3D–F) and delayed enhancement sequences. Material with the same signal characteristics was also seen in the left atrial appendage that was almost completely obliterated (Figure 3E). No areas of subendocardial or intramural delayed enhancement suggestive of fibrosis were found. The signal characteristics of the material adhering to the LV and left atrial appendage was similar to that commonly found in early haemorrhage and led to diagnose massive very acute thrombosis in DCM.
Administration of unfractioned heparin (intravenous bolus of 5000 UI followed by continuous infusion of 20 000–40 000 UI per day), based on activated partial thromboplastin time (APTT), in addiction to diuretics, bisoprolol 1.25 mg once daily and ramipril 2.5 mg once daily, was introduced. Although APTT was maintained at 1.5–2.0-fold of the control level, about 1 week after CMR and the beginning of heparin therapy, echocardiography showed an unexpected change of intracardiac masses: in spite of being reduced, they appeared markedly increased in dimension, cone-shaped and hyperechogenic with enhanced consistency, thus fulfilling echocardiographic criteria of solid and fixed thrombi (Figure 4A–C). Contrast-enhanced computed tomography, performed in the same day of latter echocardiography, confirmed the presence of hypodense material, mainly in the LV apex, suggestive of huge intraventricular thrombosis and excluded concomitant pulmonary thromboembolism (Figure 5). Thus, the patient started warfarin 5 mg once daily in addition to unfractioned heparin, by maintaining an APTT constantly at two-fold of the normal level. Contemporarily, as central and peripheral congestion was resolved, de-escalation of diuretic therapy up to oral dose of furosemide 25 mg three times a day was done. Then, unfractioned heparin was stopped when international normalized ratio reached 2.5.
One week later, no sign of thrombosis was identifiable any more at echocardiography (Figure 4D). However, the patient could not be discharged at home, due to onset of frequent ventricular arrhythmias, which were treated by intravenous continuous infusion of magnesium sulfate (10 g per day) and amiodarone (900 mg per day). Inotropes, such as dobutamine, which would have been useful to increase LV contractility, were avoided due to risk of worsen ventricular arrhythmia. Similarly, bromocriptine treatment, which would have been useful in our patient because of high rate of full LV recovery reported, could not be administered due to its prothrombotic effect.
About 15 days after starting medical therapy, LV dysfunction persisted associated to electrical instability, so that defibrillator implantation was firstly considered, but, as she was young, heart transplantation was also prematurely proposed. After brief screening, on Day 18th, the patient was urgently transferred to the referring transplant centre in another hospital. Bridge therapy to transplant, such as LV assist device, was planned, while only titration of bisoprolol up to 1.25 mg b.i.d. could be attempted. Further escalation of heart failure therapy could not be realized, due to prohibitive arterial pressure values. Neprilysin inhibitor was not approved for treatment at the time of patient hospitalization. In the meanwhile, ventricular arrhythmias became more and more frequent and sustained. Thanks to prompt availability of donor, no bridge therapy was actually needed, and the patient was urgently transplanted. No histopathological examination was done on the diseased heart, in order to confirm imaging findings. Unfortunately, we only knew that transplantation was successful, but patient follow-up was missed in our hospital and no other clinical data were available.
Figure 1 Two-dimensional (A) and three-dimensional (B) transthoracic echocardiographic images in four-chamber view. Intraventricular apical masses (arrows) look like bubbles or cysts.
Figure 2 Cardiac magnetic resonance images, in horizontal (A) and vertical (B) long-axis views and in short-axis view (C) by cine Steady State Free Precession sequence. Multislice images in short-axis view from basal (D, G) to apical (F, I), by T1- (D–F) and T2- (G–I) weighted sequences, showing hyperintense signal.
Figure 3 Cardiac magnetic resonance short axis images, from basal (A) to apical (C) levels, during first pass perfusion sequence (A-C), displaying the absence of contrast uptake. Early enhancement sequence images in horizontal (D) and vertical (E) long-axis and in short-axis views (F), showing the hypointense signal of the masses. Trombus in left atrial appendage is marked by (*).
Figure 4 Trans-oesophageal (A, B) and transthoracic (C) echocardiographic images 1 week after starting unfractioned heparin showing changed masses. At discharge (D), disappearance of masses can be seen.
Figure 5 Axial images by computed tomography, acquired at two different levels (A, B) after administration of iodinated contrast agent. Hypodense masses without contrast uptake can be seen filling left ventricular cavity.
Discussion
Subacute or chronic intraventricular thrombi appear, at echocardiography, as solid, hyperechogenic masses, which can be irregular, layered, immobile, and broad-based, located mainly where blood flow slows down. In a previous report of PPC,5 ‘fresh’ thrombi were described as shaggy, irregular, non-laminar, and disappeared after 4 days of intravenous heparin. Besides echo-density and size, a strain rate ≥1 s−1 has been proposed to distinguish ‘fresh’ from old thrombosis.6 Deformation imaging was not used at the time of first echocardiographic examination in our case, as thrombotic nature of the masses was not sure, and their appearance could be in keeping with cysts. Moreover, in our patient, in the time interval previously defined for ‘fresh’ thrombosis,6 thrombi rapidly evolved from the very acute to the sub-acute phases: whether it is associated to changes in strain rate values is not known. CMR remains the gold standard in tissue characterization of cardiac masses. In cine sequences, thrombi typically appear as filling defects, mobile or attached to the endocardium; they are very dark both in early and delayed enhancement sequences and are usually hypo-perfused at the first pass. In the Spin-Echo T1 and T2-weighted sequences, acute and sub-acute thrombi can be hyperintense, due to red blood cell lysis and accumulation of paramagnetic compounds such as deoxyhaemoglobin and methaemoglobin, while chronic thrombi become isointense or hypointense due to the progressive replacement by fibrous tissue.4 Although hyperintensity on T2-weighted images is also typical of tumour masses,4 hyperintensity in T1-weighted sequences and strong hypo-intensity at early and delayed enhancement sequences (with an inversion time ≥442 ms required to define thrombi with the best diagnostic accuracy) has a decisive role in establishing the thrombotic nature.7
Such an extensive left ventricle very acute thrombosis has never been reported before at CMR. It is likely that, in our patient, diuretic therapy used to treat heart failure, together with hypercoagulable state usually persisting for 6 weeks after delivery, might have worsened haemoconcentration, thus favouring the thrombus evolution, despite heparin administration. Thus, diuretics and hemoconcentration could have counterbalanced anticoagulant effect of unfractioned heparin. Previous reports do not strictly fit our findings, which uniquely detected the very early phase of thrombi evolution.
Conclusions
In the very acute phase, LV fresh thrombosis may resemble cyst or bubble, with echocardiographic appearance very different from that usually seen, and therapeutic management may be challenging in hypercoagulability states and hemoconcentration. Specific imaging features reveal diagnosis and may tell the natural history of LV thrombosis throughout different stages.
Lead author biography
Dr Gabriella Locorotondo graduated in Medicine and Surgery in 2007 and specialized in Cardiology in 2012. She currently practices transthoracic and transoesophageal echocardiography and has skills in myocardial contrast echocardiography, stress echo, coronary reserve, 3D, and strain. Dr Locorotondo is certified for second level competence in cardiac magnetic resonance imaging and has got a certification of competence for percutaneous treatment of valve heart disease. She has published research articles and book chapter about echocardiography, myocardial contrast echocardiography, and cardiac magnetic resonance, including participation in the EACVI textbook of echocardiography.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
ytaa533_Supplementary_Data Click here for additional data file.
Acknowledgements
We thank Dr R. Marano for support in CMR reporting, Prof. A.G. Rebuzzi and Prof. F. Crea for approving the manuscript.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared. | AMIODARONE, BISOPROLOL, FUROSEMIDE, HEPARIN SODIUM, MAGNESIUM SULFATE, RAMIPRIL, SPIRONOLACTONE, WARFARIN | DrugsGivenReaction | CC BY-NC | 33598615 | 20,050,010 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemoconcentration'. | 'The bubble heart': an unusual natural history told by multimodality imaging- a case report.
Intracardiac thrombosis is a relatively common pathological condition. Often, it is diagnosed at echocardiography during the subacute or chronic phase. In the very acute phase, tissue composition can make thrombus appearance very different from that usually seen. Fresh thrombosis has been previously found also in peripartum cardiomyopathy (PPC), but with imaging features different from our case.
A 27-year-old woman was referred to our hospital for PPC, with echocardiographic finding of intraventricular masses, resembling big bubbles. Cardiac magnetic resonance (CMR) allowed definitively diagnosing intracardiac 'very acute' thrombosis, which is rarely detected.
Our case provides a practical lesson about management of an unusual presentation of a common problem. When early echocardiography does not allow making a certain diagnosis, CMR can be helpful and decisive, due to its unique ability to provide characterization of intracardiac masses.
Learning points
Fresh thrombi can show a cystic appearance, with echo-lucent centre and hyperechoic boundaries.
They appear hypoperfused at the first pass sequences and look very dark in early enhancement sequences.
Fresh thrombi appear hyperintense in T1 and T2-weighted sequences, depending on presence of oxyhaemoglobin and slowly flowing blood.
Introduction
Intracardiac thrombosis is reported in up to 53% of peripartum cardiomyopathy (PPC), due to the peculiar hypercoagulability state.1 Early certain diagnosis allows promptly starting anticoagulation therapy, but during the very acute phase it can be challenging, because of the unusual appearance of thrombi as ‘bubbles’ or ‘cysts’, as compared to the more widely codified features of high or mid-echo-density masses.2 Indeed, very acute fresh thrombosis may appear at echocardiography as mass with a relatively echo-lucent centre and hyperechoic boundaries between fluid and more organized regions.3 Its diagnosis may be confirmed by cardiac magnetic resonance (CMR).4
Timeline
Delivery after a normal pregnancy
8 weeks after delivery Onset and worsening of dyspnoea
Admission, Day 0 The patient was breathless with pulmonary and peripheral congestion. Blood pressure, heart rate, and respiratory rate were 100/70 mmHg, 130 b.p.m., and 20 breaths per minute, respectively
Echocardiography showed severe left ventricular dilation and contractile dysfunction, with several masses with a soft consistency, a smooth surface, a central core of reduced echogenicity, and a hyperechogenic thin cap
Day 1 Cardiac magnetic resonance allowed to diagnose intracardiac fresh thrombosis
Therapy with intravenous heparin was started
Day 8 Echocardiography showed solid and fixed thrombi
Contrast-enhanced computed tomography confirmed the huge intraventricular thrombosis and excluded concomitant pulmonary thromboembolism
Warfarin therapy was started
Day 15 No sign of thrombus was identifiable at echocardiography
Day 20 Urgent transplant due to absence of contractile improvement and onset of ventricular arrhythmias
Case presentation
A 27-year-old woman, with no previous cardiovascular events, but a family history of dilated cardiomyopathy (DCM), was referred to our intensive care unit 2 months after delivery from her first pregnancy, due to onset of worsening dyspnoea. The patient was not taking any medication before admission, since her previous medical history was unremarkable and delivery was uneventful. She started experiencing breathlessness about 6 weeks after delivery. After started, breathlessness rapidly worsened in 2 weeks, so she was hospitalized. On admission, she appeared breathless, with diffuse pulmonary rales and bilateral legs oedema. Although central venous pressure was not measured, the patient had distended jugular veins, thus suggesting high venous pressure. Blood pressure was 100/70 mmHg, heart rate was 130 beats per minute, and respiratory rate was 20 breaths per minute.
A twelve-lead electrocardiogram showed sinus tachycardia, with two ventricular ectopies, low amplitude of R wave in anterior precordial leads, and low amplitude of QRS in peripheral leads. Chest X-ray demonstrated bilateral pleural effusion and pulmonary interstitial oedema. High-sensitivity troponin I was slightly increased (0.09 ng/mL, normal value < 0.04) and NT-pro-B-type natriuretic peptide was 1973 pg/mL (normal value < 450). Mild elevation of white blood cell count and mild anaemia were also found, without any abnormality in renal and liver functions. Intravenous infusion of furosemide (240 mg per day) and spironolactone (200 mg once daily) were promptly started. A transthoracic echocardiography showed severely dilated and globally hypokinetic left ventricle, with ejection fraction 11% and thinned walls. A significant dilation of both atria together with mild enlargement and hypokinesia of the right ventricle and moderate tricuspid and mitral regurgitations were also found. Moreover, an unusual finding was detected within left ventricular (LV) cavity: the sub-endocardial border of left ventricle seemed entirely covered, from mid-cavity to apex, by several masses, resembling big bubbles. They looked regular, of soft consistency, with a smooth surface and hyperechogenic thin cap with a central core, which appeared with low echogenicity at 3D and mainly 2D echocardiography (Figure 1). No blood flowing inside them was identified by colour Doppler mode, so that non-compaction cardiomyopathy could be excluded. Neither deformation imaging was performed, nor contrast echocardiography for LV opacification, which would have helped with the diagnosis, as the patient was thought to be in a critical condition and ultrasound contrast agent administration was not deemed safe.
A CMR, performed the day after echocardiography, confirmed the severe LV dilatation with global hypokinesia and severe depression of both left and right ventricular systolic function. Endoluminal material was present in the LV chamber, along the subendocardial layer: it obliterated completely the apex, spreading along the septal, inferior and anterior wall and the LV outflow tract and appeared lobulated, hypointense, ‘floating’ in the cine sequences (Figure 2A–C). These masses were lobulated, with smooth regular surface, hyper intense in both T1 (Figure 2D–F) and T2 (Figure 2G–I)-weighted sequences (with fat suppression), hypo intense during the first pass (Figure 3A–C) and both in the early (Figure 3D–F) and delayed enhancement sequences. Material with the same signal characteristics was also seen in the left atrial appendage that was almost completely obliterated (Figure 3E). No areas of subendocardial or intramural delayed enhancement suggestive of fibrosis were found. The signal characteristics of the material adhering to the LV and left atrial appendage was similar to that commonly found in early haemorrhage and led to diagnose massive very acute thrombosis in DCM.
Administration of unfractioned heparin (intravenous bolus of 5000 UI followed by continuous infusion of 20 000–40 000 UI per day), based on activated partial thromboplastin time (APTT), in addiction to diuretics, bisoprolol 1.25 mg once daily and ramipril 2.5 mg once daily, was introduced. Although APTT was maintained at 1.5–2.0-fold of the control level, about 1 week after CMR and the beginning of heparin therapy, echocardiography showed an unexpected change of intracardiac masses: in spite of being reduced, they appeared markedly increased in dimension, cone-shaped and hyperechogenic with enhanced consistency, thus fulfilling echocardiographic criteria of solid and fixed thrombi (Figure 4A–C). Contrast-enhanced computed tomography, performed in the same day of latter echocardiography, confirmed the presence of hypodense material, mainly in the LV apex, suggestive of huge intraventricular thrombosis and excluded concomitant pulmonary thromboembolism (Figure 5). Thus, the patient started warfarin 5 mg once daily in addition to unfractioned heparin, by maintaining an APTT constantly at two-fold of the normal level. Contemporarily, as central and peripheral congestion was resolved, de-escalation of diuretic therapy up to oral dose of furosemide 25 mg three times a day was done. Then, unfractioned heparin was stopped when international normalized ratio reached 2.5.
One week later, no sign of thrombosis was identifiable any more at echocardiography (Figure 4D). However, the patient could not be discharged at home, due to onset of frequent ventricular arrhythmias, which were treated by intravenous continuous infusion of magnesium sulfate (10 g per day) and amiodarone (900 mg per day). Inotropes, such as dobutamine, which would have been useful to increase LV contractility, were avoided due to risk of worsen ventricular arrhythmia. Similarly, bromocriptine treatment, which would have been useful in our patient because of high rate of full LV recovery reported, could not be administered due to its prothrombotic effect.
About 15 days after starting medical therapy, LV dysfunction persisted associated to electrical instability, so that defibrillator implantation was firstly considered, but, as she was young, heart transplantation was also prematurely proposed. After brief screening, on Day 18th, the patient was urgently transferred to the referring transplant centre in another hospital. Bridge therapy to transplant, such as LV assist device, was planned, while only titration of bisoprolol up to 1.25 mg b.i.d. could be attempted. Further escalation of heart failure therapy could not be realized, due to prohibitive arterial pressure values. Neprilysin inhibitor was not approved for treatment at the time of patient hospitalization. In the meanwhile, ventricular arrhythmias became more and more frequent and sustained. Thanks to prompt availability of donor, no bridge therapy was actually needed, and the patient was urgently transplanted. No histopathological examination was done on the diseased heart, in order to confirm imaging findings. Unfortunately, we only knew that transplantation was successful, but patient follow-up was missed in our hospital and no other clinical data were available.
Figure 1 Two-dimensional (A) and three-dimensional (B) transthoracic echocardiographic images in four-chamber view. Intraventricular apical masses (arrows) look like bubbles or cysts.
Figure 2 Cardiac magnetic resonance images, in horizontal (A) and vertical (B) long-axis views and in short-axis view (C) by cine Steady State Free Precession sequence. Multislice images in short-axis view from basal (D, G) to apical (F, I), by T1- (D–F) and T2- (G–I) weighted sequences, showing hyperintense signal.
Figure 3 Cardiac magnetic resonance short axis images, from basal (A) to apical (C) levels, during first pass perfusion sequence (A-C), displaying the absence of contrast uptake. Early enhancement sequence images in horizontal (D) and vertical (E) long-axis and in short-axis views (F), showing the hypointense signal of the masses. Trombus in left atrial appendage is marked by (*).
Figure 4 Trans-oesophageal (A, B) and transthoracic (C) echocardiographic images 1 week after starting unfractioned heparin showing changed masses. At discharge (D), disappearance of masses can be seen.
Figure 5 Axial images by computed tomography, acquired at two different levels (A, B) after administration of iodinated contrast agent. Hypodense masses without contrast uptake can be seen filling left ventricular cavity.
Discussion
Subacute or chronic intraventricular thrombi appear, at echocardiography, as solid, hyperechogenic masses, which can be irregular, layered, immobile, and broad-based, located mainly where blood flow slows down. In a previous report of PPC,5 ‘fresh’ thrombi were described as shaggy, irregular, non-laminar, and disappeared after 4 days of intravenous heparin. Besides echo-density and size, a strain rate ≥1 s−1 has been proposed to distinguish ‘fresh’ from old thrombosis.6 Deformation imaging was not used at the time of first echocardiographic examination in our case, as thrombotic nature of the masses was not sure, and their appearance could be in keeping with cysts. Moreover, in our patient, in the time interval previously defined for ‘fresh’ thrombosis,6 thrombi rapidly evolved from the very acute to the sub-acute phases: whether it is associated to changes in strain rate values is not known. CMR remains the gold standard in tissue characterization of cardiac masses. In cine sequences, thrombi typically appear as filling defects, mobile or attached to the endocardium; they are very dark both in early and delayed enhancement sequences and are usually hypo-perfused at the first pass. In the Spin-Echo T1 and T2-weighted sequences, acute and sub-acute thrombi can be hyperintense, due to red blood cell lysis and accumulation of paramagnetic compounds such as deoxyhaemoglobin and methaemoglobin, while chronic thrombi become isointense or hypointense due to the progressive replacement by fibrous tissue.4 Although hyperintensity on T2-weighted images is also typical of tumour masses,4 hyperintensity in T1-weighted sequences and strong hypo-intensity at early and delayed enhancement sequences (with an inversion time ≥442 ms required to define thrombi with the best diagnostic accuracy) has a decisive role in establishing the thrombotic nature.7
Such an extensive left ventricle very acute thrombosis has never been reported before at CMR. It is likely that, in our patient, diuretic therapy used to treat heart failure, together with hypercoagulable state usually persisting for 6 weeks after delivery, might have worsened haemoconcentration, thus favouring the thrombus evolution, despite heparin administration. Thus, diuretics and hemoconcentration could have counterbalanced anticoagulant effect of unfractioned heparin. Previous reports do not strictly fit our findings, which uniquely detected the very early phase of thrombi evolution.
Conclusions
In the very acute phase, LV fresh thrombosis may resemble cyst or bubble, with echocardiographic appearance very different from that usually seen, and therapeutic management may be challenging in hypercoagulability states and hemoconcentration. Specific imaging features reveal diagnosis and may tell the natural history of LV thrombosis throughout different stages.
Lead author biography
Dr Gabriella Locorotondo graduated in Medicine and Surgery in 2007 and specialized in Cardiology in 2012. She currently practices transthoracic and transoesophageal echocardiography and has skills in myocardial contrast echocardiography, stress echo, coronary reserve, 3D, and strain. Dr Locorotondo is certified for second level competence in cardiac magnetic resonance imaging and has got a certification of competence for percutaneous treatment of valve heart disease. She has published research articles and book chapter about echocardiography, myocardial contrast echocardiography, and cardiac magnetic resonance, including participation in the EACVI textbook of echocardiography.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
ytaa533_Supplementary_Data Click here for additional data file.
Acknowledgements
We thank Dr R. Marano for support in CMR reporting, Prof. A.G. Rebuzzi and Prof. F. Crea for approving the manuscript.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared. | FUROSEMIDE, SPIRONOLACTONE | DrugsGivenReaction | CC BY-NC | 33598615 | 20,050,868 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ventricular dysfunction'. | 'The bubble heart': an unusual natural history told by multimodality imaging- a case report.
Intracardiac thrombosis is a relatively common pathological condition. Often, it is diagnosed at echocardiography during the subacute or chronic phase. In the very acute phase, tissue composition can make thrombus appearance very different from that usually seen. Fresh thrombosis has been previously found also in peripartum cardiomyopathy (PPC), but with imaging features different from our case.
A 27-year-old woman was referred to our hospital for PPC, with echocardiographic finding of intraventricular masses, resembling big bubbles. Cardiac magnetic resonance (CMR) allowed definitively diagnosing intracardiac 'very acute' thrombosis, which is rarely detected.
Our case provides a practical lesson about management of an unusual presentation of a common problem. When early echocardiography does not allow making a certain diagnosis, CMR can be helpful and decisive, due to its unique ability to provide characterization of intracardiac masses.
Learning points
Fresh thrombi can show a cystic appearance, with echo-lucent centre and hyperechoic boundaries.
They appear hypoperfused at the first pass sequences and look very dark in early enhancement sequences.
Fresh thrombi appear hyperintense in T1 and T2-weighted sequences, depending on presence of oxyhaemoglobin and slowly flowing blood.
Introduction
Intracardiac thrombosis is reported in up to 53% of peripartum cardiomyopathy (PPC), due to the peculiar hypercoagulability state.1 Early certain diagnosis allows promptly starting anticoagulation therapy, but during the very acute phase it can be challenging, because of the unusual appearance of thrombi as ‘bubbles’ or ‘cysts’, as compared to the more widely codified features of high or mid-echo-density masses.2 Indeed, very acute fresh thrombosis may appear at echocardiography as mass with a relatively echo-lucent centre and hyperechoic boundaries between fluid and more organized regions.3 Its diagnosis may be confirmed by cardiac magnetic resonance (CMR).4
Timeline
Delivery after a normal pregnancy
8 weeks after delivery Onset and worsening of dyspnoea
Admission, Day 0 The patient was breathless with pulmonary and peripheral congestion. Blood pressure, heart rate, and respiratory rate were 100/70 mmHg, 130 b.p.m., and 20 breaths per minute, respectively
Echocardiography showed severe left ventricular dilation and contractile dysfunction, with several masses with a soft consistency, a smooth surface, a central core of reduced echogenicity, and a hyperechogenic thin cap
Day 1 Cardiac magnetic resonance allowed to diagnose intracardiac fresh thrombosis
Therapy with intravenous heparin was started
Day 8 Echocardiography showed solid and fixed thrombi
Contrast-enhanced computed tomography confirmed the huge intraventricular thrombosis and excluded concomitant pulmonary thromboembolism
Warfarin therapy was started
Day 15 No sign of thrombus was identifiable at echocardiography
Day 20 Urgent transplant due to absence of contractile improvement and onset of ventricular arrhythmias
Case presentation
A 27-year-old woman, with no previous cardiovascular events, but a family history of dilated cardiomyopathy (DCM), was referred to our intensive care unit 2 months after delivery from her first pregnancy, due to onset of worsening dyspnoea. The patient was not taking any medication before admission, since her previous medical history was unremarkable and delivery was uneventful. She started experiencing breathlessness about 6 weeks after delivery. After started, breathlessness rapidly worsened in 2 weeks, so she was hospitalized. On admission, she appeared breathless, with diffuse pulmonary rales and bilateral legs oedema. Although central venous pressure was not measured, the patient had distended jugular veins, thus suggesting high venous pressure. Blood pressure was 100/70 mmHg, heart rate was 130 beats per minute, and respiratory rate was 20 breaths per minute.
A twelve-lead electrocardiogram showed sinus tachycardia, with two ventricular ectopies, low amplitude of R wave in anterior precordial leads, and low amplitude of QRS in peripheral leads. Chest X-ray demonstrated bilateral pleural effusion and pulmonary interstitial oedema. High-sensitivity troponin I was slightly increased (0.09 ng/mL, normal value < 0.04) and NT-pro-B-type natriuretic peptide was 1973 pg/mL (normal value < 450). Mild elevation of white blood cell count and mild anaemia were also found, without any abnormality in renal and liver functions. Intravenous infusion of furosemide (240 mg per day) and spironolactone (200 mg once daily) were promptly started. A transthoracic echocardiography showed severely dilated and globally hypokinetic left ventricle, with ejection fraction 11% and thinned walls. A significant dilation of both atria together with mild enlargement and hypokinesia of the right ventricle and moderate tricuspid and mitral regurgitations were also found. Moreover, an unusual finding was detected within left ventricular (LV) cavity: the sub-endocardial border of left ventricle seemed entirely covered, from mid-cavity to apex, by several masses, resembling big bubbles. They looked regular, of soft consistency, with a smooth surface and hyperechogenic thin cap with a central core, which appeared with low echogenicity at 3D and mainly 2D echocardiography (Figure 1). No blood flowing inside them was identified by colour Doppler mode, so that non-compaction cardiomyopathy could be excluded. Neither deformation imaging was performed, nor contrast echocardiography for LV opacification, which would have helped with the diagnosis, as the patient was thought to be in a critical condition and ultrasound contrast agent administration was not deemed safe.
A CMR, performed the day after echocardiography, confirmed the severe LV dilatation with global hypokinesia and severe depression of both left and right ventricular systolic function. Endoluminal material was present in the LV chamber, along the subendocardial layer: it obliterated completely the apex, spreading along the septal, inferior and anterior wall and the LV outflow tract and appeared lobulated, hypointense, ‘floating’ in the cine sequences (Figure 2A–C). These masses were lobulated, with smooth regular surface, hyper intense in both T1 (Figure 2D–F) and T2 (Figure 2G–I)-weighted sequences (with fat suppression), hypo intense during the first pass (Figure 3A–C) and both in the early (Figure 3D–F) and delayed enhancement sequences. Material with the same signal characteristics was also seen in the left atrial appendage that was almost completely obliterated (Figure 3E). No areas of subendocardial or intramural delayed enhancement suggestive of fibrosis were found. The signal characteristics of the material adhering to the LV and left atrial appendage was similar to that commonly found in early haemorrhage and led to diagnose massive very acute thrombosis in DCM.
Administration of unfractioned heparin (intravenous bolus of 5000 UI followed by continuous infusion of 20 000–40 000 UI per day), based on activated partial thromboplastin time (APTT), in addiction to diuretics, bisoprolol 1.25 mg once daily and ramipril 2.5 mg once daily, was introduced. Although APTT was maintained at 1.5–2.0-fold of the control level, about 1 week after CMR and the beginning of heparin therapy, echocardiography showed an unexpected change of intracardiac masses: in spite of being reduced, they appeared markedly increased in dimension, cone-shaped and hyperechogenic with enhanced consistency, thus fulfilling echocardiographic criteria of solid and fixed thrombi (Figure 4A–C). Contrast-enhanced computed tomography, performed in the same day of latter echocardiography, confirmed the presence of hypodense material, mainly in the LV apex, suggestive of huge intraventricular thrombosis and excluded concomitant pulmonary thromboembolism (Figure 5). Thus, the patient started warfarin 5 mg once daily in addition to unfractioned heparin, by maintaining an APTT constantly at two-fold of the normal level. Contemporarily, as central and peripheral congestion was resolved, de-escalation of diuretic therapy up to oral dose of furosemide 25 mg three times a day was done. Then, unfractioned heparin was stopped when international normalized ratio reached 2.5.
One week later, no sign of thrombosis was identifiable any more at echocardiography (Figure 4D). However, the patient could not be discharged at home, due to onset of frequent ventricular arrhythmias, which were treated by intravenous continuous infusion of magnesium sulfate (10 g per day) and amiodarone (900 mg per day). Inotropes, such as dobutamine, which would have been useful to increase LV contractility, were avoided due to risk of worsen ventricular arrhythmia. Similarly, bromocriptine treatment, which would have been useful in our patient because of high rate of full LV recovery reported, could not be administered due to its prothrombotic effect.
About 15 days after starting medical therapy, LV dysfunction persisted associated to electrical instability, so that defibrillator implantation was firstly considered, but, as she was young, heart transplantation was also prematurely proposed. After brief screening, on Day 18th, the patient was urgently transferred to the referring transplant centre in another hospital. Bridge therapy to transplant, such as LV assist device, was planned, while only titration of bisoprolol up to 1.25 mg b.i.d. could be attempted. Further escalation of heart failure therapy could not be realized, due to prohibitive arterial pressure values. Neprilysin inhibitor was not approved for treatment at the time of patient hospitalization. In the meanwhile, ventricular arrhythmias became more and more frequent and sustained. Thanks to prompt availability of donor, no bridge therapy was actually needed, and the patient was urgently transplanted. No histopathological examination was done on the diseased heart, in order to confirm imaging findings. Unfortunately, we only knew that transplantation was successful, but patient follow-up was missed in our hospital and no other clinical data were available.
Figure 1 Two-dimensional (A) and three-dimensional (B) transthoracic echocardiographic images in four-chamber view. Intraventricular apical masses (arrows) look like bubbles or cysts.
Figure 2 Cardiac magnetic resonance images, in horizontal (A) and vertical (B) long-axis views and in short-axis view (C) by cine Steady State Free Precession sequence. Multislice images in short-axis view from basal (D, G) to apical (F, I), by T1- (D–F) and T2- (G–I) weighted sequences, showing hyperintense signal.
Figure 3 Cardiac magnetic resonance short axis images, from basal (A) to apical (C) levels, during first pass perfusion sequence (A-C), displaying the absence of contrast uptake. Early enhancement sequence images in horizontal (D) and vertical (E) long-axis and in short-axis views (F), showing the hypointense signal of the masses. Trombus in left atrial appendage is marked by (*).
Figure 4 Trans-oesophageal (A, B) and transthoracic (C) echocardiographic images 1 week after starting unfractioned heparin showing changed masses. At discharge (D), disappearance of masses can be seen.
Figure 5 Axial images by computed tomography, acquired at two different levels (A, B) after administration of iodinated contrast agent. Hypodense masses without contrast uptake can be seen filling left ventricular cavity.
Discussion
Subacute or chronic intraventricular thrombi appear, at echocardiography, as solid, hyperechogenic masses, which can be irregular, layered, immobile, and broad-based, located mainly where blood flow slows down. In a previous report of PPC,5 ‘fresh’ thrombi were described as shaggy, irregular, non-laminar, and disappeared after 4 days of intravenous heparin. Besides echo-density and size, a strain rate ≥1 s−1 has been proposed to distinguish ‘fresh’ from old thrombosis.6 Deformation imaging was not used at the time of first echocardiographic examination in our case, as thrombotic nature of the masses was not sure, and their appearance could be in keeping with cysts. Moreover, in our patient, in the time interval previously defined for ‘fresh’ thrombosis,6 thrombi rapidly evolved from the very acute to the sub-acute phases: whether it is associated to changes in strain rate values is not known. CMR remains the gold standard in tissue characterization of cardiac masses. In cine sequences, thrombi typically appear as filling defects, mobile or attached to the endocardium; they are very dark both in early and delayed enhancement sequences and are usually hypo-perfused at the first pass. In the Spin-Echo T1 and T2-weighted sequences, acute and sub-acute thrombi can be hyperintense, due to red blood cell lysis and accumulation of paramagnetic compounds such as deoxyhaemoglobin and methaemoglobin, while chronic thrombi become isointense or hypointense due to the progressive replacement by fibrous tissue.4 Although hyperintensity on T2-weighted images is also typical of tumour masses,4 hyperintensity in T1-weighted sequences and strong hypo-intensity at early and delayed enhancement sequences (with an inversion time ≥442 ms required to define thrombi with the best diagnostic accuracy) has a decisive role in establishing the thrombotic nature.7
Such an extensive left ventricle very acute thrombosis has never been reported before at CMR. It is likely that, in our patient, diuretic therapy used to treat heart failure, together with hypercoagulable state usually persisting for 6 weeks after delivery, might have worsened haemoconcentration, thus favouring the thrombus evolution, despite heparin administration. Thus, diuretics and hemoconcentration could have counterbalanced anticoagulant effect of unfractioned heparin. Previous reports do not strictly fit our findings, which uniquely detected the very early phase of thrombi evolution.
Conclusions
In the very acute phase, LV fresh thrombosis may resemble cyst or bubble, with echocardiographic appearance very different from that usually seen, and therapeutic management may be challenging in hypercoagulability states and hemoconcentration. Specific imaging features reveal diagnosis and may tell the natural history of LV thrombosis throughout different stages.
Lead author biography
Dr Gabriella Locorotondo graduated in Medicine and Surgery in 2007 and specialized in Cardiology in 2012. She currently practices transthoracic and transoesophageal echocardiography and has skills in myocardial contrast echocardiography, stress echo, coronary reserve, 3D, and strain. Dr Locorotondo is certified for second level competence in cardiac magnetic resonance imaging and has got a certification of competence for percutaneous treatment of valve heart disease. She has published research articles and book chapter about echocardiography, myocardial contrast echocardiography, and cardiac magnetic resonance, including participation in the EACVI textbook of echocardiography.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
ytaa533_Supplementary_Data Click here for additional data file.
Acknowledgements
We thank Dr R. Marano for support in CMR reporting, Prof. A.G. Rebuzzi and Prof. F. Crea for approving the manuscript.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared. | FUROSEMIDE, SPIRONOLACTONE | DrugsGivenReaction | CC BY-NC | 33598615 | 20,050,868 | 2021-02 |
What was the administration route of drug 'AMIODARONE'? | 'The bubble heart': an unusual natural history told by multimodality imaging- a case report.
Intracardiac thrombosis is a relatively common pathological condition. Often, it is diagnosed at echocardiography during the subacute or chronic phase. In the very acute phase, tissue composition can make thrombus appearance very different from that usually seen. Fresh thrombosis has been previously found also in peripartum cardiomyopathy (PPC), but with imaging features different from our case.
A 27-year-old woman was referred to our hospital for PPC, with echocardiographic finding of intraventricular masses, resembling big bubbles. Cardiac magnetic resonance (CMR) allowed definitively diagnosing intracardiac 'very acute' thrombosis, which is rarely detected.
Our case provides a practical lesson about management of an unusual presentation of a common problem. When early echocardiography does not allow making a certain diagnosis, CMR can be helpful and decisive, due to its unique ability to provide characterization of intracardiac masses.
Learning points
Fresh thrombi can show a cystic appearance, with echo-lucent centre and hyperechoic boundaries.
They appear hypoperfused at the first pass sequences and look very dark in early enhancement sequences.
Fresh thrombi appear hyperintense in T1 and T2-weighted sequences, depending on presence of oxyhaemoglobin and slowly flowing blood.
Introduction
Intracardiac thrombosis is reported in up to 53% of peripartum cardiomyopathy (PPC), due to the peculiar hypercoagulability state.1 Early certain diagnosis allows promptly starting anticoagulation therapy, but during the very acute phase it can be challenging, because of the unusual appearance of thrombi as ‘bubbles’ or ‘cysts’, as compared to the more widely codified features of high or mid-echo-density masses.2 Indeed, very acute fresh thrombosis may appear at echocardiography as mass with a relatively echo-lucent centre and hyperechoic boundaries between fluid and more organized regions.3 Its diagnosis may be confirmed by cardiac magnetic resonance (CMR).4
Timeline
Delivery after a normal pregnancy
8 weeks after delivery Onset and worsening of dyspnoea
Admission, Day 0 The patient was breathless with pulmonary and peripheral congestion. Blood pressure, heart rate, and respiratory rate were 100/70 mmHg, 130 b.p.m., and 20 breaths per minute, respectively
Echocardiography showed severe left ventricular dilation and contractile dysfunction, with several masses with a soft consistency, a smooth surface, a central core of reduced echogenicity, and a hyperechogenic thin cap
Day 1 Cardiac magnetic resonance allowed to diagnose intracardiac fresh thrombosis
Therapy with intravenous heparin was started
Day 8 Echocardiography showed solid and fixed thrombi
Contrast-enhanced computed tomography confirmed the huge intraventricular thrombosis and excluded concomitant pulmonary thromboembolism
Warfarin therapy was started
Day 15 No sign of thrombus was identifiable at echocardiography
Day 20 Urgent transplant due to absence of contractile improvement and onset of ventricular arrhythmias
Case presentation
A 27-year-old woman, with no previous cardiovascular events, but a family history of dilated cardiomyopathy (DCM), was referred to our intensive care unit 2 months after delivery from her first pregnancy, due to onset of worsening dyspnoea. The patient was not taking any medication before admission, since her previous medical history was unremarkable and delivery was uneventful. She started experiencing breathlessness about 6 weeks after delivery. After started, breathlessness rapidly worsened in 2 weeks, so she was hospitalized. On admission, she appeared breathless, with diffuse pulmonary rales and bilateral legs oedema. Although central venous pressure was not measured, the patient had distended jugular veins, thus suggesting high venous pressure. Blood pressure was 100/70 mmHg, heart rate was 130 beats per minute, and respiratory rate was 20 breaths per minute.
A twelve-lead electrocardiogram showed sinus tachycardia, with two ventricular ectopies, low amplitude of R wave in anterior precordial leads, and low amplitude of QRS in peripheral leads. Chest X-ray demonstrated bilateral pleural effusion and pulmonary interstitial oedema. High-sensitivity troponin I was slightly increased (0.09 ng/mL, normal value < 0.04) and NT-pro-B-type natriuretic peptide was 1973 pg/mL (normal value < 450). Mild elevation of white blood cell count and mild anaemia were also found, without any abnormality in renal and liver functions. Intravenous infusion of furosemide (240 mg per day) and spironolactone (200 mg once daily) were promptly started. A transthoracic echocardiography showed severely dilated and globally hypokinetic left ventricle, with ejection fraction 11% and thinned walls. A significant dilation of both atria together with mild enlargement and hypokinesia of the right ventricle and moderate tricuspid and mitral regurgitations were also found. Moreover, an unusual finding was detected within left ventricular (LV) cavity: the sub-endocardial border of left ventricle seemed entirely covered, from mid-cavity to apex, by several masses, resembling big bubbles. They looked regular, of soft consistency, with a smooth surface and hyperechogenic thin cap with a central core, which appeared with low echogenicity at 3D and mainly 2D echocardiography (Figure 1). No blood flowing inside them was identified by colour Doppler mode, so that non-compaction cardiomyopathy could be excluded. Neither deformation imaging was performed, nor contrast echocardiography for LV opacification, which would have helped with the diagnosis, as the patient was thought to be in a critical condition and ultrasound contrast agent administration was not deemed safe.
A CMR, performed the day after echocardiography, confirmed the severe LV dilatation with global hypokinesia and severe depression of both left and right ventricular systolic function. Endoluminal material was present in the LV chamber, along the subendocardial layer: it obliterated completely the apex, spreading along the septal, inferior and anterior wall and the LV outflow tract and appeared lobulated, hypointense, ‘floating’ in the cine sequences (Figure 2A–C). These masses were lobulated, with smooth regular surface, hyper intense in both T1 (Figure 2D–F) and T2 (Figure 2G–I)-weighted sequences (with fat suppression), hypo intense during the first pass (Figure 3A–C) and both in the early (Figure 3D–F) and delayed enhancement sequences. Material with the same signal characteristics was also seen in the left atrial appendage that was almost completely obliterated (Figure 3E). No areas of subendocardial or intramural delayed enhancement suggestive of fibrosis were found. The signal characteristics of the material adhering to the LV and left atrial appendage was similar to that commonly found in early haemorrhage and led to diagnose massive very acute thrombosis in DCM.
Administration of unfractioned heparin (intravenous bolus of 5000 UI followed by continuous infusion of 20 000–40 000 UI per day), based on activated partial thromboplastin time (APTT), in addiction to diuretics, bisoprolol 1.25 mg once daily and ramipril 2.5 mg once daily, was introduced. Although APTT was maintained at 1.5–2.0-fold of the control level, about 1 week after CMR and the beginning of heparin therapy, echocardiography showed an unexpected change of intracardiac masses: in spite of being reduced, they appeared markedly increased in dimension, cone-shaped and hyperechogenic with enhanced consistency, thus fulfilling echocardiographic criteria of solid and fixed thrombi (Figure 4A–C). Contrast-enhanced computed tomography, performed in the same day of latter echocardiography, confirmed the presence of hypodense material, mainly in the LV apex, suggestive of huge intraventricular thrombosis and excluded concomitant pulmonary thromboembolism (Figure 5). Thus, the patient started warfarin 5 mg once daily in addition to unfractioned heparin, by maintaining an APTT constantly at two-fold of the normal level. Contemporarily, as central and peripheral congestion was resolved, de-escalation of diuretic therapy up to oral dose of furosemide 25 mg three times a day was done. Then, unfractioned heparin was stopped when international normalized ratio reached 2.5.
One week later, no sign of thrombosis was identifiable any more at echocardiography (Figure 4D). However, the patient could not be discharged at home, due to onset of frequent ventricular arrhythmias, which were treated by intravenous continuous infusion of magnesium sulfate (10 g per day) and amiodarone (900 mg per day). Inotropes, such as dobutamine, which would have been useful to increase LV contractility, were avoided due to risk of worsen ventricular arrhythmia. Similarly, bromocriptine treatment, which would have been useful in our patient because of high rate of full LV recovery reported, could not be administered due to its prothrombotic effect.
About 15 days after starting medical therapy, LV dysfunction persisted associated to electrical instability, so that defibrillator implantation was firstly considered, but, as she was young, heart transplantation was also prematurely proposed. After brief screening, on Day 18th, the patient was urgently transferred to the referring transplant centre in another hospital. Bridge therapy to transplant, such as LV assist device, was planned, while only titration of bisoprolol up to 1.25 mg b.i.d. could be attempted. Further escalation of heart failure therapy could not be realized, due to prohibitive arterial pressure values. Neprilysin inhibitor was not approved for treatment at the time of patient hospitalization. In the meanwhile, ventricular arrhythmias became more and more frequent and sustained. Thanks to prompt availability of donor, no bridge therapy was actually needed, and the patient was urgently transplanted. No histopathological examination was done on the diseased heart, in order to confirm imaging findings. Unfortunately, we only knew that transplantation was successful, but patient follow-up was missed in our hospital and no other clinical data were available.
Figure 1 Two-dimensional (A) and three-dimensional (B) transthoracic echocardiographic images in four-chamber view. Intraventricular apical masses (arrows) look like bubbles or cysts.
Figure 2 Cardiac magnetic resonance images, in horizontal (A) and vertical (B) long-axis views and in short-axis view (C) by cine Steady State Free Precession sequence. Multislice images in short-axis view from basal (D, G) to apical (F, I), by T1- (D–F) and T2- (G–I) weighted sequences, showing hyperintense signal.
Figure 3 Cardiac magnetic resonance short axis images, from basal (A) to apical (C) levels, during first pass perfusion sequence (A-C), displaying the absence of contrast uptake. Early enhancement sequence images in horizontal (D) and vertical (E) long-axis and in short-axis views (F), showing the hypointense signal of the masses. Trombus in left atrial appendage is marked by (*).
Figure 4 Trans-oesophageal (A, B) and transthoracic (C) echocardiographic images 1 week after starting unfractioned heparin showing changed masses. At discharge (D), disappearance of masses can be seen.
Figure 5 Axial images by computed tomography, acquired at two different levels (A, B) after administration of iodinated contrast agent. Hypodense masses without contrast uptake can be seen filling left ventricular cavity.
Discussion
Subacute or chronic intraventricular thrombi appear, at echocardiography, as solid, hyperechogenic masses, which can be irregular, layered, immobile, and broad-based, located mainly where blood flow slows down. In a previous report of PPC,5 ‘fresh’ thrombi were described as shaggy, irregular, non-laminar, and disappeared after 4 days of intravenous heparin. Besides echo-density and size, a strain rate ≥1 s−1 has been proposed to distinguish ‘fresh’ from old thrombosis.6 Deformation imaging was not used at the time of first echocardiographic examination in our case, as thrombotic nature of the masses was not sure, and their appearance could be in keeping with cysts. Moreover, in our patient, in the time interval previously defined for ‘fresh’ thrombosis,6 thrombi rapidly evolved from the very acute to the sub-acute phases: whether it is associated to changes in strain rate values is not known. CMR remains the gold standard in tissue characterization of cardiac masses. In cine sequences, thrombi typically appear as filling defects, mobile or attached to the endocardium; they are very dark both in early and delayed enhancement sequences and are usually hypo-perfused at the first pass. In the Spin-Echo T1 and T2-weighted sequences, acute and sub-acute thrombi can be hyperintense, due to red blood cell lysis and accumulation of paramagnetic compounds such as deoxyhaemoglobin and methaemoglobin, while chronic thrombi become isointense or hypointense due to the progressive replacement by fibrous tissue.4 Although hyperintensity on T2-weighted images is also typical of tumour masses,4 hyperintensity in T1-weighted sequences and strong hypo-intensity at early and delayed enhancement sequences (with an inversion time ≥442 ms required to define thrombi with the best diagnostic accuracy) has a decisive role in establishing the thrombotic nature.7
Such an extensive left ventricle very acute thrombosis has never been reported before at CMR. It is likely that, in our patient, diuretic therapy used to treat heart failure, together with hypercoagulable state usually persisting for 6 weeks after delivery, might have worsened haemoconcentration, thus favouring the thrombus evolution, despite heparin administration. Thus, diuretics and hemoconcentration could have counterbalanced anticoagulant effect of unfractioned heparin. Previous reports do not strictly fit our findings, which uniquely detected the very early phase of thrombi evolution.
Conclusions
In the very acute phase, LV fresh thrombosis may resemble cyst or bubble, with echocardiographic appearance very different from that usually seen, and therapeutic management may be challenging in hypercoagulability states and hemoconcentration. Specific imaging features reveal diagnosis and may tell the natural history of LV thrombosis throughout different stages.
Lead author biography
Dr Gabriella Locorotondo graduated in Medicine and Surgery in 2007 and specialized in Cardiology in 2012. She currently practices transthoracic and transoesophageal echocardiography and has skills in myocardial contrast echocardiography, stress echo, coronary reserve, 3D, and strain. Dr Locorotondo is certified for second level competence in cardiac magnetic resonance imaging and has got a certification of competence for percutaneous treatment of valve heart disease. She has published research articles and book chapter about echocardiography, myocardial contrast echocardiography, and cardiac magnetic resonance, including participation in the EACVI textbook of echocardiography.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
ytaa533_Supplementary_Data Click here for additional data file.
Acknowledgements
We thank Dr R. Marano for support in CMR reporting, Prof. A.G. Rebuzzi and Prof. F. Crea for approving the manuscript.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33598615 | 20,050,010 | 2021-02 |
What was the administration route of drug 'HEPARIN SODIUM'? | 'The bubble heart': an unusual natural history told by multimodality imaging- a case report.
Intracardiac thrombosis is a relatively common pathological condition. Often, it is diagnosed at echocardiography during the subacute or chronic phase. In the very acute phase, tissue composition can make thrombus appearance very different from that usually seen. Fresh thrombosis has been previously found also in peripartum cardiomyopathy (PPC), but with imaging features different from our case.
A 27-year-old woman was referred to our hospital for PPC, with echocardiographic finding of intraventricular masses, resembling big bubbles. Cardiac magnetic resonance (CMR) allowed definitively diagnosing intracardiac 'very acute' thrombosis, which is rarely detected.
Our case provides a practical lesson about management of an unusual presentation of a common problem. When early echocardiography does not allow making a certain diagnosis, CMR can be helpful and decisive, due to its unique ability to provide characterization of intracardiac masses.
Learning points
Fresh thrombi can show a cystic appearance, with echo-lucent centre and hyperechoic boundaries.
They appear hypoperfused at the first pass sequences and look very dark in early enhancement sequences.
Fresh thrombi appear hyperintense in T1 and T2-weighted sequences, depending on presence of oxyhaemoglobin and slowly flowing blood.
Introduction
Intracardiac thrombosis is reported in up to 53% of peripartum cardiomyopathy (PPC), due to the peculiar hypercoagulability state.1 Early certain diagnosis allows promptly starting anticoagulation therapy, but during the very acute phase it can be challenging, because of the unusual appearance of thrombi as ‘bubbles’ or ‘cysts’, as compared to the more widely codified features of high or mid-echo-density masses.2 Indeed, very acute fresh thrombosis may appear at echocardiography as mass with a relatively echo-lucent centre and hyperechoic boundaries between fluid and more organized regions.3 Its diagnosis may be confirmed by cardiac magnetic resonance (CMR).4
Timeline
Delivery after a normal pregnancy
8 weeks after delivery Onset and worsening of dyspnoea
Admission, Day 0 The patient was breathless with pulmonary and peripheral congestion. Blood pressure, heart rate, and respiratory rate were 100/70 mmHg, 130 b.p.m., and 20 breaths per minute, respectively
Echocardiography showed severe left ventricular dilation and contractile dysfunction, with several masses with a soft consistency, a smooth surface, a central core of reduced echogenicity, and a hyperechogenic thin cap
Day 1 Cardiac magnetic resonance allowed to diagnose intracardiac fresh thrombosis
Therapy with intravenous heparin was started
Day 8 Echocardiography showed solid and fixed thrombi
Contrast-enhanced computed tomography confirmed the huge intraventricular thrombosis and excluded concomitant pulmonary thromboembolism
Warfarin therapy was started
Day 15 No sign of thrombus was identifiable at echocardiography
Day 20 Urgent transplant due to absence of contractile improvement and onset of ventricular arrhythmias
Case presentation
A 27-year-old woman, with no previous cardiovascular events, but a family history of dilated cardiomyopathy (DCM), was referred to our intensive care unit 2 months after delivery from her first pregnancy, due to onset of worsening dyspnoea. The patient was not taking any medication before admission, since her previous medical history was unremarkable and delivery was uneventful. She started experiencing breathlessness about 6 weeks after delivery. After started, breathlessness rapidly worsened in 2 weeks, so she was hospitalized. On admission, she appeared breathless, with diffuse pulmonary rales and bilateral legs oedema. Although central venous pressure was not measured, the patient had distended jugular veins, thus suggesting high venous pressure. Blood pressure was 100/70 mmHg, heart rate was 130 beats per minute, and respiratory rate was 20 breaths per minute.
A twelve-lead electrocardiogram showed sinus tachycardia, with two ventricular ectopies, low amplitude of R wave in anterior precordial leads, and low amplitude of QRS in peripheral leads. Chest X-ray demonstrated bilateral pleural effusion and pulmonary interstitial oedema. High-sensitivity troponin I was slightly increased (0.09 ng/mL, normal value < 0.04) and NT-pro-B-type natriuretic peptide was 1973 pg/mL (normal value < 450). Mild elevation of white blood cell count and mild anaemia were also found, without any abnormality in renal and liver functions. Intravenous infusion of furosemide (240 mg per day) and spironolactone (200 mg once daily) were promptly started. A transthoracic echocardiography showed severely dilated and globally hypokinetic left ventricle, with ejection fraction 11% and thinned walls. A significant dilation of both atria together with mild enlargement and hypokinesia of the right ventricle and moderate tricuspid and mitral regurgitations were also found. Moreover, an unusual finding was detected within left ventricular (LV) cavity: the sub-endocardial border of left ventricle seemed entirely covered, from mid-cavity to apex, by several masses, resembling big bubbles. They looked regular, of soft consistency, with a smooth surface and hyperechogenic thin cap with a central core, which appeared with low echogenicity at 3D and mainly 2D echocardiography (Figure 1). No blood flowing inside them was identified by colour Doppler mode, so that non-compaction cardiomyopathy could be excluded. Neither deformation imaging was performed, nor contrast echocardiography for LV opacification, which would have helped with the diagnosis, as the patient was thought to be in a critical condition and ultrasound contrast agent administration was not deemed safe.
A CMR, performed the day after echocardiography, confirmed the severe LV dilatation with global hypokinesia and severe depression of both left and right ventricular systolic function. Endoluminal material was present in the LV chamber, along the subendocardial layer: it obliterated completely the apex, spreading along the septal, inferior and anterior wall and the LV outflow tract and appeared lobulated, hypointense, ‘floating’ in the cine sequences (Figure 2A–C). These masses were lobulated, with smooth regular surface, hyper intense in both T1 (Figure 2D–F) and T2 (Figure 2G–I)-weighted sequences (with fat suppression), hypo intense during the first pass (Figure 3A–C) and both in the early (Figure 3D–F) and delayed enhancement sequences. Material with the same signal characteristics was also seen in the left atrial appendage that was almost completely obliterated (Figure 3E). No areas of subendocardial or intramural delayed enhancement suggestive of fibrosis were found. The signal characteristics of the material adhering to the LV and left atrial appendage was similar to that commonly found in early haemorrhage and led to diagnose massive very acute thrombosis in DCM.
Administration of unfractioned heparin (intravenous bolus of 5000 UI followed by continuous infusion of 20 000–40 000 UI per day), based on activated partial thromboplastin time (APTT), in addiction to diuretics, bisoprolol 1.25 mg once daily and ramipril 2.5 mg once daily, was introduced. Although APTT was maintained at 1.5–2.0-fold of the control level, about 1 week after CMR and the beginning of heparin therapy, echocardiography showed an unexpected change of intracardiac masses: in spite of being reduced, they appeared markedly increased in dimension, cone-shaped and hyperechogenic with enhanced consistency, thus fulfilling echocardiographic criteria of solid and fixed thrombi (Figure 4A–C). Contrast-enhanced computed tomography, performed in the same day of latter echocardiography, confirmed the presence of hypodense material, mainly in the LV apex, suggestive of huge intraventricular thrombosis and excluded concomitant pulmonary thromboembolism (Figure 5). Thus, the patient started warfarin 5 mg once daily in addition to unfractioned heparin, by maintaining an APTT constantly at two-fold of the normal level. Contemporarily, as central and peripheral congestion was resolved, de-escalation of diuretic therapy up to oral dose of furosemide 25 mg three times a day was done. Then, unfractioned heparin was stopped when international normalized ratio reached 2.5.
One week later, no sign of thrombosis was identifiable any more at echocardiography (Figure 4D). However, the patient could not be discharged at home, due to onset of frequent ventricular arrhythmias, which were treated by intravenous continuous infusion of magnesium sulfate (10 g per day) and amiodarone (900 mg per day). Inotropes, such as dobutamine, which would have been useful to increase LV contractility, were avoided due to risk of worsen ventricular arrhythmia. Similarly, bromocriptine treatment, which would have been useful in our patient because of high rate of full LV recovery reported, could not be administered due to its prothrombotic effect.
About 15 days after starting medical therapy, LV dysfunction persisted associated to electrical instability, so that defibrillator implantation was firstly considered, but, as she was young, heart transplantation was also prematurely proposed. After brief screening, on Day 18th, the patient was urgently transferred to the referring transplant centre in another hospital. Bridge therapy to transplant, such as LV assist device, was planned, while only titration of bisoprolol up to 1.25 mg b.i.d. could be attempted. Further escalation of heart failure therapy could not be realized, due to prohibitive arterial pressure values. Neprilysin inhibitor was not approved for treatment at the time of patient hospitalization. In the meanwhile, ventricular arrhythmias became more and more frequent and sustained. Thanks to prompt availability of donor, no bridge therapy was actually needed, and the patient was urgently transplanted. No histopathological examination was done on the diseased heart, in order to confirm imaging findings. Unfortunately, we only knew that transplantation was successful, but patient follow-up was missed in our hospital and no other clinical data were available.
Figure 1 Two-dimensional (A) and three-dimensional (B) transthoracic echocardiographic images in four-chamber view. Intraventricular apical masses (arrows) look like bubbles or cysts.
Figure 2 Cardiac magnetic resonance images, in horizontal (A) and vertical (B) long-axis views and in short-axis view (C) by cine Steady State Free Precession sequence. Multislice images in short-axis view from basal (D, G) to apical (F, I), by T1- (D–F) and T2- (G–I) weighted sequences, showing hyperintense signal.
Figure 3 Cardiac magnetic resonance short axis images, from basal (A) to apical (C) levels, during first pass perfusion sequence (A-C), displaying the absence of contrast uptake. Early enhancement sequence images in horizontal (D) and vertical (E) long-axis and in short-axis views (F), showing the hypointense signal of the masses. Trombus in left atrial appendage is marked by (*).
Figure 4 Trans-oesophageal (A, B) and transthoracic (C) echocardiographic images 1 week after starting unfractioned heparin showing changed masses. At discharge (D), disappearance of masses can be seen.
Figure 5 Axial images by computed tomography, acquired at two different levels (A, B) after administration of iodinated contrast agent. Hypodense masses without contrast uptake can be seen filling left ventricular cavity.
Discussion
Subacute or chronic intraventricular thrombi appear, at echocardiography, as solid, hyperechogenic masses, which can be irregular, layered, immobile, and broad-based, located mainly where blood flow slows down. In a previous report of PPC,5 ‘fresh’ thrombi were described as shaggy, irregular, non-laminar, and disappeared after 4 days of intravenous heparin. Besides echo-density and size, a strain rate ≥1 s−1 has been proposed to distinguish ‘fresh’ from old thrombosis.6 Deformation imaging was not used at the time of first echocardiographic examination in our case, as thrombotic nature of the masses was not sure, and their appearance could be in keeping with cysts. Moreover, in our patient, in the time interval previously defined for ‘fresh’ thrombosis,6 thrombi rapidly evolved from the very acute to the sub-acute phases: whether it is associated to changes in strain rate values is not known. CMR remains the gold standard in tissue characterization of cardiac masses. In cine sequences, thrombi typically appear as filling defects, mobile or attached to the endocardium; they are very dark both in early and delayed enhancement sequences and are usually hypo-perfused at the first pass. In the Spin-Echo T1 and T2-weighted sequences, acute and sub-acute thrombi can be hyperintense, due to red blood cell lysis and accumulation of paramagnetic compounds such as deoxyhaemoglobin and methaemoglobin, while chronic thrombi become isointense or hypointense due to the progressive replacement by fibrous tissue.4 Although hyperintensity on T2-weighted images is also typical of tumour masses,4 hyperintensity in T1-weighted sequences and strong hypo-intensity at early and delayed enhancement sequences (with an inversion time ≥442 ms required to define thrombi with the best diagnostic accuracy) has a decisive role in establishing the thrombotic nature.7
Such an extensive left ventricle very acute thrombosis has never been reported before at CMR. It is likely that, in our patient, diuretic therapy used to treat heart failure, together with hypercoagulable state usually persisting for 6 weeks after delivery, might have worsened haemoconcentration, thus favouring the thrombus evolution, despite heparin administration. Thus, diuretics and hemoconcentration could have counterbalanced anticoagulant effect of unfractioned heparin. Previous reports do not strictly fit our findings, which uniquely detected the very early phase of thrombi evolution.
Conclusions
In the very acute phase, LV fresh thrombosis may resemble cyst or bubble, with echocardiographic appearance very different from that usually seen, and therapeutic management may be challenging in hypercoagulability states and hemoconcentration. Specific imaging features reveal diagnosis and may tell the natural history of LV thrombosis throughout different stages.
Lead author biography
Dr Gabriella Locorotondo graduated in Medicine and Surgery in 2007 and specialized in Cardiology in 2012. She currently practices transthoracic and transoesophageal echocardiography and has skills in myocardial contrast echocardiography, stress echo, coronary reserve, 3D, and strain. Dr Locorotondo is certified for second level competence in cardiac magnetic resonance imaging and has got a certification of competence for percutaneous treatment of valve heart disease. She has published research articles and book chapter about echocardiography, myocardial contrast echocardiography, and cardiac magnetic resonance, including participation in the EACVI textbook of echocardiography.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
ytaa533_Supplementary_Data Click here for additional data file.
Acknowledgements
We thank Dr R. Marano for support in CMR reporting, Prof. A.G. Rebuzzi and Prof. F. Crea for approving the manuscript.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33598615 | 20,050,010 | 2021-02 |
What was the administration route of drug 'MAGNESIUM SULFATE'? | 'The bubble heart': an unusual natural history told by multimodality imaging- a case report.
Intracardiac thrombosis is a relatively common pathological condition. Often, it is diagnosed at echocardiography during the subacute or chronic phase. In the very acute phase, tissue composition can make thrombus appearance very different from that usually seen. Fresh thrombosis has been previously found also in peripartum cardiomyopathy (PPC), but with imaging features different from our case.
A 27-year-old woman was referred to our hospital for PPC, with echocardiographic finding of intraventricular masses, resembling big bubbles. Cardiac magnetic resonance (CMR) allowed definitively diagnosing intracardiac 'very acute' thrombosis, which is rarely detected.
Our case provides a practical lesson about management of an unusual presentation of a common problem. When early echocardiography does not allow making a certain diagnosis, CMR can be helpful and decisive, due to its unique ability to provide characterization of intracardiac masses.
Learning points
Fresh thrombi can show a cystic appearance, with echo-lucent centre and hyperechoic boundaries.
They appear hypoperfused at the first pass sequences and look very dark in early enhancement sequences.
Fresh thrombi appear hyperintense in T1 and T2-weighted sequences, depending on presence of oxyhaemoglobin and slowly flowing blood.
Introduction
Intracardiac thrombosis is reported in up to 53% of peripartum cardiomyopathy (PPC), due to the peculiar hypercoagulability state.1 Early certain diagnosis allows promptly starting anticoagulation therapy, but during the very acute phase it can be challenging, because of the unusual appearance of thrombi as ‘bubbles’ or ‘cysts’, as compared to the more widely codified features of high or mid-echo-density masses.2 Indeed, very acute fresh thrombosis may appear at echocardiography as mass with a relatively echo-lucent centre and hyperechoic boundaries between fluid and more organized regions.3 Its diagnosis may be confirmed by cardiac magnetic resonance (CMR).4
Timeline
Delivery after a normal pregnancy
8 weeks after delivery Onset and worsening of dyspnoea
Admission, Day 0 The patient was breathless with pulmonary and peripheral congestion. Blood pressure, heart rate, and respiratory rate were 100/70 mmHg, 130 b.p.m., and 20 breaths per minute, respectively
Echocardiography showed severe left ventricular dilation and contractile dysfunction, with several masses with a soft consistency, a smooth surface, a central core of reduced echogenicity, and a hyperechogenic thin cap
Day 1 Cardiac magnetic resonance allowed to diagnose intracardiac fresh thrombosis
Therapy with intravenous heparin was started
Day 8 Echocardiography showed solid and fixed thrombi
Contrast-enhanced computed tomography confirmed the huge intraventricular thrombosis and excluded concomitant pulmonary thromboembolism
Warfarin therapy was started
Day 15 No sign of thrombus was identifiable at echocardiography
Day 20 Urgent transplant due to absence of contractile improvement and onset of ventricular arrhythmias
Case presentation
A 27-year-old woman, with no previous cardiovascular events, but a family history of dilated cardiomyopathy (DCM), was referred to our intensive care unit 2 months after delivery from her first pregnancy, due to onset of worsening dyspnoea. The patient was not taking any medication before admission, since her previous medical history was unremarkable and delivery was uneventful. She started experiencing breathlessness about 6 weeks after delivery. After started, breathlessness rapidly worsened in 2 weeks, so she was hospitalized. On admission, she appeared breathless, with diffuse pulmonary rales and bilateral legs oedema. Although central venous pressure was not measured, the patient had distended jugular veins, thus suggesting high venous pressure. Blood pressure was 100/70 mmHg, heart rate was 130 beats per minute, and respiratory rate was 20 breaths per minute.
A twelve-lead electrocardiogram showed sinus tachycardia, with two ventricular ectopies, low amplitude of R wave in anterior precordial leads, and low amplitude of QRS in peripheral leads. Chest X-ray demonstrated bilateral pleural effusion and pulmonary interstitial oedema. High-sensitivity troponin I was slightly increased (0.09 ng/mL, normal value < 0.04) and NT-pro-B-type natriuretic peptide was 1973 pg/mL (normal value < 450). Mild elevation of white blood cell count and mild anaemia were also found, without any abnormality in renal and liver functions. Intravenous infusion of furosemide (240 mg per day) and spironolactone (200 mg once daily) were promptly started. A transthoracic echocardiography showed severely dilated and globally hypokinetic left ventricle, with ejection fraction 11% and thinned walls. A significant dilation of both atria together with mild enlargement and hypokinesia of the right ventricle and moderate tricuspid and mitral regurgitations were also found. Moreover, an unusual finding was detected within left ventricular (LV) cavity: the sub-endocardial border of left ventricle seemed entirely covered, from mid-cavity to apex, by several masses, resembling big bubbles. They looked regular, of soft consistency, with a smooth surface and hyperechogenic thin cap with a central core, which appeared with low echogenicity at 3D and mainly 2D echocardiography (Figure 1). No blood flowing inside them was identified by colour Doppler mode, so that non-compaction cardiomyopathy could be excluded. Neither deformation imaging was performed, nor contrast echocardiography for LV opacification, which would have helped with the diagnosis, as the patient was thought to be in a critical condition and ultrasound contrast agent administration was not deemed safe.
A CMR, performed the day after echocardiography, confirmed the severe LV dilatation with global hypokinesia and severe depression of both left and right ventricular systolic function. Endoluminal material was present in the LV chamber, along the subendocardial layer: it obliterated completely the apex, spreading along the septal, inferior and anterior wall and the LV outflow tract and appeared lobulated, hypointense, ‘floating’ in the cine sequences (Figure 2A–C). These masses were lobulated, with smooth regular surface, hyper intense in both T1 (Figure 2D–F) and T2 (Figure 2G–I)-weighted sequences (with fat suppression), hypo intense during the first pass (Figure 3A–C) and both in the early (Figure 3D–F) and delayed enhancement sequences. Material with the same signal characteristics was also seen in the left atrial appendage that was almost completely obliterated (Figure 3E). No areas of subendocardial or intramural delayed enhancement suggestive of fibrosis were found. The signal characteristics of the material adhering to the LV and left atrial appendage was similar to that commonly found in early haemorrhage and led to diagnose massive very acute thrombosis in DCM.
Administration of unfractioned heparin (intravenous bolus of 5000 UI followed by continuous infusion of 20 000–40 000 UI per day), based on activated partial thromboplastin time (APTT), in addiction to diuretics, bisoprolol 1.25 mg once daily and ramipril 2.5 mg once daily, was introduced. Although APTT was maintained at 1.5–2.0-fold of the control level, about 1 week after CMR and the beginning of heparin therapy, echocardiography showed an unexpected change of intracardiac masses: in spite of being reduced, they appeared markedly increased in dimension, cone-shaped and hyperechogenic with enhanced consistency, thus fulfilling echocardiographic criteria of solid and fixed thrombi (Figure 4A–C). Contrast-enhanced computed tomography, performed in the same day of latter echocardiography, confirmed the presence of hypodense material, mainly in the LV apex, suggestive of huge intraventricular thrombosis and excluded concomitant pulmonary thromboembolism (Figure 5). Thus, the patient started warfarin 5 mg once daily in addition to unfractioned heparin, by maintaining an APTT constantly at two-fold of the normal level. Contemporarily, as central and peripheral congestion was resolved, de-escalation of diuretic therapy up to oral dose of furosemide 25 mg three times a day was done. Then, unfractioned heparin was stopped when international normalized ratio reached 2.5.
One week later, no sign of thrombosis was identifiable any more at echocardiography (Figure 4D). However, the patient could not be discharged at home, due to onset of frequent ventricular arrhythmias, which were treated by intravenous continuous infusion of magnesium sulfate (10 g per day) and amiodarone (900 mg per day). Inotropes, such as dobutamine, which would have been useful to increase LV contractility, were avoided due to risk of worsen ventricular arrhythmia. Similarly, bromocriptine treatment, which would have been useful in our patient because of high rate of full LV recovery reported, could not be administered due to its prothrombotic effect.
About 15 days after starting medical therapy, LV dysfunction persisted associated to electrical instability, so that defibrillator implantation was firstly considered, but, as she was young, heart transplantation was also prematurely proposed. After brief screening, on Day 18th, the patient was urgently transferred to the referring transplant centre in another hospital. Bridge therapy to transplant, such as LV assist device, was planned, while only titration of bisoprolol up to 1.25 mg b.i.d. could be attempted. Further escalation of heart failure therapy could not be realized, due to prohibitive arterial pressure values. Neprilysin inhibitor was not approved for treatment at the time of patient hospitalization. In the meanwhile, ventricular arrhythmias became more and more frequent and sustained. Thanks to prompt availability of donor, no bridge therapy was actually needed, and the patient was urgently transplanted. No histopathological examination was done on the diseased heart, in order to confirm imaging findings. Unfortunately, we only knew that transplantation was successful, but patient follow-up was missed in our hospital and no other clinical data were available.
Figure 1 Two-dimensional (A) and three-dimensional (B) transthoracic echocardiographic images in four-chamber view. Intraventricular apical masses (arrows) look like bubbles or cysts.
Figure 2 Cardiac magnetic resonance images, in horizontal (A) and vertical (B) long-axis views and in short-axis view (C) by cine Steady State Free Precession sequence. Multislice images in short-axis view from basal (D, G) to apical (F, I), by T1- (D–F) and T2- (G–I) weighted sequences, showing hyperintense signal.
Figure 3 Cardiac magnetic resonance short axis images, from basal (A) to apical (C) levels, during first pass perfusion sequence (A-C), displaying the absence of contrast uptake. Early enhancement sequence images in horizontal (D) and vertical (E) long-axis and in short-axis views (F), showing the hypointense signal of the masses. Trombus in left atrial appendage is marked by (*).
Figure 4 Trans-oesophageal (A, B) and transthoracic (C) echocardiographic images 1 week after starting unfractioned heparin showing changed masses. At discharge (D), disappearance of masses can be seen.
Figure 5 Axial images by computed tomography, acquired at two different levels (A, B) after administration of iodinated contrast agent. Hypodense masses without contrast uptake can be seen filling left ventricular cavity.
Discussion
Subacute or chronic intraventricular thrombi appear, at echocardiography, as solid, hyperechogenic masses, which can be irregular, layered, immobile, and broad-based, located mainly where blood flow slows down. In a previous report of PPC,5 ‘fresh’ thrombi were described as shaggy, irregular, non-laminar, and disappeared after 4 days of intravenous heparin. Besides echo-density and size, a strain rate ≥1 s−1 has been proposed to distinguish ‘fresh’ from old thrombosis.6 Deformation imaging was not used at the time of first echocardiographic examination in our case, as thrombotic nature of the masses was not sure, and their appearance could be in keeping with cysts. Moreover, in our patient, in the time interval previously defined for ‘fresh’ thrombosis,6 thrombi rapidly evolved from the very acute to the sub-acute phases: whether it is associated to changes in strain rate values is not known. CMR remains the gold standard in tissue characterization of cardiac masses. In cine sequences, thrombi typically appear as filling defects, mobile or attached to the endocardium; they are very dark both in early and delayed enhancement sequences and are usually hypo-perfused at the first pass. In the Spin-Echo T1 and T2-weighted sequences, acute and sub-acute thrombi can be hyperintense, due to red blood cell lysis and accumulation of paramagnetic compounds such as deoxyhaemoglobin and methaemoglobin, while chronic thrombi become isointense or hypointense due to the progressive replacement by fibrous tissue.4 Although hyperintensity on T2-weighted images is also typical of tumour masses,4 hyperintensity in T1-weighted sequences and strong hypo-intensity at early and delayed enhancement sequences (with an inversion time ≥442 ms required to define thrombi with the best diagnostic accuracy) has a decisive role in establishing the thrombotic nature.7
Such an extensive left ventricle very acute thrombosis has never been reported before at CMR. It is likely that, in our patient, diuretic therapy used to treat heart failure, together with hypercoagulable state usually persisting for 6 weeks after delivery, might have worsened haemoconcentration, thus favouring the thrombus evolution, despite heparin administration. Thus, diuretics and hemoconcentration could have counterbalanced anticoagulant effect of unfractioned heparin. Previous reports do not strictly fit our findings, which uniquely detected the very early phase of thrombi evolution.
Conclusions
In the very acute phase, LV fresh thrombosis may resemble cyst or bubble, with echocardiographic appearance very different from that usually seen, and therapeutic management may be challenging in hypercoagulability states and hemoconcentration. Specific imaging features reveal diagnosis and may tell the natural history of LV thrombosis throughout different stages.
Lead author biography
Dr Gabriella Locorotondo graduated in Medicine and Surgery in 2007 and specialized in Cardiology in 2012. She currently practices transthoracic and transoesophageal echocardiography and has skills in myocardial contrast echocardiography, stress echo, coronary reserve, 3D, and strain. Dr Locorotondo is certified for second level competence in cardiac magnetic resonance imaging and has got a certification of competence for percutaneous treatment of valve heart disease. She has published research articles and book chapter about echocardiography, myocardial contrast echocardiography, and cardiac magnetic resonance, including participation in the EACVI textbook of echocardiography.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
ytaa533_Supplementary_Data Click here for additional data file.
Acknowledgements
We thank Dr R. Marano for support in CMR reporting, Prof. A.G. Rebuzzi and Prof. F. Crea for approving the manuscript.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33598615 | 20,050,010 | 2021-02 |
What was the administration route of drug 'SPIRONOLACTONE'? | 'The bubble heart': an unusual natural history told by multimodality imaging- a case report.
Intracardiac thrombosis is a relatively common pathological condition. Often, it is diagnosed at echocardiography during the subacute or chronic phase. In the very acute phase, tissue composition can make thrombus appearance very different from that usually seen. Fresh thrombosis has been previously found also in peripartum cardiomyopathy (PPC), but with imaging features different from our case.
A 27-year-old woman was referred to our hospital for PPC, with echocardiographic finding of intraventricular masses, resembling big bubbles. Cardiac magnetic resonance (CMR) allowed definitively diagnosing intracardiac 'very acute' thrombosis, which is rarely detected.
Our case provides a practical lesson about management of an unusual presentation of a common problem. When early echocardiography does not allow making a certain diagnosis, CMR can be helpful and decisive, due to its unique ability to provide characterization of intracardiac masses.
Learning points
Fresh thrombi can show a cystic appearance, with echo-lucent centre and hyperechoic boundaries.
They appear hypoperfused at the first pass sequences and look very dark in early enhancement sequences.
Fresh thrombi appear hyperintense in T1 and T2-weighted sequences, depending on presence of oxyhaemoglobin and slowly flowing blood.
Introduction
Intracardiac thrombosis is reported in up to 53% of peripartum cardiomyopathy (PPC), due to the peculiar hypercoagulability state.1 Early certain diagnosis allows promptly starting anticoagulation therapy, but during the very acute phase it can be challenging, because of the unusual appearance of thrombi as ‘bubbles’ or ‘cysts’, as compared to the more widely codified features of high or mid-echo-density masses.2 Indeed, very acute fresh thrombosis may appear at echocardiography as mass with a relatively echo-lucent centre and hyperechoic boundaries between fluid and more organized regions.3 Its diagnosis may be confirmed by cardiac magnetic resonance (CMR).4
Timeline
Delivery after a normal pregnancy
8 weeks after delivery Onset and worsening of dyspnoea
Admission, Day 0 The patient was breathless with pulmonary and peripheral congestion. Blood pressure, heart rate, and respiratory rate were 100/70 mmHg, 130 b.p.m., and 20 breaths per minute, respectively
Echocardiography showed severe left ventricular dilation and contractile dysfunction, with several masses with a soft consistency, a smooth surface, a central core of reduced echogenicity, and a hyperechogenic thin cap
Day 1 Cardiac magnetic resonance allowed to diagnose intracardiac fresh thrombosis
Therapy with intravenous heparin was started
Day 8 Echocardiography showed solid and fixed thrombi
Contrast-enhanced computed tomography confirmed the huge intraventricular thrombosis and excluded concomitant pulmonary thromboembolism
Warfarin therapy was started
Day 15 No sign of thrombus was identifiable at echocardiography
Day 20 Urgent transplant due to absence of contractile improvement and onset of ventricular arrhythmias
Case presentation
A 27-year-old woman, with no previous cardiovascular events, but a family history of dilated cardiomyopathy (DCM), was referred to our intensive care unit 2 months after delivery from her first pregnancy, due to onset of worsening dyspnoea. The patient was not taking any medication before admission, since her previous medical history was unremarkable and delivery was uneventful. She started experiencing breathlessness about 6 weeks after delivery. After started, breathlessness rapidly worsened in 2 weeks, so she was hospitalized. On admission, she appeared breathless, with diffuse pulmonary rales and bilateral legs oedema. Although central venous pressure was not measured, the patient had distended jugular veins, thus suggesting high venous pressure. Blood pressure was 100/70 mmHg, heart rate was 130 beats per minute, and respiratory rate was 20 breaths per minute.
A twelve-lead electrocardiogram showed sinus tachycardia, with two ventricular ectopies, low amplitude of R wave in anterior precordial leads, and low amplitude of QRS in peripheral leads. Chest X-ray demonstrated bilateral pleural effusion and pulmonary interstitial oedema. High-sensitivity troponin I was slightly increased (0.09 ng/mL, normal value < 0.04) and NT-pro-B-type natriuretic peptide was 1973 pg/mL (normal value < 450). Mild elevation of white blood cell count and mild anaemia were also found, without any abnormality in renal and liver functions. Intravenous infusion of furosemide (240 mg per day) and spironolactone (200 mg once daily) were promptly started. A transthoracic echocardiography showed severely dilated and globally hypokinetic left ventricle, with ejection fraction 11% and thinned walls. A significant dilation of both atria together with mild enlargement and hypokinesia of the right ventricle and moderate tricuspid and mitral regurgitations were also found. Moreover, an unusual finding was detected within left ventricular (LV) cavity: the sub-endocardial border of left ventricle seemed entirely covered, from mid-cavity to apex, by several masses, resembling big bubbles. They looked regular, of soft consistency, with a smooth surface and hyperechogenic thin cap with a central core, which appeared with low echogenicity at 3D and mainly 2D echocardiography (Figure 1). No blood flowing inside them was identified by colour Doppler mode, so that non-compaction cardiomyopathy could be excluded. Neither deformation imaging was performed, nor contrast echocardiography for LV opacification, which would have helped with the diagnosis, as the patient was thought to be in a critical condition and ultrasound contrast agent administration was not deemed safe.
A CMR, performed the day after echocardiography, confirmed the severe LV dilatation with global hypokinesia and severe depression of both left and right ventricular systolic function. Endoluminal material was present in the LV chamber, along the subendocardial layer: it obliterated completely the apex, spreading along the septal, inferior and anterior wall and the LV outflow tract and appeared lobulated, hypointense, ‘floating’ in the cine sequences (Figure 2A–C). These masses were lobulated, with smooth regular surface, hyper intense in both T1 (Figure 2D–F) and T2 (Figure 2G–I)-weighted sequences (with fat suppression), hypo intense during the first pass (Figure 3A–C) and both in the early (Figure 3D–F) and delayed enhancement sequences. Material with the same signal characteristics was also seen in the left atrial appendage that was almost completely obliterated (Figure 3E). No areas of subendocardial or intramural delayed enhancement suggestive of fibrosis were found. The signal characteristics of the material adhering to the LV and left atrial appendage was similar to that commonly found in early haemorrhage and led to diagnose massive very acute thrombosis in DCM.
Administration of unfractioned heparin (intravenous bolus of 5000 UI followed by continuous infusion of 20 000–40 000 UI per day), based on activated partial thromboplastin time (APTT), in addiction to diuretics, bisoprolol 1.25 mg once daily and ramipril 2.5 mg once daily, was introduced. Although APTT was maintained at 1.5–2.0-fold of the control level, about 1 week after CMR and the beginning of heparin therapy, echocardiography showed an unexpected change of intracardiac masses: in spite of being reduced, they appeared markedly increased in dimension, cone-shaped and hyperechogenic with enhanced consistency, thus fulfilling echocardiographic criteria of solid and fixed thrombi (Figure 4A–C). Contrast-enhanced computed tomography, performed in the same day of latter echocardiography, confirmed the presence of hypodense material, mainly in the LV apex, suggestive of huge intraventricular thrombosis and excluded concomitant pulmonary thromboembolism (Figure 5). Thus, the patient started warfarin 5 mg once daily in addition to unfractioned heparin, by maintaining an APTT constantly at two-fold of the normal level. Contemporarily, as central and peripheral congestion was resolved, de-escalation of diuretic therapy up to oral dose of furosemide 25 mg three times a day was done. Then, unfractioned heparin was stopped when international normalized ratio reached 2.5.
One week later, no sign of thrombosis was identifiable any more at echocardiography (Figure 4D). However, the patient could not be discharged at home, due to onset of frequent ventricular arrhythmias, which were treated by intravenous continuous infusion of magnesium sulfate (10 g per day) and amiodarone (900 mg per day). Inotropes, such as dobutamine, which would have been useful to increase LV contractility, were avoided due to risk of worsen ventricular arrhythmia. Similarly, bromocriptine treatment, which would have been useful in our patient because of high rate of full LV recovery reported, could not be administered due to its prothrombotic effect.
About 15 days after starting medical therapy, LV dysfunction persisted associated to electrical instability, so that defibrillator implantation was firstly considered, but, as she was young, heart transplantation was also prematurely proposed. After brief screening, on Day 18th, the patient was urgently transferred to the referring transplant centre in another hospital. Bridge therapy to transplant, such as LV assist device, was planned, while only titration of bisoprolol up to 1.25 mg b.i.d. could be attempted. Further escalation of heart failure therapy could not be realized, due to prohibitive arterial pressure values. Neprilysin inhibitor was not approved for treatment at the time of patient hospitalization. In the meanwhile, ventricular arrhythmias became more and more frequent and sustained. Thanks to prompt availability of donor, no bridge therapy was actually needed, and the patient was urgently transplanted. No histopathological examination was done on the diseased heart, in order to confirm imaging findings. Unfortunately, we only knew that transplantation was successful, but patient follow-up was missed in our hospital and no other clinical data were available.
Figure 1 Two-dimensional (A) and three-dimensional (B) transthoracic echocardiographic images in four-chamber view. Intraventricular apical masses (arrows) look like bubbles or cysts.
Figure 2 Cardiac magnetic resonance images, in horizontal (A) and vertical (B) long-axis views and in short-axis view (C) by cine Steady State Free Precession sequence. Multislice images in short-axis view from basal (D, G) to apical (F, I), by T1- (D–F) and T2- (G–I) weighted sequences, showing hyperintense signal.
Figure 3 Cardiac magnetic resonance short axis images, from basal (A) to apical (C) levels, during first pass perfusion sequence (A-C), displaying the absence of contrast uptake. Early enhancement sequence images in horizontal (D) and vertical (E) long-axis and in short-axis views (F), showing the hypointense signal of the masses. Trombus in left atrial appendage is marked by (*).
Figure 4 Trans-oesophageal (A, B) and transthoracic (C) echocardiographic images 1 week after starting unfractioned heparin showing changed masses. At discharge (D), disappearance of masses can be seen.
Figure 5 Axial images by computed tomography, acquired at two different levels (A, B) after administration of iodinated contrast agent. Hypodense masses without contrast uptake can be seen filling left ventricular cavity.
Discussion
Subacute or chronic intraventricular thrombi appear, at echocardiography, as solid, hyperechogenic masses, which can be irregular, layered, immobile, and broad-based, located mainly where blood flow slows down. In a previous report of PPC,5 ‘fresh’ thrombi were described as shaggy, irregular, non-laminar, and disappeared after 4 days of intravenous heparin. Besides echo-density and size, a strain rate ≥1 s−1 has been proposed to distinguish ‘fresh’ from old thrombosis.6 Deformation imaging was not used at the time of first echocardiographic examination in our case, as thrombotic nature of the masses was not sure, and their appearance could be in keeping with cysts. Moreover, in our patient, in the time interval previously defined for ‘fresh’ thrombosis,6 thrombi rapidly evolved from the very acute to the sub-acute phases: whether it is associated to changes in strain rate values is not known. CMR remains the gold standard in tissue characterization of cardiac masses. In cine sequences, thrombi typically appear as filling defects, mobile or attached to the endocardium; they are very dark both in early and delayed enhancement sequences and are usually hypo-perfused at the first pass. In the Spin-Echo T1 and T2-weighted sequences, acute and sub-acute thrombi can be hyperintense, due to red blood cell lysis and accumulation of paramagnetic compounds such as deoxyhaemoglobin and methaemoglobin, while chronic thrombi become isointense or hypointense due to the progressive replacement by fibrous tissue.4 Although hyperintensity on T2-weighted images is also typical of tumour masses,4 hyperintensity in T1-weighted sequences and strong hypo-intensity at early and delayed enhancement sequences (with an inversion time ≥442 ms required to define thrombi with the best diagnostic accuracy) has a decisive role in establishing the thrombotic nature.7
Such an extensive left ventricle very acute thrombosis has never been reported before at CMR. It is likely that, in our patient, diuretic therapy used to treat heart failure, together with hypercoagulable state usually persisting for 6 weeks after delivery, might have worsened haemoconcentration, thus favouring the thrombus evolution, despite heparin administration. Thus, diuretics and hemoconcentration could have counterbalanced anticoagulant effect of unfractioned heparin. Previous reports do not strictly fit our findings, which uniquely detected the very early phase of thrombi evolution.
Conclusions
In the very acute phase, LV fresh thrombosis may resemble cyst or bubble, with echocardiographic appearance very different from that usually seen, and therapeutic management may be challenging in hypercoagulability states and hemoconcentration. Specific imaging features reveal diagnosis and may tell the natural history of LV thrombosis throughout different stages.
Lead author biography
Dr Gabriella Locorotondo graduated in Medicine and Surgery in 2007 and specialized in Cardiology in 2012. She currently practices transthoracic and transoesophageal echocardiography and has skills in myocardial contrast echocardiography, stress echo, coronary reserve, 3D, and strain. Dr Locorotondo is certified for second level competence in cardiac magnetic resonance imaging and has got a certification of competence for percutaneous treatment of valve heart disease. She has published research articles and book chapter about echocardiography, myocardial contrast echocardiography, and cardiac magnetic resonance, including participation in the EACVI textbook of echocardiography.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
ytaa533_Supplementary_Data Click here for additional data file.
Acknowledgements
We thank Dr R. Marano for support in CMR reporting, Prof. A.G. Rebuzzi and Prof. F. Crea for approving the manuscript.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33598615 | 20,039,449 | 2021-02 |
What was the dosage of drug 'HEPARIN SODIUM'? | 'The bubble heart': an unusual natural history told by multimodality imaging- a case report.
Intracardiac thrombosis is a relatively common pathological condition. Often, it is diagnosed at echocardiography during the subacute or chronic phase. In the very acute phase, tissue composition can make thrombus appearance very different from that usually seen. Fresh thrombosis has been previously found also in peripartum cardiomyopathy (PPC), but with imaging features different from our case.
A 27-year-old woman was referred to our hospital for PPC, with echocardiographic finding of intraventricular masses, resembling big bubbles. Cardiac magnetic resonance (CMR) allowed definitively diagnosing intracardiac 'very acute' thrombosis, which is rarely detected.
Our case provides a practical lesson about management of an unusual presentation of a common problem. When early echocardiography does not allow making a certain diagnosis, CMR can be helpful and decisive, due to its unique ability to provide characterization of intracardiac masses.
Learning points
Fresh thrombi can show a cystic appearance, with echo-lucent centre and hyperechoic boundaries.
They appear hypoperfused at the first pass sequences and look very dark in early enhancement sequences.
Fresh thrombi appear hyperintense in T1 and T2-weighted sequences, depending on presence of oxyhaemoglobin and slowly flowing blood.
Introduction
Intracardiac thrombosis is reported in up to 53% of peripartum cardiomyopathy (PPC), due to the peculiar hypercoagulability state.1 Early certain diagnosis allows promptly starting anticoagulation therapy, but during the very acute phase it can be challenging, because of the unusual appearance of thrombi as ‘bubbles’ or ‘cysts’, as compared to the more widely codified features of high or mid-echo-density masses.2 Indeed, very acute fresh thrombosis may appear at echocardiography as mass with a relatively echo-lucent centre and hyperechoic boundaries between fluid and more organized regions.3 Its diagnosis may be confirmed by cardiac magnetic resonance (CMR).4
Timeline
Delivery after a normal pregnancy
8 weeks after delivery Onset and worsening of dyspnoea
Admission, Day 0 The patient was breathless with pulmonary and peripheral congestion. Blood pressure, heart rate, and respiratory rate were 100/70 mmHg, 130 b.p.m., and 20 breaths per minute, respectively
Echocardiography showed severe left ventricular dilation and contractile dysfunction, with several masses with a soft consistency, a smooth surface, a central core of reduced echogenicity, and a hyperechogenic thin cap
Day 1 Cardiac magnetic resonance allowed to diagnose intracardiac fresh thrombosis
Therapy with intravenous heparin was started
Day 8 Echocardiography showed solid and fixed thrombi
Contrast-enhanced computed tomography confirmed the huge intraventricular thrombosis and excluded concomitant pulmonary thromboembolism
Warfarin therapy was started
Day 15 No sign of thrombus was identifiable at echocardiography
Day 20 Urgent transplant due to absence of contractile improvement and onset of ventricular arrhythmias
Case presentation
A 27-year-old woman, with no previous cardiovascular events, but a family history of dilated cardiomyopathy (DCM), was referred to our intensive care unit 2 months after delivery from her first pregnancy, due to onset of worsening dyspnoea. The patient was not taking any medication before admission, since her previous medical history was unremarkable and delivery was uneventful. She started experiencing breathlessness about 6 weeks after delivery. After started, breathlessness rapidly worsened in 2 weeks, so she was hospitalized. On admission, she appeared breathless, with diffuse pulmonary rales and bilateral legs oedema. Although central venous pressure was not measured, the patient had distended jugular veins, thus suggesting high venous pressure. Blood pressure was 100/70 mmHg, heart rate was 130 beats per minute, and respiratory rate was 20 breaths per minute.
A twelve-lead electrocardiogram showed sinus tachycardia, with two ventricular ectopies, low amplitude of R wave in anterior precordial leads, and low amplitude of QRS in peripheral leads. Chest X-ray demonstrated bilateral pleural effusion and pulmonary interstitial oedema. High-sensitivity troponin I was slightly increased (0.09 ng/mL, normal value < 0.04) and NT-pro-B-type natriuretic peptide was 1973 pg/mL (normal value < 450). Mild elevation of white blood cell count and mild anaemia were also found, without any abnormality in renal and liver functions. Intravenous infusion of furosemide (240 mg per day) and spironolactone (200 mg once daily) were promptly started. A transthoracic echocardiography showed severely dilated and globally hypokinetic left ventricle, with ejection fraction 11% and thinned walls. A significant dilation of both atria together with mild enlargement and hypokinesia of the right ventricle and moderate tricuspid and mitral regurgitations were also found. Moreover, an unusual finding was detected within left ventricular (LV) cavity: the sub-endocardial border of left ventricle seemed entirely covered, from mid-cavity to apex, by several masses, resembling big bubbles. They looked regular, of soft consistency, with a smooth surface and hyperechogenic thin cap with a central core, which appeared with low echogenicity at 3D and mainly 2D echocardiography (Figure 1). No blood flowing inside them was identified by colour Doppler mode, so that non-compaction cardiomyopathy could be excluded. Neither deformation imaging was performed, nor contrast echocardiography for LV opacification, which would have helped with the diagnosis, as the patient was thought to be in a critical condition and ultrasound contrast agent administration was not deemed safe.
A CMR, performed the day after echocardiography, confirmed the severe LV dilatation with global hypokinesia and severe depression of both left and right ventricular systolic function. Endoluminal material was present in the LV chamber, along the subendocardial layer: it obliterated completely the apex, spreading along the septal, inferior and anterior wall and the LV outflow tract and appeared lobulated, hypointense, ‘floating’ in the cine sequences (Figure 2A–C). These masses were lobulated, with smooth regular surface, hyper intense in both T1 (Figure 2D–F) and T2 (Figure 2G–I)-weighted sequences (with fat suppression), hypo intense during the first pass (Figure 3A–C) and both in the early (Figure 3D–F) and delayed enhancement sequences. Material with the same signal characteristics was also seen in the left atrial appendage that was almost completely obliterated (Figure 3E). No areas of subendocardial or intramural delayed enhancement suggestive of fibrosis were found. The signal characteristics of the material adhering to the LV and left atrial appendage was similar to that commonly found in early haemorrhage and led to diagnose massive very acute thrombosis in DCM.
Administration of unfractioned heparin (intravenous bolus of 5000 UI followed by continuous infusion of 20 000–40 000 UI per day), based on activated partial thromboplastin time (APTT), in addiction to diuretics, bisoprolol 1.25 mg once daily and ramipril 2.5 mg once daily, was introduced. Although APTT was maintained at 1.5–2.0-fold of the control level, about 1 week after CMR and the beginning of heparin therapy, echocardiography showed an unexpected change of intracardiac masses: in spite of being reduced, they appeared markedly increased in dimension, cone-shaped and hyperechogenic with enhanced consistency, thus fulfilling echocardiographic criteria of solid and fixed thrombi (Figure 4A–C). Contrast-enhanced computed tomography, performed in the same day of latter echocardiography, confirmed the presence of hypodense material, mainly in the LV apex, suggestive of huge intraventricular thrombosis and excluded concomitant pulmonary thromboembolism (Figure 5). Thus, the patient started warfarin 5 mg once daily in addition to unfractioned heparin, by maintaining an APTT constantly at two-fold of the normal level. Contemporarily, as central and peripheral congestion was resolved, de-escalation of diuretic therapy up to oral dose of furosemide 25 mg three times a day was done. Then, unfractioned heparin was stopped when international normalized ratio reached 2.5.
One week later, no sign of thrombosis was identifiable any more at echocardiography (Figure 4D). However, the patient could not be discharged at home, due to onset of frequent ventricular arrhythmias, which were treated by intravenous continuous infusion of magnesium sulfate (10 g per day) and amiodarone (900 mg per day). Inotropes, such as dobutamine, which would have been useful to increase LV contractility, were avoided due to risk of worsen ventricular arrhythmia. Similarly, bromocriptine treatment, which would have been useful in our patient because of high rate of full LV recovery reported, could not be administered due to its prothrombotic effect.
About 15 days after starting medical therapy, LV dysfunction persisted associated to electrical instability, so that defibrillator implantation was firstly considered, but, as she was young, heart transplantation was also prematurely proposed. After brief screening, on Day 18th, the patient was urgently transferred to the referring transplant centre in another hospital. Bridge therapy to transplant, such as LV assist device, was planned, while only titration of bisoprolol up to 1.25 mg b.i.d. could be attempted. Further escalation of heart failure therapy could not be realized, due to prohibitive arterial pressure values. Neprilysin inhibitor was not approved for treatment at the time of patient hospitalization. In the meanwhile, ventricular arrhythmias became more and more frequent and sustained. Thanks to prompt availability of donor, no bridge therapy was actually needed, and the patient was urgently transplanted. No histopathological examination was done on the diseased heart, in order to confirm imaging findings. Unfortunately, we only knew that transplantation was successful, but patient follow-up was missed in our hospital and no other clinical data were available.
Figure 1 Two-dimensional (A) and three-dimensional (B) transthoracic echocardiographic images in four-chamber view. Intraventricular apical masses (arrows) look like bubbles or cysts.
Figure 2 Cardiac magnetic resonance images, in horizontal (A) and vertical (B) long-axis views and in short-axis view (C) by cine Steady State Free Precession sequence. Multislice images in short-axis view from basal (D, G) to apical (F, I), by T1- (D–F) and T2- (G–I) weighted sequences, showing hyperintense signal.
Figure 3 Cardiac magnetic resonance short axis images, from basal (A) to apical (C) levels, during first pass perfusion sequence (A-C), displaying the absence of contrast uptake. Early enhancement sequence images in horizontal (D) and vertical (E) long-axis and in short-axis views (F), showing the hypointense signal of the masses. Trombus in left atrial appendage is marked by (*).
Figure 4 Trans-oesophageal (A, B) and transthoracic (C) echocardiographic images 1 week after starting unfractioned heparin showing changed masses. At discharge (D), disappearance of masses can be seen.
Figure 5 Axial images by computed tomography, acquired at two different levels (A, B) after administration of iodinated contrast agent. Hypodense masses without contrast uptake can be seen filling left ventricular cavity.
Discussion
Subacute or chronic intraventricular thrombi appear, at echocardiography, as solid, hyperechogenic masses, which can be irregular, layered, immobile, and broad-based, located mainly where blood flow slows down. In a previous report of PPC,5 ‘fresh’ thrombi were described as shaggy, irregular, non-laminar, and disappeared after 4 days of intravenous heparin. Besides echo-density and size, a strain rate ≥1 s−1 has been proposed to distinguish ‘fresh’ from old thrombosis.6 Deformation imaging was not used at the time of first echocardiographic examination in our case, as thrombotic nature of the masses was not sure, and their appearance could be in keeping with cysts. Moreover, in our patient, in the time interval previously defined for ‘fresh’ thrombosis,6 thrombi rapidly evolved from the very acute to the sub-acute phases: whether it is associated to changes in strain rate values is not known. CMR remains the gold standard in tissue characterization of cardiac masses. In cine sequences, thrombi typically appear as filling defects, mobile or attached to the endocardium; they are very dark both in early and delayed enhancement sequences and are usually hypo-perfused at the first pass. In the Spin-Echo T1 and T2-weighted sequences, acute and sub-acute thrombi can be hyperintense, due to red blood cell lysis and accumulation of paramagnetic compounds such as deoxyhaemoglobin and methaemoglobin, while chronic thrombi become isointense or hypointense due to the progressive replacement by fibrous tissue.4 Although hyperintensity on T2-weighted images is also typical of tumour masses,4 hyperintensity in T1-weighted sequences and strong hypo-intensity at early and delayed enhancement sequences (with an inversion time ≥442 ms required to define thrombi with the best diagnostic accuracy) has a decisive role in establishing the thrombotic nature.7
Such an extensive left ventricle very acute thrombosis has never been reported before at CMR. It is likely that, in our patient, diuretic therapy used to treat heart failure, together with hypercoagulable state usually persisting for 6 weeks after delivery, might have worsened haemoconcentration, thus favouring the thrombus evolution, despite heparin administration. Thus, diuretics and hemoconcentration could have counterbalanced anticoagulant effect of unfractioned heparin. Previous reports do not strictly fit our findings, which uniquely detected the very early phase of thrombi evolution.
Conclusions
In the very acute phase, LV fresh thrombosis may resemble cyst or bubble, with echocardiographic appearance very different from that usually seen, and therapeutic management may be challenging in hypercoagulability states and hemoconcentration. Specific imaging features reveal diagnosis and may tell the natural history of LV thrombosis throughout different stages.
Lead author biography
Dr Gabriella Locorotondo graduated in Medicine and Surgery in 2007 and specialized in Cardiology in 2012. She currently practices transthoracic and transoesophageal echocardiography and has skills in myocardial contrast echocardiography, stress echo, coronary reserve, 3D, and strain. Dr Locorotondo is certified for second level competence in cardiac magnetic resonance imaging and has got a certification of competence for percutaneous treatment of valve heart disease. She has published research articles and book chapter about echocardiography, myocardial contrast echocardiography, and cardiac magnetic resonance, including participation in the EACVI textbook of echocardiography.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
ytaa533_Supplementary_Data Click here for additional data file.
Acknowledgements
We thank Dr R. Marano for support in CMR reporting, Prof. A.G. Rebuzzi and Prof. F. Crea for approving the manuscript.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared. | INTRAVENOUS BOLUS OF 5000 UI FOLLOWED BY CONTINUOUS INFUSION OF 20000-40000 UI PER DAY | DrugDosageText | CC BY-NC | 33598615 | 20,050,010 | 2021-02 |
What was the outcome of reaction 'Cardiac ventricular thrombosis'? | 'The bubble heart': an unusual natural history told by multimodality imaging- a case report.
Intracardiac thrombosis is a relatively common pathological condition. Often, it is diagnosed at echocardiography during the subacute or chronic phase. In the very acute phase, tissue composition can make thrombus appearance very different from that usually seen. Fresh thrombosis has been previously found also in peripartum cardiomyopathy (PPC), but with imaging features different from our case.
A 27-year-old woman was referred to our hospital for PPC, with echocardiographic finding of intraventricular masses, resembling big bubbles. Cardiac magnetic resonance (CMR) allowed definitively diagnosing intracardiac 'very acute' thrombosis, which is rarely detected.
Our case provides a practical lesson about management of an unusual presentation of a common problem. When early echocardiography does not allow making a certain diagnosis, CMR can be helpful and decisive, due to its unique ability to provide characterization of intracardiac masses.
Learning points
Fresh thrombi can show a cystic appearance, with echo-lucent centre and hyperechoic boundaries.
They appear hypoperfused at the first pass sequences and look very dark in early enhancement sequences.
Fresh thrombi appear hyperintense in T1 and T2-weighted sequences, depending on presence of oxyhaemoglobin and slowly flowing blood.
Introduction
Intracardiac thrombosis is reported in up to 53% of peripartum cardiomyopathy (PPC), due to the peculiar hypercoagulability state.1 Early certain diagnosis allows promptly starting anticoagulation therapy, but during the very acute phase it can be challenging, because of the unusual appearance of thrombi as ‘bubbles’ or ‘cysts’, as compared to the more widely codified features of high or mid-echo-density masses.2 Indeed, very acute fresh thrombosis may appear at echocardiography as mass with a relatively echo-lucent centre and hyperechoic boundaries between fluid and more organized regions.3 Its diagnosis may be confirmed by cardiac magnetic resonance (CMR).4
Timeline
Delivery after a normal pregnancy
8 weeks after delivery Onset and worsening of dyspnoea
Admission, Day 0 The patient was breathless with pulmonary and peripheral congestion. Blood pressure, heart rate, and respiratory rate were 100/70 mmHg, 130 b.p.m., and 20 breaths per minute, respectively
Echocardiography showed severe left ventricular dilation and contractile dysfunction, with several masses with a soft consistency, a smooth surface, a central core of reduced echogenicity, and a hyperechogenic thin cap
Day 1 Cardiac magnetic resonance allowed to diagnose intracardiac fresh thrombosis
Therapy with intravenous heparin was started
Day 8 Echocardiography showed solid and fixed thrombi
Contrast-enhanced computed tomography confirmed the huge intraventricular thrombosis and excluded concomitant pulmonary thromboembolism
Warfarin therapy was started
Day 15 No sign of thrombus was identifiable at echocardiography
Day 20 Urgent transplant due to absence of contractile improvement and onset of ventricular arrhythmias
Case presentation
A 27-year-old woman, with no previous cardiovascular events, but a family history of dilated cardiomyopathy (DCM), was referred to our intensive care unit 2 months after delivery from her first pregnancy, due to onset of worsening dyspnoea. The patient was not taking any medication before admission, since her previous medical history was unremarkable and delivery was uneventful. She started experiencing breathlessness about 6 weeks after delivery. After started, breathlessness rapidly worsened in 2 weeks, so she was hospitalized. On admission, she appeared breathless, with diffuse pulmonary rales and bilateral legs oedema. Although central venous pressure was not measured, the patient had distended jugular veins, thus suggesting high venous pressure. Blood pressure was 100/70 mmHg, heart rate was 130 beats per minute, and respiratory rate was 20 breaths per minute.
A twelve-lead electrocardiogram showed sinus tachycardia, with two ventricular ectopies, low amplitude of R wave in anterior precordial leads, and low amplitude of QRS in peripheral leads. Chest X-ray demonstrated bilateral pleural effusion and pulmonary interstitial oedema. High-sensitivity troponin I was slightly increased (0.09 ng/mL, normal value < 0.04) and NT-pro-B-type natriuretic peptide was 1973 pg/mL (normal value < 450). Mild elevation of white blood cell count and mild anaemia were also found, without any abnormality in renal and liver functions. Intravenous infusion of furosemide (240 mg per day) and spironolactone (200 mg once daily) were promptly started. A transthoracic echocardiography showed severely dilated and globally hypokinetic left ventricle, with ejection fraction 11% and thinned walls. A significant dilation of both atria together with mild enlargement and hypokinesia of the right ventricle and moderate tricuspid and mitral regurgitations were also found. Moreover, an unusual finding was detected within left ventricular (LV) cavity: the sub-endocardial border of left ventricle seemed entirely covered, from mid-cavity to apex, by several masses, resembling big bubbles. They looked regular, of soft consistency, with a smooth surface and hyperechogenic thin cap with a central core, which appeared with low echogenicity at 3D and mainly 2D echocardiography (Figure 1). No blood flowing inside them was identified by colour Doppler mode, so that non-compaction cardiomyopathy could be excluded. Neither deformation imaging was performed, nor contrast echocardiography for LV opacification, which would have helped with the diagnosis, as the patient was thought to be in a critical condition and ultrasound contrast agent administration was not deemed safe.
A CMR, performed the day after echocardiography, confirmed the severe LV dilatation with global hypokinesia and severe depression of both left and right ventricular systolic function. Endoluminal material was present in the LV chamber, along the subendocardial layer: it obliterated completely the apex, spreading along the septal, inferior and anterior wall and the LV outflow tract and appeared lobulated, hypointense, ‘floating’ in the cine sequences (Figure 2A–C). These masses were lobulated, with smooth regular surface, hyper intense in both T1 (Figure 2D–F) and T2 (Figure 2G–I)-weighted sequences (with fat suppression), hypo intense during the first pass (Figure 3A–C) and both in the early (Figure 3D–F) and delayed enhancement sequences. Material with the same signal characteristics was also seen in the left atrial appendage that was almost completely obliterated (Figure 3E). No areas of subendocardial or intramural delayed enhancement suggestive of fibrosis were found. The signal characteristics of the material adhering to the LV and left atrial appendage was similar to that commonly found in early haemorrhage and led to diagnose massive very acute thrombosis in DCM.
Administration of unfractioned heparin (intravenous bolus of 5000 UI followed by continuous infusion of 20 000–40 000 UI per day), based on activated partial thromboplastin time (APTT), in addiction to diuretics, bisoprolol 1.25 mg once daily and ramipril 2.5 mg once daily, was introduced. Although APTT was maintained at 1.5–2.0-fold of the control level, about 1 week after CMR and the beginning of heparin therapy, echocardiography showed an unexpected change of intracardiac masses: in spite of being reduced, they appeared markedly increased in dimension, cone-shaped and hyperechogenic with enhanced consistency, thus fulfilling echocardiographic criteria of solid and fixed thrombi (Figure 4A–C). Contrast-enhanced computed tomography, performed in the same day of latter echocardiography, confirmed the presence of hypodense material, mainly in the LV apex, suggestive of huge intraventricular thrombosis and excluded concomitant pulmonary thromboembolism (Figure 5). Thus, the patient started warfarin 5 mg once daily in addition to unfractioned heparin, by maintaining an APTT constantly at two-fold of the normal level. Contemporarily, as central and peripheral congestion was resolved, de-escalation of diuretic therapy up to oral dose of furosemide 25 mg three times a day was done. Then, unfractioned heparin was stopped when international normalized ratio reached 2.5.
One week later, no sign of thrombosis was identifiable any more at echocardiography (Figure 4D). However, the patient could not be discharged at home, due to onset of frequent ventricular arrhythmias, which were treated by intravenous continuous infusion of magnesium sulfate (10 g per day) and amiodarone (900 mg per day). Inotropes, such as dobutamine, which would have been useful to increase LV contractility, were avoided due to risk of worsen ventricular arrhythmia. Similarly, bromocriptine treatment, which would have been useful in our patient because of high rate of full LV recovery reported, could not be administered due to its prothrombotic effect.
About 15 days after starting medical therapy, LV dysfunction persisted associated to electrical instability, so that defibrillator implantation was firstly considered, but, as she was young, heart transplantation was also prematurely proposed. After brief screening, on Day 18th, the patient was urgently transferred to the referring transplant centre in another hospital. Bridge therapy to transplant, such as LV assist device, was planned, while only titration of bisoprolol up to 1.25 mg b.i.d. could be attempted. Further escalation of heart failure therapy could not be realized, due to prohibitive arterial pressure values. Neprilysin inhibitor was not approved for treatment at the time of patient hospitalization. In the meanwhile, ventricular arrhythmias became more and more frequent and sustained. Thanks to prompt availability of donor, no bridge therapy was actually needed, and the patient was urgently transplanted. No histopathological examination was done on the diseased heart, in order to confirm imaging findings. Unfortunately, we only knew that transplantation was successful, but patient follow-up was missed in our hospital and no other clinical data were available.
Figure 1 Two-dimensional (A) and three-dimensional (B) transthoracic echocardiographic images in four-chamber view. Intraventricular apical masses (arrows) look like bubbles or cysts.
Figure 2 Cardiac magnetic resonance images, in horizontal (A) and vertical (B) long-axis views and in short-axis view (C) by cine Steady State Free Precession sequence. Multislice images in short-axis view from basal (D, G) to apical (F, I), by T1- (D–F) and T2- (G–I) weighted sequences, showing hyperintense signal.
Figure 3 Cardiac magnetic resonance short axis images, from basal (A) to apical (C) levels, during first pass perfusion sequence (A-C), displaying the absence of contrast uptake. Early enhancement sequence images in horizontal (D) and vertical (E) long-axis and in short-axis views (F), showing the hypointense signal of the masses. Trombus in left atrial appendage is marked by (*).
Figure 4 Trans-oesophageal (A, B) and transthoracic (C) echocardiographic images 1 week after starting unfractioned heparin showing changed masses. At discharge (D), disappearance of masses can be seen.
Figure 5 Axial images by computed tomography, acquired at two different levels (A, B) after administration of iodinated contrast agent. Hypodense masses without contrast uptake can be seen filling left ventricular cavity.
Discussion
Subacute or chronic intraventricular thrombi appear, at echocardiography, as solid, hyperechogenic masses, which can be irregular, layered, immobile, and broad-based, located mainly where blood flow slows down. In a previous report of PPC,5 ‘fresh’ thrombi were described as shaggy, irregular, non-laminar, and disappeared after 4 days of intravenous heparin. Besides echo-density and size, a strain rate ≥1 s−1 has been proposed to distinguish ‘fresh’ from old thrombosis.6 Deformation imaging was not used at the time of first echocardiographic examination in our case, as thrombotic nature of the masses was not sure, and their appearance could be in keeping with cysts. Moreover, in our patient, in the time interval previously defined for ‘fresh’ thrombosis,6 thrombi rapidly evolved from the very acute to the sub-acute phases: whether it is associated to changes in strain rate values is not known. CMR remains the gold standard in tissue characterization of cardiac masses. In cine sequences, thrombi typically appear as filling defects, mobile or attached to the endocardium; they are very dark both in early and delayed enhancement sequences and are usually hypo-perfused at the first pass. In the Spin-Echo T1 and T2-weighted sequences, acute and sub-acute thrombi can be hyperintense, due to red blood cell lysis and accumulation of paramagnetic compounds such as deoxyhaemoglobin and methaemoglobin, while chronic thrombi become isointense or hypointense due to the progressive replacement by fibrous tissue.4 Although hyperintensity on T2-weighted images is also typical of tumour masses,4 hyperintensity in T1-weighted sequences and strong hypo-intensity at early and delayed enhancement sequences (with an inversion time ≥442 ms required to define thrombi with the best diagnostic accuracy) has a decisive role in establishing the thrombotic nature.7
Such an extensive left ventricle very acute thrombosis has never been reported before at CMR. It is likely that, in our patient, diuretic therapy used to treat heart failure, together with hypercoagulable state usually persisting for 6 weeks after delivery, might have worsened haemoconcentration, thus favouring the thrombus evolution, despite heparin administration. Thus, diuretics and hemoconcentration could have counterbalanced anticoagulant effect of unfractioned heparin. Previous reports do not strictly fit our findings, which uniquely detected the very early phase of thrombi evolution.
Conclusions
In the very acute phase, LV fresh thrombosis may resemble cyst or bubble, with echocardiographic appearance very different from that usually seen, and therapeutic management may be challenging in hypercoagulability states and hemoconcentration. Specific imaging features reveal diagnosis and may tell the natural history of LV thrombosis throughout different stages.
Lead author biography
Dr Gabriella Locorotondo graduated in Medicine and Surgery in 2007 and specialized in Cardiology in 2012. She currently practices transthoracic and transoesophageal echocardiography and has skills in myocardial contrast echocardiography, stress echo, coronary reserve, 3D, and strain. Dr Locorotondo is certified for second level competence in cardiac magnetic resonance imaging and has got a certification of competence for percutaneous treatment of valve heart disease. She has published research articles and book chapter about echocardiography, myocardial contrast echocardiography, and cardiac magnetic resonance, including participation in the EACVI textbook of echocardiography.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
ytaa533_Supplementary_Data Click here for additional data file.
Acknowledgements
We thank Dr R. Marano for support in CMR reporting, Prof. A.G. Rebuzzi and Prof. F. Crea for approving the manuscript.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared. | Recovered | ReactionOutcome | CC BY-NC | 33598615 | 20,050,868 | 2021-02 |
What was the outcome of reaction 'Haemoconcentration'? | 'The bubble heart': an unusual natural history told by multimodality imaging- a case report.
Intracardiac thrombosis is a relatively common pathological condition. Often, it is diagnosed at echocardiography during the subacute or chronic phase. In the very acute phase, tissue composition can make thrombus appearance very different from that usually seen. Fresh thrombosis has been previously found also in peripartum cardiomyopathy (PPC), but with imaging features different from our case.
A 27-year-old woman was referred to our hospital for PPC, with echocardiographic finding of intraventricular masses, resembling big bubbles. Cardiac magnetic resonance (CMR) allowed definitively diagnosing intracardiac 'very acute' thrombosis, which is rarely detected.
Our case provides a practical lesson about management of an unusual presentation of a common problem. When early echocardiography does not allow making a certain diagnosis, CMR can be helpful and decisive, due to its unique ability to provide characterization of intracardiac masses.
Learning points
Fresh thrombi can show a cystic appearance, with echo-lucent centre and hyperechoic boundaries.
They appear hypoperfused at the first pass sequences and look very dark in early enhancement sequences.
Fresh thrombi appear hyperintense in T1 and T2-weighted sequences, depending on presence of oxyhaemoglobin and slowly flowing blood.
Introduction
Intracardiac thrombosis is reported in up to 53% of peripartum cardiomyopathy (PPC), due to the peculiar hypercoagulability state.1 Early certain diagnosis allows promptly starting anticoagulation therapy, but during the very acute phase it can be challenging, because of the unusual appearance of thrombi as ‘bubbles’ or ‘cysts’, as compared to the more widely codified features of high or mid-echo-density masses.2 Indeed, very acute fresh thrombosis may appear at echocardiography as mass with a relatively echo-lucent centre and hyperechoic boundaries between fluid and more organized regions.3 Its diagnosis may be confirmed by cardiac magnetic resonance (CMR).4
Timeline
Delivery after a normal pregnancy
8 weeks after delivery Onset and worsening of dyspnoea
Admission, Day 0 The patient was breathless with pulmonary and peripheral congestion. Blood pressure, heart rate, and respiratory rate were 100/70 mmHg, 130 b.p.m., and 20 breaths per minute, respectively
Echocardiography showed severe left ventricular dilation and contractile dysfunction, with several masses with a soft consistency, a smooth surface, a central core of reduced echogenicity, and a hyperechogenic thin cap
Day 1 Cardiac magnetic resonance allowed to diagnose intracardiac fresh thrombosis
Therapy with intravenous heparin was started
Day 8 Echocardiography showed solid and fixed thrombi
Contrast-enhanced computed tomography confirmed the huge intraventricular thrombosis and excluded concomitant pulmonary thromboembolism
Warfarin therapy was started
Day 15 No sign of thrombus was identifiable at echocardiography
Day 20 Urgent transplant due to absence of contractile improvement and onset of ventricular arrhythmias
Case presentation
A 27-year-old woman, with no previous cardiovascular events, but a family history of dilated cardiomyopathy (DCM), was referred to our intensive care unit 2 months after delivery from her first pregnancy, due to onset of worsening dyspnoea. The patient was not taking any medication before admission, since her previous medical history was unremarkable and delivery was uneventful. She started experiencing breathlessness about 6 weeks after delivery. After started, breathlessness rapidly worsened in 2 weeks, so she was hospitalized. On admission, she appeared breathless, with diffuse pulmonary rales and bilateral legs oedema. Although central venous pressure was not measured, the patient had distended jugular veins, thus suggesting high venous pressure. Blood pressure was 100/70 mmHg, heart rate was 130 beats per minute, and respiratory rate was 20 breaths per minute.
A twelve-lead electrocardiogram showed sinus tachycardia, with two ventricular ectopies, low amplitude of R wave in anterior precordial leads, and low amplitude of QRS in peripheral leads. Chest X-ray demonstrated bilateral pleural effusion and pulmonary interstitial oedema. High-sensitivity troponin I was slightly increased (0.09 ng/mL, normal value < 0.04) and NT-pro-B-type natriuretic peptide was 1973 pg/mL (normal value < 450). Mild elevation of white blood cell count and mild anaemia were also found, without any abnormality in renal and liver functions. Intravenous infusion of furosemide (240 mg per day) and spironolactone (200 mg once daily) were promptly started. A transthoracic echocardiography showed severely dilated and globally hypokinetic left ventricle, with ejection fraction 11% and thinned walls. A significant dilation of both atria together with mild enlargement and hypokinesia of the right ventricle and moderate tricuspid and mitral regurgitations were also found. Moreover, an unusual finding was detected within left ventricular (LV) cavity: the sub-endocardial border of left ventricle seemed entirely covered, from mid-cavity to apex, by several masses, resembling big bubbles. They looked regular, of soft consistency, with a smooth surface and hyperechogenic thin cap with a central core, which appeared with low echogenicity at 3D and mainly 2D echocardiography (Figure 1). No blood flowing inside them was identified by colour Doppler mode, so that non-compaction cardiomyopathy could be excluded. Neither deformation imaging was performed, nor contrast echocardiography for LV opacification, which would have helped with the diagnosis, as the patient was thought to be in a critical condition and ultrasound contrast agent administration was not deemed safe.
A CMR, performed the day after echocardiography, confirmed the severe LV dilatation with global hypokinesia and severe depression of both left and right ventricular systolic function. Endoluminal material was present in the LV chamber, along the subendocardial layer: it obliterated completely the apex, spreading along the septal, inferior and anterior wall and the LV outflow tract and appeared lobulated, hypointense, ‘floating’ in the cine sequences (Figure 2A–C). These masses were lobulated, with smooth regular surface, hyper intense in both T1 (Figure 2D–F) and T2 (Figure 2G–I)-weighted sequences (with fat suppression), hypo intense during the first pass (Figure 3A–C) and both in the early (Figure 3D–F) and delayed enhancement sequences. Material with the same signal characteristics was also seen in the left atrial appendage that was almost completely obliterated (Figure 3E). No areas of subendocardial or intramural delayed enhancement suggestive of fibrosis were found. The signal characteristics of the material adhering to the LV and left atrial appendage was similar to that commonly found in early haemorrhage and led to diagnose massive very acute thrombosis in DCM.
Administration of unfractioned heparin (intravenous bolus of 5000 UI followed by continuous infusion of 20 000–40 000 UI per day), based on activated partial thromboplastin time (APTT), in addiction to diuretics, bisoprolol 1.25 mg once daily and ramipril 2.5 mg once daily, was introduced. Although APTT was maintained at 1.5–2.0-fold of the control level, about 1 week after CMR and the beginning of heparin therapy, echocardiography showed an unexpected change of intracardiac masses: in spite of being reduced, they appeared markedly increased in dimension, cone-shaped and hyperechogenic with enhanced consistency, thus fulfilling echocardiographic criteria of solid and fixed thrombi (Figure 4A–C). Contrast-enhanced computed tomography, performed in the same day of latter echocardiography, confirmed the presence of hypodense material, mainly in the LV apex, suggestive of huge intraventricular thrombosis and excluded concomitant pulmonary thromboembolism (Figure 5). Thus, the patient started warfarin 5 mg once daily in addition to unfractioned heparin, by maintaining an APTT constantly at two-fold of the normal level. Contemporarily, as central and peripheral congestion was resolved, de-escalation of diuretic therapy up to oral dose of furosemide 25 mg three times a day was done. Then, unfractioned heparin was stopped when international normalized ratio reached 2.5.
One week later, no sign of thrombosis was identifiable any more at echocardiography (Figure 4D). However, the patient could not be discharged at home, due to onset of frequent ventricular arrhythmias, which were treated by intravenous continuous infusion of magnesium sulfate (10 g per day) and amiodarone (900 mg per day). Inotropes, such as dobutamine, which would have been useful to increase LV contractility, were avoided due to risk of worsen ventricular arrhythmia. Similarly, bromocriptine treatment, which would have been useful in our patient because of high rate of full LV recovery reported, could not be administered due to its prothrombotic effect.
About 15 days after starting medical therapy, LV dysfunction persisted associated to electrical instability, so that defibrillator implantation was firstly considered, but, as she was young, heart transplantation was also prematurely proposed. After brief screening, on Day 18th, the patient was urgently transferred to the referring transplant centre in another hospital. Bridge therapy to transplant, such as LV assist device, was planned, while only titration of bisoprolol up to 1.25 mg b.i.d. could be attempted. Further escalation of heart failure therapy could not be realized, due to prohibitive arterial pressure values. Neprilysin inhibitor was not approved for treatment at the time of patient hospitalization. In the meanwhile, ventricular arrhythmias became more and more frequent and sustained. Thanks to prompt availability of donor, no bridge therapy was actually needed, and the patient was urgently transplanted. No histopathological examination was done on the diseased heart, in order to confirm imaging findings. Unfortunately, we only knew that transplantation was successful, but patient follow-up was missed in our hospital and no other clinical data were available.
Figure 1 Two-dimensional (A) and three-dimensional (B) transthoracic echocardiographic images in four-chamber view. Intraventricular apical masses (arrows) look like bubbles or cysts.
Figure 2 Cardiac magnetic resonance images, in horizontal (A) and vertical (B) long-axis views and in short-axis view (C) by cine Steady State Free Precession sequence. Multislice images in short-axis view from basal (D, G) to apical (F, I), by T1- (D–F) and T2- (G–I) weighted sequences, showing hyperintense signal.
Figure 3 Cardiac magnetic resonance short axis images, from basal (A) to apical (C) levels, during first pass perfusion sequence (A-C), displaying the absence of contrast uptake. Early enhancement sequence images in horizontal (D) and vertical (E) long-axis and in short-axis views (F), showing the hypointense signal of the masses. Trombus in left atrial appendage is marked by (*).
Figure 4 Trans-oesophageal (A, B) and transthoracic (C) echocardiographic images 1 week after starting unfractioned heparin showing changed masses. At discharge (D), disappearance of masses can be seen.
Figure 5 Axial images by computed tomography, acquired at two different levels (A, B) after administration of iodinated contrast agent. Hypodense masses without contrast uptake can be seen filling left ventricular cavity.
Discussion
Subacute or chronic intraventricular thrombi appear, at echocardiography, as solid, hyperechogenic masses, which can be irregular, layered, immobile, and broad-based, located mainly where blood flow slows down. In a previous report of PPC,5 ‘fresh’ thrombi were described as shaggy, irregular, non-laminar, and disappeared after 4 days of intravenous heparin. Besides echo-density and size, a strain rate ≥1 s−1 has been proposed to distinguish ‘fresh’ from old thrombosis.6 Deformation imaging was not used at the time of first echocardiographic examination in our case, as thrombotic nature of the masses was not sure, and their appearance could be in keeping with cysts. Moreover, in our patient, in the time interval previously defined for ‘fresh’ thrombosis,6 thrombi rapidly evolved from the very acute to the sub-acute phases: whether it is associated to changes in strain rate values is not known. CMR remains the gold standard in tissue characterization of cardiac masses. In cine sequences, thrombi typically appear as filling defects, mobile or attached to the endocardium; they are very dark both in early and delayed enhancement sequences and are usually hypo-perfused at the first pass. In the Spin-Echo T1 and T2-weighted sequences, acute and sub-acute thrombi can be hyperintense, due to red blood cell lysis and accumulation of paramagnetic compounds such as deoxyhaemoglobin and methaemoglobin, while chronic thrombi become isointense or hypointense due to the progressive replacement by fibrous tissue.4 Although hyperintensity on T2-weighted images is also typical of tumour masses,4 hyperintensity in T1-weighted sequences and strong hypo-intensity at early and delayed enhancement sequences (with an inversion time ≥442 ms required to define thrombi with the best diagnostic accuracy) has a decisive role in establishing the thrombotic nature.7
Such an extensive left ventricle very acute thrombosis has never been reported before at CMR. It is likely that, in our patient, diuretic therapy used to treat heart failure, together with hypercoagulable state usually persisting for 6 weeks after delivery, might have worsened haemoconcentration, thus favouring the thrombus evolution, despite heparin administration. Thus, diuretics and hemoconcentration could have counterbalanced anticoagulant effect of unfractioned heparin. Previous reports do not strictly fit our findings, which uniquely detected the very early phase of thrombi evolution.
Conclusions
In the very acute phase, LV fresh thrombosis may resemble cyst or bubble, with echocardiographic appearance very different from that usually seen, and therapeutic management may be challenging in hypercoagulability states and hemoconcentration. Specific imaging features reveal diagnosis and may tell the natural history of LV thrombosis throughout different stages.
Lead author biography
Dr Gabriella Locorotondo graduated in Medicine and Surgery in 2007 and specialized in Cardiology in 2012. She currently practices transthoracic and transoesophageal echocardiography and has skills in myocardial contrast echocardiography, stress echo, coronary reserve, 3D, and strain. Dr Locorotondo is certified for second level competence in cardiac magnetic resonance imaging and has got a certification of competence for percutaneous treatment of valve heart disease. She has published research articles and book chapter about echocardiography, myocardial contrast echocardiography, and cardiac magnetic resonance, including participation in the EACVI textbook of echocardiography.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
ytaa533_Supplementary_Data Click here for additional data file.
Acknowledgements
We thank Dr R. Marano for support in CMR reporting, Prof. A.G. Rebuzzi and Prof. F. Crea for approving the manuscript.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared. | Recovered | ReactionOutcome | CC BY-NC | 33598615 | 20,050,868 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy non-responder'. | The characteristics and efficacy of catheter ablation of focal atrial tachycardia arising from an epicardial site.
BACKGROUND
Although epicardial structures around the atrium such as adipose tissue possess arrhythmogenicity, little is known about atrial tachycardias (ATs) originating from epicardial sites (Epi-ATs). This study aimed to elucidate the prevalence, characteristics, and outcome after radiofrequency catheter ablation (RFCA) of Epi-ATs and to reveal the association between Epi-ATs and the epicardial structures.
METHODS
The electrocardiographic, electrophysiologic, and anatomical properties and results of RFCA were analyzed in 42 patients with a total of 49 ectopic ATs.
RESULTS
Six Epi-ATs (12%) were observed in six patients (14%). Four of six were respiratory cycle-dependent ATs and one was a swallowing-induced AT. The Epi-AT origins were adjacent to a pulmonary vein (five cases) and vein of Marshall (one case). A Valsalva maneuver or atropine infusion to define the arrhythmia mechanism affected the appearance of the Epi-ATs. The congruity rate between epicardial adipose tissue and the AT origin was significantly higher (100% vs. 44%, p = .045), and the epicardial adipose tissue volume of the atrium was significantly larger (104.1 vs. 64.6 ml, p = .04) in the Epi-AT group. Endocardial RFCA targeting the AT foci resulted in acute success in five of five cases. However, electrical isolation including of the AT foci resulted in acute failures (two of three cases) or a recurrence (one of one case).
CONCLUSIONS
Six Epi-ATs were associated with thoracic veins and epicardial arrhythmogenic structures. The main cause provoking the Epi-ATs was associated with autonomic nerve activity.
1 INTRODUCTION
The epicardial structures in the atrium such as the coronary sinus (CS), ligament of Marshall (LOM), and epicardial adipose tissue are associated with atrial arrhythmogenicity. 1 , 2 , 3 , 4 , 5 The mechanism has not been fully clarified and is considered multifactorial. One factor is that these are autonomic nerve rich structures and include ganglionated plexi (GPs). Post ganglionic efferent fibers innervate the atrial myocardium and can provoke supraventricular arrhythmias especially atrial fibrillation. 1 Other earlier studies 2 , 3 , 4 , 5 have reported the participation of chronic low‐grade inflammation, oxidative stress, and the formation of reentrant circuits from intramyocardial fat and via the muscular bundles of the LOM and/or CS. On the other hand, focal atrial tachycardias (ATs) arising from the epicardial side (Epi‐AT) are rare arrhythmias or may be underestimated or unrecognized during catheter ablation (CA), because Epi‐ATs can often be successfully treated with a similar procedure as that used in ablation of ordinary ectopic ATs, and because such ATs may be recognized as unmappable ATs during endocardial CA. Only a few Epi‐AT cases using the percutaneous epicardial approach or high density contact mapping approach have been demonstrated and successfully ablated. 6 , 7 , 8 At present, little is known about the clinical and electrophysiologic characteristics of Epi‐ATs. Therefore, we investigated the incidence and the electrophysiologic properties of Epi‐ATs, their origins, effects of drugs and the Valsalva maneuver, and the efficacy of CA, along with the clinical background in patients with Epi‐ATs. The clinical course of Epi‐ATs and their outcomes after CA were also compared with other focal non‐Epi‐ATs.
2 METHODS
2.1 Study population and definition of Epi‐AT and other terms
From April 2016 to April 2018, 42 consecutive patients with a total of 49 focal ATs were referred to the Nippon Medical School Main Hospital and underwent a radiofrequency (RF) CA. Written informed consent was obtained, and this study was approved by the ethics committee of Nippon Medical School. We analyzed the clinical characteristics of the patients, electrocardiographic and electrophysiology properties of the ATs, and results of the CA. For each patient, the data were obtained from the patient chart, body surface electrocardiograms before, during and after the electrophysiology study, 24‐hour Holter monitoring, echocardiography, and intracardiac electrograms during the electrophysiology study. Electroanatomical mapping data were also analyzed. We defined an Epi‐AT as an AT which had multiple earliest activation sites (EASs) on the endocardial activation map or which had a centrifugal activation pattern and could be eliminated by RF applications at remote epicardial regions from the EASs. The mechanism of respiratory cycle‐dependent AT (RCAT) and swallowing‐induced AT (SIAT) has been considered to be related to GPs including epicardial adipose tissue. 9 , 10 An RCAT was defined as an AT that occurred after initiating inspiration and ceased during the following expiration during a minimum of five consecutive respiration cycles. 9 SIAT was defined as an AT that occurred only after swallowing.
2.2 Pharmacological properties
Before or during the electrophysiology study, some drugs (isoproterenol, adenosine‐triphosphate, and atropine) were administered to determine the mechanism of the Epi‐ATs. Isoproterenol (0.005–0.01 mg/kg−1/h−1) was administered during and after the EP study to observe the appearance, inducibility, or persistence of the Epi‐ATs. An adenosine‐triphosphate bolus infusion was performed for observing whether the Epi‐ATs transiently terminated after the infusion. In the case that an RCAT or SIAT was detected before the EP study, an atropine (0.5 mg) bolus infusion was performed to observe the appearance or persistence of these ATs.
2.3 Electrophysiologic study, mapping of tachycardias, and radiofrequency ablation
The study was performed in the fasting state, with unconscious sedation using dexmedetomidine. All antiarrhythmic drugs were discontinued for a minimum of five half‐lives before the procedure. An electroanatomical mapping system was used in all patients: a CARTO system (Biosense Webster Inc., Diamond Bar, CA) or EnSite Velocity system (Velocity, Abbott, Abbot Park, IL). A 20‐polar catheter with 2–2–2 mm interelectrode spacing (BeeAT, Japan Lifeline Co., Ltd, Tokyo, Japan) was introduced from the right internal jugular vein and advanced into the CS. An irrigated RF ablation catheter (SmartTouch, Biosense Webster Inc. or FlexAbility, Abbott), which was also used as a mapping catheter with the electroanatomical mapping system, was introduced into the atrium. In patients who required isolation of the pulmonary veins (PVs), a 20‐pole circumferential catheter (Lasso, Biosense Webster or Optima, Abbott) and/or a 20‐pole mapping catheter (PentaRay, Biosense Webster) was located at the ostium of the target vein and was used to create the electroanatomical map. Body surface ECGs and bipolar endocardial electrograms were monitored continuously and recorded with an EP‐WorkMate (Abbott) recording system at a filter setting of 30–500 Hz. Bipolar pacing was performed using an EP MedSystems programmable stimulator. In patients in whom spontaneous AT did not emerge, programmed atrial stimulation was delivered using burst pacing or an eight‐stimulus drive train followed by single or double extrastimuli from the CS with and without an isoproterenol infusion. The anatomical localization of the atrial focus was accomplished during the tachycardia by the analysis of the high density atrial activation using a 20‐pole circumferential and/or PentaRay catheter with electroanatomical mapping system. 11 , 12 When the tachycardia was considered to have a left‐sided origin, a trans‐septal puncture using conventional techniques with the use of a long vascular sheath was performed. When the tachycardia was considered to be related to the Marshall bundle, we cannulated the vein of Marshall (VOM) with a 2 Fr octa‐polar electrode catheter (EP star Fix, Japan Lifeline) through the lumen of a deca‐polar catheter (Response, Abbott). RF energy was delivered between the distal electrode of the ablation catheter and a cutaneous adhesive electrode on the lower trunk using a RF generator (Stockert J70 RF Generator, Stockert GmbH, Freiburg, Germany, or Ampere RF Ablation Generator, Abbott). RF energy was delivered for 20–60 seconds. The temperature control mode was limited to 38°C and a maximum power of 40 W. Acute success of the ablation procedure was defined as the absence of any spontaneous or induced AT by programmed stimulation with and without an isoproterenol infusion (0.005–0.01 mg/kg−1/h−1) for at least 30 minutes after the ablation.
2.4 Measurement and analysis of epicardial adipose tissue
The epicardial adipose tissue volume was calculated from contrast images obtained with a 3D spiral computed tomography (CT) scanner (320‐row detector, dynamic volume CT scanner; Aquilion ONE, Toshiba Medical Systems, Tokyo, Japan) before the radiofrequency catheter ablation (RFCA). The data transferred to the EnSite Verismo segmentation tool (Velocity, Abbott, Abbott Park, IL) was used for the analysis of the epicardial adipose tissue. The CT value threshold was set between −50 and −200 Hounsfield units to detect the epicardial adipose tissue. The volume of the epicardial adipose tissue surrounding each chamber was manually segmented from the total epicardial adipose tissue. 13 The segmented planes of each chamber were overlayed on the mitral annulus and tricuspid annulus in order to separate them between the atrium and the ventricle and on the connected plane between the anterior antrum of the right PV and ostium of the CS to separate both atria. These CT images were merged or compared with the 3D electroanatomical maps. The CT images were analyzed by 1 electrophysiologist and 1 clinical engineer in a blinded manner.
2.5 Statistical analysis
The data were expressed as the mean ± SD for continuous variables and as the frequency (number [%]) for categorical variables. For the continuous variables, the differences between groups were compared using the Mann–Whitney U‐test and Student's t‐test. Because the results were similar, only the latter are presented. For categorical variables, the differences between groups were compared using a Fisher exact test. The correlation coefficient was determined by linear regression analysis. All tests were two‐sided, and a p < .05 was considered significant. All statistical analyses were conducted using EZR software 14 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a convenient user interface for R (The R foundation for Statistical Computing, Vienna, Austria).
3 RESULTS
3.1 Clinical characteristics of Epi‐ATs and a comparison of Epi‐ATs and non‐Epi‐ATs
Among the 42 patients with a total of 49 non‐reentrant focal ATs, six distinct Epi‐ATs (12%) were found in six patients (14%) (AT‐1 to −6: four males and two females) with a mean age of 61 ± 7 [55–76] years‐old. The clinical characteristics of the patients with Epi‐ATs and non‐Epi‐ATs are shown in Table 1. The age was significantly younger and prevalence of RCATs significantly higher in the Epi‐AT group, while no other significant differences were confirmed in terms of the clinical characteristics between the patients in the two groups. The successful ablation sites of the six Epi‐ATs were compared with the 43 focal non‐Epi‐ATs. The successful ablation site was at the antrum of the right PV in three Epi‐ATs and three non‐Epi‐ATs (50% vs. 7%, p = .02), or at the LA posterior roof close to the left PV in two Epi‐ATs and no non‐Epi‐ATs (33% vs. 0%, p = .01). The clinical characteristics of the six Epi‐ATs are presented in Table 2. There was no detectable structural heart disease in any of the Epi‐AT patients. In five patients (AT‐1, −2, −3 ‐5, and −6), the ATs were of an incessant form (4 RCATs and 1 SIAT). The average coupling interval of 100 RCAT and SIAT events (analysis of 20 events in each RCAT and SIAT) was 303 ± 46 ms. All RCATs and 1 SIAT were irregular, and the mean AT cycle length varied among the ATs, ranging from 265 to 358 ms. AT‐4 showed a persistent AT with a regular tachycardia cycle length of 450 ms. In that case, we performed post pacing interval mapping and there were no sites remote from the EAS where the return cycle after entrainment pacing was identical to the tachycardia cycle length because of the exclusion of macro‐reentrant ATs such as a Marshall bundle reentry. 15 In AT‐1, AT‐2, AT‐5, and AT‐6, 3 RCATs and 1 SIAT, were suppressed during and shortly after (two or three respiratory cycles) a Valsalva maneuver during the end‐inspiratory phase (see the Video S1).
TABLE 1 Comparison of the characteristics between the patients with an Epi‐AT and those with a non‐Epi‐AT
Total (42 patients, 49 ATs) Epi‐AT (six patients, six ATs) Non‐Epi‐AT (36 patients, 43 ATs) p value
Age, years 68 ± 11 61 ± 7 69 ± 11 .03
Male gender, N (%) 22 (52) 4 (67) 18 (50) .67
BMI 23 ± 4 25 ± 4 22 ± 3 .11
RCAT 6 (12) 4 (67) 2 (5) .002
Recurrence of AT, N (%) 11 (22) 1 (17) 10 (23) 1.00
P wave duration during AT (ms) 80 ± 20 89 ± 22 78 ± 19 .22
AF, N (%) 27 (64) 4 (67) 23 (64) 1.00
Persistent AF, N (%) 13 (31) 1 (25) 12 (33) .60
Recurrence of AF, N (%) 4 (10) 0 4 (13) .56
Structural heart disease, N (%) 6 (14) 0 6 (17) .57
Hypertensive heart disease 2 (5) 0 2 (6) 1.00
TCM 1 (2) 0 1 (3) 1.00
Other cardiomyopathies 3 (7) 0 3 (8) 1.00
Follow‐up period, month 13 ± 7 13 ± 8 13 ± 7 .98
Echocardiographic parameters
LV ejection fraction, % 66 ± 11 69 ± 4 65 ± 12 .45
LA dimension, mm 38 ± 8 38 ± 7 38 ± 8 .95
Abbreviations: AF, atrial fibrillation; AT, atrial tachycardia; BMI, body mass index; Epi‐AT, epicardial origin atrial tachycardia; RCAT, respiratory cycle‐dependent atrial tachycardia; TCM, tachycardia‐induced cardiomyopathy.
TABLE 2 The clinical and electrophysiologic properties of the Epi‐ATs
AT Age, years Sex Earliest activation site (M = multiple sites) Mean tachycardia cycle length (range), ms Ablation site or target Efficacy of electrical isolation of AT RF power required to eliminate, W Form of AT GP reaction during successful RF application Fractionated potential/abnormal voltage at the successful site
1 58 M LA roof (M) 275 (262–298) LA posterior wall isolation Acute success but recurrence 40 RCAT SB +/‐
2 60 F LA inferior (M), VOM 358 (295–449) Marshall bundle NA 35 RCAT ‐ ‐/‐
3 55 M LA posteroinferior (M) 265 (231–315) AT focus or ARGP NA 30 RCAT ‐ +/‐
4 76 F SVC‐RA connection 450 (NA) AT focus or ARGP Acute unsuccess 35 Regular AT SB +/+
5 58 M LA posteroinferior 308 (268–340) AT focus or ARGP NA 30 RCAT SB ‐/‐
6 56 M LSPV (M) 309 (278–340) AT focus or SLGP Acute unsuccess 40 SIAT SB +/‐
AT Preceded time from the P wave at the success site, ms Time between the EAS to success site, ms Pre‐applied drugs and effects to the Epi‐AT
1 NA (electrical isolation) NA (electrical isolation) Bisoprolol 2.5 mg, Flecainide 200 mg NA, NA
2 5 5 Bisoprolol 2.5 mg No
3 40 30 NA NA
4 NA (electrically isolated) NA (electrically isolated) Pilsicainide 150 mg, Sotalol 120 mg NA, NA
5 −10 70 Pilsicainide 150 mg, Atropine 0.5 mg no transiently suppressed
6 50 5 Flecainide 150 mg, Atropine 0.5 mg no, transiently suppressed
Abbreviations: ARGP, anterior right ganglionated plexi; AT, atrial tachycardia; EAS, earliest activation site; Epi‐AT, epicardial origin atrial tachycardia; GP, ganglionated plexi; RCAT, respiratory cycle‐dependent atrial tachycardia; SB, sinus bradycardia; SIAT swallowing induced atrial tachycardia; SLGP superior left ganglionated plexi; SVC superior vena cava.
3.2 Pharmacological properties
The Epi‐ATs were refractory to 1.2 ± 0.4 drugs including class I and class III antiarrhythmic agents and beta blockers. Isoproterenol and 10 mg of an adenosine‐triphosphate infusion during the electrophysiologic study did not affect the inducibility or persistence of the Epi‐ATs in all patients. A 0.5 mg atropine infusion transiently suppressed the Epi‐ATs in AT‐5 and AT‐6.
3.3 Mapping and outcomes of catheter ablation in patients with Epi‐ATs
The bipolar electrogram at the EASs preceded the onset of the P wave by 39 ± 18 ms (10–70). The electroanatomical maps and CT images of each Epi‐AT case are presented in Figures 1 and 2. In AT‐4, the electroanatomical map (Figure 1(A)‐(b)) from the endocardium exhibited a centrifugal activation pattern and the EAS was located at the connection between the RA and SVC. The EAS and successful site were anatomically separate from each other, and the successful site was electrically isolated the anterior right PV antrum. In AT‐1, AT‐2, AT‐3, and AT‐6, there were multiple EASs on the endocardial activation maps at the LA posterior roof close to the left PV, LA inferior, LA posteroinferior adjacent to the right inferior PV, LA posteroinferior adjacent to the right inferior PV, and the left superior PV, respectively. In AT‐2, the actual EAS was located in the VOM opposite the EAS on the endocardial map (Figure 1(B)‐(a)). A pacemap was performed because the EAS was detected at an epicardial site during the AT. The P wave morphology was only identical at the successful site with high amplitude pacing (Figure 1(B)‐(b)). A focal RF delivery on the endocardial side of the LA that was opposite the actual EAS in the VOM successfully eliminated AT‐2. Electrical isolation of the left posterior wall including the EASs was performed in AT‐1, which resulted in the complete suppression of the Epi‐AT with no ectopic beats inside the posterior wall (Figure 1(A)‐(a)). On the other hand, an extensive left PV isolation including of the EASs was not effective in AT‐6 (Figure 1(A)‐(c)). After the left PV isolation with complete exit block, the EAS was displaced to outside the isolation line. Although an RF application at the displaced EAS could not eliminate AT‐6, AT‐6 was successfully ablated at the site of the isolated left superior PV antrum, which was located 1 cm from the isolation line. In AT‐3 and AT‐5, a successful ablation was achieved during a right PV isolation of AF (still not isolated) at the anterior aspect of the right superior PV antrum, which was at least 2 cm from each EAS (Figure 1(C)). In AT‐4 and AT‐5 the ablation sites after unsuccessful applications at the EASs and/or electrical isolation were determined due to the experience in AT‐3. In AT‐3, after an unsuccessful RF application at the EAS, we performed a right PV isolation of the AF and could unexpectedly eliminate AT‐3 at the anterior right superior PV antrum, in which the anterior right GPs were often located. Parasympathetic nerve responses during and shortly after the successful RF application such as a sinus pause or atrioventricular block were observed in AT‐1, AT‐4, AT‐5, and AT‐6. Fractionated potentials and an abnormal voltage during the AT or sinus rhythm at the success sites were recorded in four of six and one of six Epi‐AT cases, respectively. Acute success during the first ablation procedure was achieved in all patients. There were no major complications during or after the ablation procedures in all cases. During the follow‐up period of 13 ± 8 months (range 4 to 29 months), no ATs were observed in any of the patients without any antiarrhythmic drug use except for AT‐1 in which the Epi‐AT recurred 1 day after the procedure.
FIGURE 1 (A) The electroanatomical maps and CT images of the atrium during AT‐1 (a), AT‐4 (b), and AT‐6 (c), respectively. The light brown structure in the CT images was epicardial adipose tissue. These three atrial tachycardias were eliminated by the electrical isolation or radio frequency (RF) applications in the electrically isolated region. (a) Although the radio frequency applications at the earliest activation site (EASs) were not effective, electrical isolation of the LA posterior wall eliminated AT‐1. (b) The activation map in the LA (b‐upper left) showed that the EAS in the LA was adjacent to the right superior PV (RSPV) isolation line. The actual EAS was at the junction between the superior vena cava and right atrium (b‐lower left). The successful application was obtained at a site with no recordable potentials (b‐upper right). (c) The activation map revealed multiple EASs at the left superior PV (LSPV, c‐upper right). A left PV isolation resulted in the movement of the EAS 1 cm away from the isolation line. Only small far field potentials at the successful site were recorded (c‐lower right). CS: coronary sinus, Eso: esophagus, LAA: left atrial appendage, MI: mitral isthmus. (B) The electroanatomical map and coronary sinus (CS) angiogram of AT‐2 showing that the vein of Marshall (VOM, arrows) was detected at a site opposite the earliest site (a‐left). We cannulated the VOM with a 2 Fr octapolar catheter (a‐upper left) and ablated that site (a‐lower left). We also performed pace‐mapping, which showed that the P‐wave morphology during high output pacing at the endocardial success site was only identical to that of AT‐2 (b). ABL: ablation catheter, AT: atrial tachycardia, Eso: esophageal catheter, HBE = His bundle electrode, LIPV: left inferior pulmonary vein, LSPV: left superior pulmonary vein, RPV: right pulmonary vein. (C) The activation maps and CT images of AT‐3 (a) and AT‐5 (b) in the LA, respectively. The elimination pattern of the tachycardias showed that the successful sites were separate from the earliest activation sites (EAS). The successful sites of both tachycardias were at the antrum of the anterior right superior pulmonary vein, which was a ganglionated plexus rich region. Indeed, epicardial adipose tissues existed at the successful sites. RF: radio frequency
3.4 Relationship between the special distribution of epicardial adipose tissue and Epi‐ATs
Cardiac CT images were obtained in five of the six Epi‐AT patients (Figure 1) and 16 of 36 non‐Epi‐AT patients: four of four AF cases and one SIAT case in the Epi‐AT group and 16 of 23 AF cases in the non‐Epi‐AT group. The clinical characteristics and analysis data of epicardial adipose tissue between the Epi‐AT and non‐Epi‐AT groups are shown in Table 3. In all Epi‐AT cases, there was epicardial adipose tissue at the Epi‐AT origin and EASs, and in contrast, in only seven of 16 cases in the non‐Epi‐AT group (100% vs. 44%, p = .045). Cardiac CT also showed that the epicardial adipose tissue volume of the total atrium was significantly larger in the Epi‐AT group (104.1 vs. 64.6 ml, p = .04), while the LA and total atrium volumes did not significantly differ. On the other hand, the total adipose tissue volume around the atrium was significantly correlated with the body weight (p = .04, r = 0.54) as in a previous report. 13 No other clinical characteristics were correlated or had any statistical differences with the presence of adipose tissue in this study.
TABLE 3 The analysis of the relationship between AT and epicardial adipose tissue
Total (21 patients, 21 ATs) Epi‐AT (five patients, five ATs) Non‐Epi‐AT (16 patients, 16 ATs) p value
Age, years 69 ± 8 61 ± 8 71 ± 6 .005
Male gender, N (%) 11 (52) 4 (80) 7 (44) .17
BMI 24 ± 4 26 ± 3 23 ± 4 .07
RCAT, N (%) 4 (19) 3 (60) 1 (6) .01
AF, N (%) 20 (95) 4 (80) 16 (100) .24
Persistent AF, N (%) 8 (38) 1 (20) 7 (44) .62
Recurrence of AF, N (%) 3 (14) 0 (0) 3 (19) 1.00
Follow‐up period, month 14 ± 7 13 ± 8 15 ± 7 .76
Computed tomography image analysis
Congruity to AT focus, N (%) 12 (57) 5 (100) 7 (44) .045
LA volume, ml 107.8 ± 34.9 98.1 ± 30.8 110.9 ± 35.5 .5
RA volume, ml 126.6 ± 58.5 130.2 ± 27.9 125. 5 ± 65.2 .88
EAT volume, ml
Total atrium 74.0 ± 36.6 104.1 ± 30.4 64.6 ± 33.1 .04
LA 42.4 ± 18.9 63.1 ± 13.1 35.9 ± 15.5 .003
RA 31.6 ± 22.1 41.0 ± 25.8 28.7 ± 20.0 .3
Abbreviations: AF, atrial fibrillation; AT, atrial tachycardia; BMI, body mass index; EAT, epicardial adipose tissue; Epi‐AT, epicardial origin atrial tachycardia; RCAT, respiratory cycle‐dependent atrial tachycardia.
FIGURE 2 The origins of each Epi‐AT were marked on CT images (number in circle). Arrow heads indicated each earliest activation sites in endocardial activation maps. LIPV: left inferior pulmonary vein, LSPV: left superior pulmonary vein, RSPV: right superior pulmonary vein, SVC: superior vena cava, VOM: the vein of Marshall
4 DISCUSSION
The present study reported that, among 49 non‐reentrant focal ATs in 42 patients, six Epi‐ATs (12%) were observed in six patients (14%). These arrhythmias were refractory to antiarrhythmic drugs and beta‐blockers. Five of six arrhythmias developed with an incessant form and the tachycardia cycle length was irregular and varied among the Epi‐ATs.
To date, only three reports of four Epi‐AT cases have been published. Phillips et al. 6 and Yamada et al. 8 demonstrated three juvenile cases with Epi‐ATs that were successfully treated by percutaneous pericardial CA. Another report, 7 exhibiting a juvenile incessant form of an Epi‐AT showed that the tachycardia was diagnosed by endocardial high density mapping and epicardial noninvasive electrocardiographic imaging and that the Epi‐AT was successfully treated at the endocardial breakout sites. These reported Epi‐ATs, all of which were located around the LA appendage, were considered to be related to the Marshall bundle. 7 However, these reports did not reveal the etiology, characteristics, and mechanisms of the ATs. To the best of our knowledge, the present study is the first report the demonstration of the characteristics and etiology of Epi‐ATs, especially in relation to the autonomic nervous system and epicardial structures.
There were three elimination patterns of the Epi‐ATs. The first was an extensive electrical isolation including of the EASs (Figure 1(A)). The second was that RF energy from the endocardium directly affected the AT origin, and the EAS was determined to be located on the epicardial side (Figure 1(B)). The third was that the RF energy also directly affected the AT origin but the endocardial EAS was not observed at the successful site (Figure 1(C)). These patterns lead to the hypothetical mechanism of the Epi‐ATs: the origin of the Epi‐AT was an epicardial muscle bundle and there were epicardial pathways bridging from the origin to the endocardial breakthrough sites such as the preferential pathway in patients with premature ventricular beats. Previous reports showed that the Marshall bundle had multiple connections with the LA myocardium and formed an arrhythmogenic substrate. 3 , 15 , 16 Barrio‐Lopez et al. 16 revealed the existence of epicardial electrical connections between the PVs and other structures and that the existence of these veno‐atrial epicardial connections made the PV isolation more difficult and worsened the isolation durability. This existence of epicardial connections was also reported to be a higher risk of atrial tachyarrhythmia recurrence after a PV circumferential isolation. 16 Other reports 17 , 18 showed that there were interatrial epicardial connections between the right‐sided PV antrum and RA. Miyazaki et al. 18 reported that a focal AT arising from the right superior PV antrum broke though the RA. In that case, the pseudo EAS in the RA was anatomically separate from the actual origin as well as in our cases. In AT‐4 and AT‐6, the difference from that case was that the RF applications at the earliest activation site in the RA and/or LA were not effective, but the successful site was localized inside the electrically isolated PV antrum with exit block (Figure 1(C)). These facts certified that there are epicardial preferential pathways and the ATs originated from the epicardial foci.
The other possibility of the Epi‐AT mechanism was that GP activity directly provoked the Epi‐ATs via their axons, which are distributed in the myocardium at the EASs. Previous canine experimental models 19 showed that focal AT was induced by GP stimulation. Another study 1 in silico for simulating the human heart demonstrated that GP stimulation, both sympathetic and parasympathetic, induced a spontaneous phase 3 early after‐depolarization like the action potentials and PV tachycardias adjacent to the stimulated GPs. Several observations in the present study suggested that the autonomic nervous system network was considered to play a major role in the provoking mechanism of Epi‐ATs. First, in five of six patients, their Epi‐ATs were RCATs or SIATs of which the main part of the mechanism was considered to be autonomic nervous irritation. 9 , 10 Second, in four of four patients, the Epi‐ATs were transiently suppressed by a Valsalva maneuver with a deep inspiration position. Suppressing arrhythmias with deep inspiration also denies the mechanical stretch theory 9 , 20 in RCAT patients. Third, a bolus infusion of atropine transiently terminated two of two ATs. Fourth, in all Epi‐AT patients, there were GP rich epicardial structures, which included epicardial adipose tissue or the LOM at the EASs and successful sites, and in four of six patients, successful RF applications provoked a GP reaction. Thus, autonomic nervous activity is considered to be the main part of the provocation etiology in Epi‐ATs, whether there are epicardial preferential pathways or GPs directly provoking at the EASs.
The mechanism of the arrhythmogenicity associated with epicardial adipose tissue is still uncertain and considered multifactorial. A previous systematic review 4 reported the possible mechanisms: inflammation, adipose infiltration, electrical remodeling, fibrosis and structure remodeling, autonomic nervous dysfunction, oxidative stress, gene expressing, local aromatase effect, and ventricular diastolic dysfunction. Nakahara et al. 10 reported that epicardial adipose tissue was adjacent to the endocardial breakthrough of an SIAT and that the most likely mechanism of the AT was considered to be a neural reflex rather than mechanical stimulation because of the long distance between the AT focus at the right superior PV antrum and esophagus. In each Epi‐AT case, the epicardial adipose tissue was not only adjacent to the EASs and successful sites but also existed and continued between the EASs and successful sites. These facts might suggest that the hypothetic formation of epicardial preferential pathways due to structure remodeling was an epicardial adipose tissue effect. Nagashima et al. 13 showed that the epicardial adipose tissue volumes on CT images correlated with a higher recurrence of AF after CA. In our Epi‐AT cases, no AF recurrences were ever recorded, however, their epicardial adipose tissue volumes were significantly larger than in the non‐Epi‐AT cases. Eliminating ectopic arrhythmia sources originating from epicardial sites could result in a reduction in AF recurrences, and conduction block between AT foci and endocardial breakout sites could lead to an actual PV isolation and greater durability. Zghaib et al. 21 reported that fractionated potentials and an abnormal endocardial bipolar voltage were associated with epicardial adipose tissue as a result of atrial remodeling. In our Epi‐AT cases, fractionated potentials were recorded in 67% of the Epi‐ATs, however, an abnormal voltage was observed in only one case. That fact might suggest that the association between epicardial adipose tissue and an abnormal voltage in the case of an Epi‐AT has a different etiology from that of AF, and these findings suggested that this was one of the reasons why no AF recurrences were recorded despite the rich epicardial adipose tissue.
The acute success rate of focal AT ablation is relatively lower at 84% than that of other supraventricular tachyarrhythmias, because focal AT is sometimes an unmappable arrhythmia during endocardial catheter ablation. 22 Knowledge of the data reported in the present study could provide therapeutic options for these unmappable and incurable focal AT cases by considering the presence of epicardial structures including epicardial adipose tissue, the vein of Marshall, and an epicardial myocardial bridge around the PVs.
5 LIMITATIONS
This study had several limitations. First, in four of six patients, the recognition of Epi‐ATs was during or just before the ablation procedure, we did not use drugs because of the risk of a modification of the arrhythmogenic substrate of the AT. The most striking finding was the degree to which these ATs were subject to modulation by the autonomic nervous system. However, in these patients, we were not able to evaluate the pharmacological effects with appropriate doses for blocking the adrenergic and/or cholinergic stimuli. Second, the atrial wall thickness was quite thin, such that an Epi‐AT might still mimic as a focal early site in the endocardial map which was not included in our definition of an Epi‐AT. ATs originating from epicardial foci might be much more common. Even in epicardial origins, they could be successfully ablated from the endocardial side leading to an underestimation of the Epi‐ATs. Therefore, there were no clinical features, ECG parameters including the P wave duration and morphology, or autonomic predictive features that should give a high index of suspicion of an Epi‐AT. Third, in our Epi‐AT cases, fortunately, acute success was achieved with endocardial RFCA, however, an electrical isolation including the EASs resulted in a recurrence and/or acute unsuccessful ablation. An indication for a pericardial puncture to access the epicardial atrial areas might be considered in the case of an acute unsuccessful ablation after an electrical isolation, when there is a confusing low voltage areas or fragment potentials, which could lead to inadequate endocardial mapping, and more likely to avoid vascular stenosis when RF applications to the thoracic veins would be required. Fourth, if ganglionated plexi directly provoke an AT, it is not necessarily true that the AT arose from the myocardia of epicardial sites. If their axons are distributed only in “normal” myocardia, should the origin of the ATs be considered to arise from the ganglionated plexi or “normal” myocardia? It was somewhat confusing that the definition of the Epi‐AT and Epi‐AT origins in the present study included these situations, which might mean they would be defined as an epicardial structure induced or related AT.
6 CONCLUSION
Six drug‐refractory ATs (12%) emerging from epicardial sites were observed out of 49 focal non‐reentrant ATs. Their foci converged around the thoracic veins including the VOM where GP rich epicardial adipose tissue was located. The epicardial adipose tissue volume of the atrium in Epi‐AT cases was significantly larger than that in non‐Epi‐AT patients, and the autonomic nerve activity directly affected the AT initiation and termination in all Epi‐AT cases. These ATs were successfully eliminated by RFCA from the endocardial side targeting AT foci or GPs, however, an electrical isolation might result in causing acute failures or recurrence.
Supporting information
Video S1 A Valsalva maneuver during the end‐inspiratory phase just after the 3rd inspiration in this video clip transiently suppressed a respiratory cycle‐dependent atrial tachycardia (AT‐2). Only 1 sequence of an atrial burst and some isolated ectopic beats were recorded during a Valsalva maneuver for about 15 seconds, which suppressed the AT even after 2 respiratory cycles.
Click here for additional data file.
ACKNOWLEDGMENTS
The authors thank Mr. Norio Watanabe for his technical assistance and Mr. John Martin for his linguistic assistance. | BISOPROLOL, FLECAINIDE | DrugsGivenReaction | CC BY | 33598933 | 19,508,571 | 2021-04 |
What was the outcome of reaction 'Electrocardiogram QT prolonged'? | Impact of Medical Castration on Malignant Arrhythmias in Patients With Prostate Cancer.
Background Medical castration, gonadotropin-releasing hormone agonists, and antiandrogens have been widely applied as a treatment for prostate cancer. Sex steroid hormones influence cardiac ion channels. However, few studies have examined the proarrhythmic properties of medical castration. Methods and Results This study included 149 patients who underwent medical castration using gonadotropin-releasing hormones with/without antiandrogen for prostate cancer. The changes in the ECG findings during the therapy and associations of the electrocardiographic findings with malignant arrhythmias were studied. The QT and corrected QT (QTc) intervals prolonged during the therapy compared with baseline (QT, 394±32 to 406±39 ms [P<0.001]; QTc, 416±27 to 439±31 ms [P<0.001]). The QTc interval was prolonged in 119 (79.9%) patients during the therapy compared with baseline. In 2 (1.3%) patients who had no structural heart disease, torsade de pointes (TdP) and ventricular fibrillation (VF) occurred ≥6 months after starting the therapy. In patients with TdP/VF, the increase in the QTc interval from the pretreatment value was >80 ms. However, in patients without TdP/VF, the prevalence of an increase in the QTc interval from the pretreatment value of >50 ms was 11%, and an increase in the QTc interval from the pretreatment value >80 ms was found in only 4 (3%) patients. Conclusions Medical castration prolongs the QT/QTc intervals in most patients with prostate cancer, and it could cause TdP/VFs even in patients with no risk of QT prolongation before the therapy. An increase in the QTc interval from the pretreatment value >50 ms might become a predictor of TdP/VF. Much attention should be paid to the QTc interval throughout all periods of medical castration to prevent malignant arrhythmias.
Nonstandard Abbreviations and Acronyms
QTc corrected QT
ΔQTc increase in the QTc interval from the pretreatment value
TdP torsade de pointes
Clinical Perspective
What Is New?
Medical castration prolonged the QT and corrected QT intervals in most patients with prostate cancer and could rarely cause torsade de pointes and ventricular fibrillation.
An increase in the corrected QT interval of >50 ms might become a predictor of malignant arrhythmias during medical castration in patients with prostate cancer.
What Are the Clinical Implications?
Much attention should be paid to the corrected QT interval throughout all periods of medical castration to prevent torsade de pointes, ventricular fibrillation, and sudden death in patients with prostate cancer.
Progress in the treatment has led to an improved survival in patients with cancer, and the importance of cardiovascular disease attributable to cardiotoxicities of drugs and radiation therapy has begun to be recognized. 1 Prostate cancer is the most common noncutaneous malignancy in men, and has been steadily rising in an aging society. 2 Medical castration, suppressing testosterone with gonadotropin‐releasing hormone analogues, is broadly effective at any stage of localized cancer (stage A and B), locally advanced cancer (stage C), and metastatic cancer (stage D). It has been shown to be as effective as surgical castration, and, nowadays, medical castration is a cornerstone in the treatment of prostate cancer. 3
Sex steroid hormones, including testosterone, influence the cardiac ion channels, and medical castration could affect the QT intervals. 4 In fact, previously castrated men could exhibit a longer duration of the corrected QT (QTc) interval than noncastrated men. 5 In patients with prostate cancer, medical castration is associated with QT prolongation, 6 and could cause torsade de pointes (TdP). 7 Recently, we also experienced a case of prostate cancer that presented TdP and ventricular fibrillation (VF) during medical castration in our hospital. 8 A previous study reported that, in patients with hypogonadism who presented with QT prolongation and/or TdP, testosterone treatment shortened the prolonged QT intervals and prevented recurrences of TdP. 7 However, from the therapeutic aspect of prostate cancer, a supplemental administration of testosterone should not be easily given to those patients. Few studies have systematically examined the incidence, characteristics, and risk factors of the QT prolongation, TdP, or VF in patients receiving medical castration for prostate cancer thus far. Accordingly, this study aimed to clarify these points.
Methods
Study Patients
The data that support the findings of this study are available from the corresponding author on reasonable request. This retrospective observational study included consecutive patients with prostate cancer who underwent medical castration using gonadotropin‐releasing hormone analogues (leuproreline, 11.25 mg per 3 months; or gosereline, 3.6 mg per a month) or gonadotropin‐releasing hormone antagonists (degarelix, 80 mg per 3 months) at the University of Fukui Hospital from April 2006 to December 2017. Patients in whom no 12‐lead ECGs were recorded before or during medical castration were available, and those who did not receive the therapy for >3 months were excluded from this study in advance. This study was approved by the Research Ethics Committee of the University of Fukui, and written consent was waived because of the retrospective design. The study complied with the Declaration of Helsinki.
Data Analysis
The electrocardiographic parameters were compared between those before and during the medical castration. The association of the electrocardiographic parameters with malignant arrhythmias was studied in this cohort. Malignant arrhythmias included TdP, ventricular tachycardia, VF, and asystole. Moreover, the plasma electrolyte levels and electrocardiographic findings were compared with the QT interval, before and during the medical castration. The QT intervals were measured in lead V2 using the tangent method for the determination of the QT end using a semiautomated digitizing program with electronic calipers by an experienced observer blinded to the clinical details in all subjects included in this study. 9 , 10 The QT interval was determined from a 5‐beat average during atrial fibrillation. 10 The presence or absence of an abnormal ST‐segment elevation in the right precordial leads, including a Brugada‐type ECG, which was diagnosed by ST‐segment elevation with a type 1 morphological feature of ≥2 mm in ≥1 leads among the V1 and/or V2 right precordial leads in the fourth intercostal space, was also evaluated. 11
Statistical Analysis
Continuous variables, except for the plasma potassium and calcium levels, are expressed as the mean±SD. Because of their nonnormality, the potassium and calcium plasma levels are given as the median (interquartile range), and outliers are defined as values above or below 1.5 times the interquartile range. Categorical variables are presented as the number and percentage. Differences in the parameters before and during the medical castration were analyzed using a paired t‐test for a comparison. A Pearson correlation coefficient was used to determine the relation between the QTc interval and other variables. All statistical analyses were performed with SPSS (Statistical Package for the Social Sciences) version 20 software (IBM Inc, Armonk, NY). A 2‐sided P<0.05 was considered statistically significant.
Results
Characteristics of the Cohort
A total of 149 patients with prostate cancer (mean age on starting of medical castration, 75±6 years) who received the gonadotropin‐releasing hormone, leuproreline (n=96 [65%]), gosereline (n=36 [24%]), or degarelix (n=17 [11%]), with antiandrogen drugs or androgen synthesis blockers (bicalutamide, flutamide, chlormadinone, enzalutamide, or abiraterone) (n=103 [69%]) or without antiandrogens (n=46 [31%]), were included in this study (Table 1). None had any malignant arrhythmias or had taken any medications of relevance for QT prolongation before and during the medical castration.
Table 1 Baseline Patient Characteristics, Therapy for Prostate Cancer, and Plasma Potassium and Calcium Levels Before and During the Therapy
Variable Total Torsade de Pointes and Ventricular Fibrillation
(n=149) Present (n=2) Absent (n=147)
Age at starting the medical castration, y 75±6 70±1 76±6
Hypertension, n (%) 84 (56) 2 (100) 82 (56)
Diabetes mellitus, n (%) 35 (23) 2 (100) 33 (22)
Dyslipidemia, n (%) 29 (19) 0 (0) 29 (20)
Stroke/transient cerebral ischemic attack, n (%) 15 (10) 0 (0) 15 (10)
Chronic heart failure, n (%) 3 (2) 0 (0) 3 (2)
Ischemic heart disease, n (%) 20 (13) 0 (0) 20 (14)
Effort angina pectoris 10 (7) 0 (0) 10 (7)
Old myocardial infarction 8 (5) 0 (0) 8 (5)
Coronary spastic angina 2 (1) 0 (0) 2 (1)
Arrhythmias, n (%) 28 (19) 0 (0) 28 (19)
Atrial fibrillation 24 (16) 0 (0) 24 (16)
Sick sinus syndrome 1 (1) 0 (0) 1 (1)
Paroxysmal supraventricular tachycardia 1 (1) 0 (0) 1 (1)
Premature ventricular contraction 1 (1) 0 (0) 1 (1)
Atrioventricular block 1 (1) 0 (0) 1 (1)
Therapy for prostate cancer
Gonadotropin‐releasing hormone, n (%)
Leuproreline 96 (62) 2 (100) 91 (62)
Goosereline 36 (24) 0 (0) 36 (24)
Degarelix 17 (11) 0 (0) 17 (12)
Antiandrogen drugs/androgen synthesis blockers, n (%) 103 (62) 1 (50) 102 (69)
Radiation therapy, n (%) 46 (30) 1 (50) 45 (31)
Plasma potassium level, mmol/L
Before the therapy (n=126) 4.2 (4.0–4.4) 5.2 4.2 (4.0–4.4)
During the therapy (n=147) 4.2 (3.9–4.5) 3.8 4.2 (4.0–4.5)
Plasma calcium level, mg/dL
Before the therapy (n=120) 9.1 (8.8–9.4) 10.3 9.0 (8.8–9.3)
During the therapy (n=145) 9.0 (8.6–9.2) 9.0 9.0 (9.0–9.3)
Values are reported as the mean±SD or number (percentage) of patients, unless otherwise noted. The plasma potassium and calcium levels are expressed as the median (interquartile range).
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Forty‐six (31%) patients had radiation therapy. Twenty‐eight patients (19%) had arrhythmias, including atrial fibrillation (n=24 [16%]), sick sinus syndrome (n=1 [1%]), paroxysmal supraventricular tachycardia (n=1 [1%]), premature ventricular contractions (n=1 [1%]), and atrioventricular block (n=1 [1%]) before medical castration. Twenty patients (13%) had cardiovascular diseases, including effort angina pectoris (n=10 [7%]), old myocardial infarctions (n=8 [5%]), and coronary spastic angina (n=2 [1%]), before the medical castration. Three patients (2%) had chronic, stable heart failure, but none had overt symptoms or signs of heart failure at the start of the medial castration therapy.
Change in the Electrocardiographic Parameters Attributable to Medical Castration
The 12‐lead ECGs during the therapy were recorded at 25±22 months (range, 3–102 months) after the start of the therapy. The heart rate increased from 68±11 to 71±14 beats per minute (P=0.006), but the PQ interval and QRS duration were comparable before and during the therapy (Table 2). The QTc intervals prolonged with the medical castration in 119 (79.9%) patients, and the QT and QTc intervals during the therapy were longer than those before the therapy (both for P<0.001; Figure 1A). QTc intervals of ≥440 ms before the therapy and those of ≥500 ms during the therapy were found in 17% and 3% of the patients, respectively (Table 2). An increase in the QTc interval from the pretreatment value (ΔQTc) of >20 and >50 ms was found in 53% and 12% of the patients, respectively. There was a slightly positive correlation between the QTc interval before the therapy and the ΔQTc (r=0.382; P<0.001). No abnormal ST‐segment elevation, including a Brugada‐type ECG, was found in the right precordial leads before or during the therapy in any of the patients.
Table 2 Change in the Electrocardiographic Parameters in All Patients
Parameter Before Therapy During Therapy P Value
Heart rate, /min 68±11 71±14 0.006
PQ interval, ms 184±88 181±30 0.725
QRS duration, ms 110±67 102±21 0.205
QT interval, ms 394±32 406±39 <0.001
QTc interval, ms 416±27 439±31 <0.001
QTc ≥440 ms, n (%) 25 (17) 121 (81) <0.001
QTc ≥500 ms, n (%) 1 (1) 5 (3) 0.214
Values are reported as the mean±SD or number (percentage) of patients. QTc indicates corrected QT.
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Figure 1 The QT and corrected QT (QTc) intervals during medical castration therapy.
A, The QT and QTc intervals before and during the medical castration therapy. B, Increase in the QT (ΔQT) interval and increase in the QTc (ΔQTc) interval from the pretreatment value in patients who developed malignant arrhythmias during the medical castration therapy and those who did not. The QT and QTc intervals and those changes during medical castration therapy.
Medical Castration and Malignant Arrhythmias
Among the 149 patients, 2 (1.3%) with QT/QTc prolongation presented with TdP/VF during the therapy (Table 3). Those 2 patients had no structural heart disease, risk of cardiovascular disease, or family history of cardiac disease, including sudden death or QT prolongation (Table 4). They were confirmed to have no ischemic heart disease by a coronary angiogram or stress thallium‐201 scintigram. No ventricular tachycardia or asystole was documented in any of the patients.
Table 3 Medical Castration and TdP/VF
Variable TdP/VF
Present (n=2) Absent (n=147)
Before therapy
Heart rate, /min 57±0 67±11
PQ interval, ms 201±39 182±87
QRS duration, ms 119±23 109±68
QT interval, ms 424±18 393±32
QTc interval, ms 416±21 416±27
QTc interval ≥440 ms, n (%) 0 (0) 25 (17)
QTc interval ≥500 ms, n (%) 0 (0) 1 (1)
During therapy
Heart rate, /min 68±5 71±14
PQ interval, ms 221±47 181±29
QRS duration, ms 113±24 102±21
QT interval, ms 480±20 405±38
QTc interval, ms 501±21 438±30
QTc interval ≥440 ms, n (%) 2 (100) 68 (46)
QTc interval ≥500 ms, n (%) 1 (50) 4 (3)
ΔQTc
Incidence, n (%)
>0 ms 2 (100) 117 (80)
>10 ms, n (%) 2 (100) 96 (65)
>20 ms, n (%) 2 (100) 77 (52)
>30 ms, n (%) 2 (100) 53 (36)
>40 ms, n (%) 2 (100) 34 (23)
>50 ms, n (%) 2 (100) 16 (11)
>60 ms, n (%) 2 (100) 8 (5)
>70 ms, n (%) 2 (100) 6 (4)
>80 ms, n (%) 2 (100) 4 (3)
Values are reported as the mean±SD or number (percentage) of patients. ∆QTc indicates increase in the QTc interval from the pretreatment value; QTc, corrected QT; TdP, torsade de pointes; and VF, ventricular fibrillation.
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Table 4 Two Patients Who Developed TdP/VF During Medical Castration Therapy
Patient No. Age, y Medical Castration Therapy Electrocardiographic Parameters Echocardiographic Parameters Plasma Electrolyte Levels
Before Therapy During Therapy After Cessation of Therapy Before Therapy During Therapy Before Therapy During Therapy
1 71 Leuprorelin, bicalutamide HR, /min 57 71 80 LVEF, % 57 21 Potassium, mEq/L 4.6 4.5
QT, ms 438 494 408 LVDd, mm 57 66 Calcium, mg/dL 9.4 8.7
QTc, ms 431 516 472 LVDs, mm 40 60 Magnesium, mg/dL NA NA
∆QTc, ms +85
2 70 Leuprorelin, brachytherapy HR, /min 57 64 69 LVEF, % 71 70 Potassium, mEq/L 5.8 3.1
QT, ms 410 466 410 LVDd, mm 50 44 Calcium, mg/dL 11.1 9.2
QTc, ms 401 482 432 LVDs, mm 30 26 Magnesium, mg/dL NA 2.1
∆QTc, ms +81
∆QTc indicates increase in the QTc interval from the pretreatment value; HR, heart rate; LVDd, left ventricular end‐diastolic diameter; LVDs, left ventricular end‐systolic diameter; LVEF, left ventricular ejection fraction; NA, not available; QTc, corrected QT; TdP, torsade de pointes; and VF, ventricular fibrillation.
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The first patient (a 71‐year‐old man) with metastatic prostate cancer (stage D) presented with a QT prolongation while receiving medical castration therapy, and the TdP/VF occurred at 6 months after starting the therapy (Table 4). Coronary angiography showed no significant stenoses of the coronary arteries. He had no mutations related to long‐QT syndrome. During the TdP/VF episode, the left ventricular (LV) wall motion diffusedly decreased, with an LV ejection fraction of 21%. However, no regional LV wall motion abnormalities, suggesting Takotsubo cardiomyopathy, were found. The LV ejection fraction recovered to the level of that before the medical castration by 11 months. The QTc interval also improved after the discontinuation of the therapy. He had done well and had no VF recurrences during 38 months of follow‐up.
The second patient (a 70‐year‐old man) with localized prostate cancer (stage B) was admitted to our hospital because of an operation for a renal cell carcinoma. His QT interval prolonged after starting the therapy, and the TdP/VF occurred 22 months after starting the therapy (Table 4 and Figure 2). At that time, the LV function was preserved, but the serum potassium level was low. Despite the correction of the serum potassium level, the QT prolongation did not completely improve. With cessation of the therapy, his QT interval had become normal. He had no VF recurrences during 72 months of follow‐up.
Figure 2 Representative ECG recordings obtained in a patient who developed torsade de pointes and ventricular fibrillation during medical castration therapy.
A, Twelve‐lead ECGs before and 22 months after the medical castration. B, Tracings of the bedside continuous single‐lead ECG monitoring. Torsade de pointes and ventricular fibrillation spontaneously occurred 22 months after the medical castration. HR indicates heart rate; and QTc, corrected QT.
Patients With and Without TdP/VF
Before the therapy, the patient characteristics, therapy for prostate cancer, and all electrocardiographic parameters were comparable between the patients with TdP/VF and those without TdP/VF (Tables 1 and 3). In 2 patients with TdP/VF, the QTc interval before the therapy was <440 ms. However, during the therapy, it was markedly prolonged, and the increase in the QTc interval before and during the therapy (ΔQTc) was >80 ms (Tables 3 and 4 and Figure 1B). On the other hand, in 147 patients without TdP/VF, 17% of the patients had a QTc interval ≥440 ms before the therapy. During the therapy, it was prolonged in 80% of the patients without TdP/VF. However, the prevalence of a ΔQTc of >50 and >60 ms was 11% and 5%, respectively, and a ΔQTc >80 ms was found in only 4 (3%) patients (Table 3 and Figure 1B). A ΔQTc >60 ms identified the development of TdP/VF with the highest accuracy (Table 5).
Table 5 Sensitivity, Specificity, and Predictive Accuracy of the Criteria for TdP/VF During Medical Castration
Criterion Sensitivity, % Specificity, % Positive Predictive Value, % Negative Predictive Value, %
ΔQTc interval >50 ms 11.1 100 100 89.1
ΔQTc interval >60 ms 20.0 100 100 94.6
∆QTc indicates increase in the corrected QT interval from the pretreatment value; TdP, torsade de pointes; and VF, ventricular fibrillation.
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QT Interval and Plasma Electrolyte Levels
The median (interquartile range) of plasma level of the potassium was 4.2 (4.0–4.5) and 4.2 (4.0–4.4) mmol/L before and during the therapy, respectively. No close relationship was found between the QTc interval and plasma potassium level before and during the therapy (before: r=0.057, P=0.526; during: r=0.184, P=0.025). The median (interquartile range) of plasma level of the calcium was 9.1 (8.8–9.4) and 9.0 (8.7–9.3) mg/dL before and during the therapy, respectively. No close relationship was found between the QTc interval and plasma level of the calcium before the therapy (r=0.144; P=0.113). However, it was slightly correlated with the calcium level during the therapy (r=0.253; P=0.002).
QT Interval and Echocardiogram Parameters
Forty‐four patients (30%) underwent an echocardiogram before and during the therapy. The LV end‐diastolic diameter during the therapy was 49±5 mm, which was comparable to that before the therapy (47±5 mm; P=0.084). The LV ejection fraction during the therapy was also comparable to that before the therapy (65%±13% versus 65%±7%; P=0.867).
No close correlation was found between the QTc interval before the therapy and the LV diastolic diameter (r=0.078; P=0.616) or LV ejection fraction (r=0.046; P=0.769). However, the QTc interval during the therapy was slightly correlated with the LV diastolic diameter (r=0.308; P=0.042) or LV ejection fraction (r=0.334; P=0.027) during the therapy.
Among 44 patients who underwent echocardiography before and during the therapy, 1 had LV systolic dysfunction with an LV ejection fraction of <50% before the therapy. No further deterioration of the LV systolic dysfunction was found during the therapy. Another 4 (9.3%) patients newly presented with LV systolic dysfunction during the therapy, and 1 of them developed TdP/VF during the therapy.
Prognosis of the Patients
During the observation period, 52 patients (mean age, 81±8 years) died: The most common cause of death (n=27 [52%]) was prostate cancer. The second most common cause of death was attributable to other cancers (n=10 [19%]). Other causes of death included infectious disease (n=8 [15%]: pneumonia [n=6], pulmonary tuberculosis [n=1], and urinary tract infections [n=1]), cerebral infarctions (n=2 [4%]), respiratory failure (n=1 [2%]), and senile decay (n=4 [8%]). None had any sudden death highly suspicious of TdP/VF.
Discussion
Major Findings
The results of this study that included 149 patient with prostate cancer receiving medical castration demonstrated the following findings: (1) medical castration prolonged the QTc interval in 79.9% of the patients; (2) TdP/VF occurred in 2 (1.3%) patients who had no structural heart disease or any arrhythmias, and it occurred later (≥6 months after receiving medical castration); (3) the QT prolongation recovered with the discontinuation of the medical castration; (4) before the therapy, all electrocardiographic parameters were comparable between the patients with TdP/VF and those without TdP/VF; and (5) during the therapy, the ΔQTc was longer in the patients with TdP/VF than in those without TdP/VF, and the incidence of TdP/VF was higher in patients with a ΔQTc of >50 ms.
These findings indicated that medical castration prolonged the QT and QTc intervals in most patients with prostate cancer and could rarely cause TdP/VF. Much attention should be paid to the QTc interval, especially the ΔQTc, throughout all periods of medical castration to prevent malignant arrhythmias in all patients.
Prolonged QT/QTc Intervals and TdP/VF During Medical Castration
Sex steroid hormones, including testosterone, play an important role in cardiac repolarization and the control of the QT intervals. 12 , 13 , 14 The sex differences in the sex hormones are considered to be the main reason for the sex difference of long‐QT syndrome and malignant arrhythmias. Medical castration, the mainstay treatment in patients with advanced prostate cancer, strongly suppresses testosterone, 2 and could affect the QT interval: castrated men could exhibit a longer duration of the QTc interval than noncastrated men, 5 and medical and surgical castration results in prolonged QT intervals in castrated men. 15 Recently, the incidence of TdP and sudden death attributable to medical castration has been examined from the international pharmacovigilance database VigiBase (n=6 560 565 individual case safety reports). 16 TdP and sudden death were found in 68 and 99 cases, respectively, indicating that medical castration could cause TdP/VF or sudden death. However, some patients received medical castration because of prostatism and androgenic alopecia, not prostate cancer. Because those data were obtained from uncontrolled sources, 16 the detailed information on the electrocardiographic measurements is lacking. Furthermore, the precise causes of sudden death in patients receiving medical castration for prostate cancer might be unclear. In that report, 16 sudden death occurred 0.25 to 90 days after starting the medical castration. Some cases of sudden death that occurred shortly after starting the medical castration might not have been attributable to TdP/VF.
In the present study, for the patients with prostate cancer receiving medical castration, we examined the incidence and characteristics of QT/QTc prolongation and the incidence and mode of the onset of TdP/VF. In patients with prostate cancer, prolongation of the QT and QTc interval developed in ≈80% during medical castration. Furthermore, although rare (2 patients [1.3%]), TdP/VF could occur during the therapy. It should be specially noted that TdP/VF could occur in patients with no structural heart disease or risk of QT prolongation before the therapy, and that it could occur several months after the initiation of the therapy. Our results indicated that special attention should be paid to the prolongation of the QT and QTc intervals throughout all periods of the medical castration in all patients with prostate cancer receiving this therapy.
Predictors of TdP/VF During Medical Castration
Several risk factors for drug‐induced TdP/VF have been reported. 17 , 18 , 19 , 20 , 21 In the present study, the pretreatment QTc intervals ≥440 ms and those ≥500 ms, known as risk factors for drug‐induced TdP/VF, 17 , 18 , 21 in patients with TdP/VF were similar to those in patients without TdP/VF. The incidence of a QTc ≥500 ms was also comparable between these 2 groups. However, the magnitude of the ΔQTc differed between these 2 groups. In patients with TdP/VF, the ΔQTc was >80 ms. On the contrary, in patients without TdP/VF, the prevalence of a ΔQTc of >50 ms was found in only 11% of the patients. Previous studies reported that a ΔQTc of >60 ms was a predictor of TdP/VF in patients receiving QT‐prolonging agents. 18 , 19 , 20 In our study, the patients were all men, and the age on starting the therapy was 75±6 years (range, 62–92 years), which seems to be older than that in the previous studies 19 , 20 including younger and/or female subjects. It is well known that, because the level of testosterone gradually decreases with age in adult men, the QTc interval in men gradually lengthens with aging. 14 Therefore, there is a possibility that the QTc interval before the therapy was longer in our patients than in those of the previous studies including young subjects and/or women. We think that, in aged patients who have relatively long‐QTc intervals before the therapy, a smaller increase in the QTc interval while receiving QT‐prolonging agents might become a risk for TdP/VF. That might be the reason why the magnitude of the ΔQTc for predicting TdP/VF was smaller in our study than in the previous studies. We believe that, in aged patients receiving QT‐prolonging agents, as in our patients, a stricter predictor, a ΔQTc >50 ms, should be used to predict TdP/VF, and the discontinuation of the therapy should be considered.
Heart failure with a reduced LV ejection fraction 19 and hypokalemia 21 are well‐known risk factors for TdP. In the present study, during the TdP/VF during the medical castration, one patient presented with LV systolic dysfunction, and the other had hypokalemia. These circumstances might facilitate the TdP/VF occurrence. In this study, the QTc interval during the medical castration correlated with the LV diastolic diameter and LV ejection fraction, which might have indicated that the medical castration might damage the cardiac myocytes and cause QT prolongation. 22 , 23 Therefore, during medical castration, it is also important to evaluate the cardiac function and avoid an electrolyte imbalance. When patients develop TdP/VF during medical castration, a prompt cessation of the therapy and a correction of the electrolyte disorder, if it exists, are indispensable to avoid recurrences of TdP/VF and sudden death.
Study Limitations
First, this study was a single‐center nonrandomized study, and further prospective studies are needed to investigate the role of QT prolongation in malignant arrhythmias. Second, the timing of obtaining an ECG during the therapy varied. Third, drug‐induced long‐QT syndrome might have been related as a carrier of congenital long‐QT syndrome disease‐causing mutations. Fourth, the QT intervals were measured in lead V2. The QT interval is preferably measured in lead II or V5 for long‐QT syndrome. 24 We initially attempted to determine that in those 2 leads. However, we could not precisely do that in those 2 leads because of the difficulty in recognizing the end of the T wave in some patients. Fifth, the plasma testosterone levels were not measured. Finally, because of the small number of patients with TdP/VF (n=2), no statistical comparisons between the patients with TdP/VF and those without could be completed.
Sources of Funding
This work was supported in part by the Akaeda Medical Research Foundation research grant (to Dr Hasegawa) and Grant‐in‐Aid for Young Scientists (Japan Society for the Promotion of Science KAKENHI, JP19K19553) (to Dr Hasegawa).
Disclosures
None.
Acknowledgments
We thank Professor Ryousuke Fujita for his critical suggestions about the statistical analyses. We also thank John Martin for his help in the preparation of the manuscript. | Recovering | ReactionOutcome | CC BY-NC-ND | 33599136 | 20,017,937 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Crohn^s disease'. | Successful treatment with vedolizumab in an adolescent with Crohn disease who had developed active pulmonary tuberculosis while receiving infliximab.
Vedolizumab (VDZ) has been approved for the treatment of inflammatory bowel diseases (IBDs) in patients aged ≥18 years. We report a case of a pediatric patient with Crohn disease (CD) who was successfully treated with VDZ. A 16-year-old female developed severe active pulmonary tuberculosis (TB) during treatment with infliximab (IFX). IFX was stopped, and TB treatment was started. After a 6-month regimen of standard TB medication, her pulmonary TB was cured; however, gastrointestinal symptoms developed. Due to the concern of the patient and parents regarding TB reactivation on restarting treatment with IFX, VDZ was started off-label. After the second dose of VDZ, the patient was in clinical remission and her remission was continuously sustained. Ileocolonoscopy at 1-year after VDZ initiation revealed endoscopic healing. Therapeutic drug monitoring conducted during VDZ treatment showed negative antibodies to VDZ. No serious adverse events occurred during the VDZ treatment. This is the first case report in Korea demonstrating the safe and effective use of VDZ treatment in a pediatric CD patient. In cases that require recommencement of treatment with biologics after recovery of active pulmonary TB caused by anti-tumor necrosis factor agents, VDZ may be a good option even in pediatric IBD.
Introduction
Crohn disease (CD) is an inflammatory bowel disease (IBD) characterized by ulcers and inflammation that develop anywhere throughout the gastrointestinal (GI) tract [1]. Approximately 25% of patients with CD are diagnosed at <20 years of age, in whom a more aggressive disease course occurs compared with adult-onset disease. Hence, an earlier introduction of immunomodulators and/or anti-tumor necrosis factor (TNF) agents is required [1-3].
Vedolizumab (VDZ) is a humanized monoclonal antibody acting on α4β7 integrin that is present on the surface of lymphocytes and binds to MadCAM-1 on the intestinal endothelium. VDZ selectively inhibits the transmigration of lymphocytes into the inflamed intestinal tissue [4]. This gut-selective mechanism of action of VDZ is advantageous in terms of safety compared to other biologics. VDZ is currently approved for use only in adults with CD and ulcerative colitis (UC) [5,6]. Anti-TNF agents, such as infliximab (IFX) and adalimumab, are the only biological agents approved for use in pediatric IBD, whereas VDZ can be administered only off-label [7,8]. Herein, we report a rare case of a pediatric CD patient who successfully achieved and maintained remission with VDZ after developing severe active pulmonary tuberculosis (TB) during treatment with IFX.
Case
A 16-year-old female was admitted to Kyungpook National University Children’s Hospital with complaints of abdominal pain, diarrhea, and hematochezia for 2 months. The past medical history of the patient was unremarkable. She had completed Bacillus Calmette–Guérin (BCG) vaccination and had no past or family history of pulmonary TB. Initial laboratory tests showed a white blood cell count of 4,500/μL, hemoglobin level of 6.2 g/dL, platelet count of 532,000/μL, albumin level of 3.0 g/dL, erythrocyte sedimentation rate (ESR) of 110 mm/hr, and C-reactive protein (CRP) level of 8.0 mg/dL. The fecal immunochemical test (FIT) was positive, and fecal calprotectin (FC) was >2,000 mg/kg. No pathogens were detected in the stool culture and stool polymerase chain reaction (PCR). Chest X-ray showed no abnormal findings in the lungs, and the interferon-gamma release assay (IGRA) was negative. Ileocolonoscopy showed multifocal ulcers throughout the terminal ileum and colon (Fig. 1). Cryptitis, crypt abscesses, and non-caseating granulomas were observed throughout the terminal ileum and colon on histology; however, the acid-fast bacillus smear and culture and PCR for TB were negative. Upper GI endoscopy revealed ulcers in the duodenum (Fig. 2A). Magnetic resonance enterography showed multisegmental wall thickening in the ileum (Fig. 2B). The patient was diagnosed with CD with a phenotype of A1b, L3+L4ab, B1, G0 according to the Paris classification. Her Pediatric Crohn’s Disease Activity Index (PCDAI) score was 50, and the Simple Endoscopic Score for Crohn’s Disease (SES-CD) was 22.
Treatment began with exclusive enteral nutrition (EEN), mesalazine, and azathioprine, which were effective. One month after treatment, her PCDAI score had decreased to 10. However, 1 month after finishing her 8-week treatment with EEN, the disease relapsed and her PCDAI score elevated to 42.5; hence, prednisolone was started per oral at a dose of 50 mg/day. Despite corticosteroid treatment, symptoms persisted, and IFX was administered. Chest X-ray before the administration of IFX showed no abnormal findings in the lungs, and the IGRA was negative. Symptoms resolved after the second dose of IFX infusion, and her PCDAI score decreased to 7.5. However, during her visit for the third IFX infusion, she complained of fever, cough, and dyspnea on exertion for a week. Radiologic examination of the chest revealed a left pleural effusion with mild pleural thickening and nodularities indicating TB pleurisy on chest X-ray and computed tomography (Fig. 3). Thoracentesis was conducted, and pulmonary TB was confirmed by a positive TB PCR test of the pleural effusion specimen and a positive IGRA test. IFX treatment was discontinued and the standard TB treatment regimen consisting of isoniazid, ethambutol, rifampin, and pyrazinamide for 2 months, followed by isoniazid, ethambutol, and rifampin for 4 months, was started. EEN was restarted and maintained for 8 weeks. Subsequently, mesalazine was administered to treat CD.
Her pulmonary TB was completely cured after 6 months of TB treatment. However, symptoms such as hematochezia, diarrhea, and weight loss began by the end of TB treatment. Laboratory tests showed a white blood cell count of 7,010/μL, hemoglobin level of 6.8 g/dL, platelet count of 477,000/μL, albumin level of 3.1 g/dL, ESR of 45 mm/hr, and CRP of 2.2 mg/dL. FIT was positive, and FC was >2,000 mg/kg. No pathogens were detected in the stool culture and stool PCR. Her PCDAI score was 47.5, and the exacerbation of CD was confirmed by ileocolonoscopy (Fig. 4A). Therefore, we planned to restart IFX. However, due to the fear of another severe disease course of active TB when IFX were to be restarted, the patient and parents preferred to start VDZ off-label instead of restarting IFX. Before starting VDZ, the patient’s weight was 57 kg. VDZ was administered according to the regular regimen approved in adults of 300 mg per dose at weeks 0, 2, and 6 for induction and 8-week intervals for maintenance treatment thereafter. The patient showed a fast response to VDZ treatment. At the week 6 visit for her third VDZ infusion, she was in clinical remission, and inflammatory markers were normalized (Table 1, Fig. 5). Ileocolonoscopy at the 1-year follow-up after VDZ treatment revealed endoscopic healing (Fig. 4B). Therapeutic drug monitoring (TDM) using commercialized enzyme-linked immunosorbent assay kits (Immundiagnostik AG, Bensheim, Germany) was conducted during VDZ treatment. An anti-drug antibody level of ≤10 AU/mL was defined as negative, according to the manufacturer’s manual. TDM results during VDZ treatment showed negative antibodies to VDZ (Table 1). The patient is currently in her second year of VDZ treatment and is maintaining clinical and biochemical remission. No serious adverse events, including TB reactivation, have occurred.
Discussion
With the introduction of anti-TNF agents in the treatment of CD, there is no doubt that treatment outcomes have improved. However, anti-TNF agents are known to increase the risk of serious infections, including TB [9]. It has been reported that anti-TNF agents are associated with a 2- to 8-fold increased risk of developing active TB [9]. Reactivation of latent TB infections (LTBI) rather than a new infection is considered to be the primary cause of active TB, as most of the active TB cases have been reported to occur within 3 to 4 months after starting anti-TNF treatment [9]. Therefore, screening for LTBI prior to anti-TNF treatment is strongly recommended worldwide, and especially in Asia, where the prevalence of LTBI is higher than that of Western countries [9]. In this case report, the patient had completed TB vaccination, did not have any history or exposure to active TB, and TB screening was negative with both chest X-ray and IGRA at both times of diagnostic evaluation of CD and before the commencement of IFX. However, the patient, unfortunately, developed symptoms of active pulmonary TB 5 weeks after starting IFX treatment, indicating that the active TB was probably due to the reactivation of LTBI, which was missed on TB screening.
It is well known that when active TB is diagnosed during anti-TNF treatment, the anti-TNF agent should be withheld, and anti-TB therapy should be started [10]. Regarding when to restart anti-TNF treatment, it is considered safe to delay the resumption of anti-TNF therapy until the completion of anti-TB treatment [10]. However, if an early resumption of anti-TNF treatment is required, anti-TNF treatment may be restarted as early as 2 months after anti-TB treatment in patients who did not have an initially severe active TB, demonstrated a favorable response to anti-TB treatment, and when drug susceptibility was proven [10]. In this case report, the patient’s symptoms of CD were fortunately well controlled without IFX until the end of TB medication. According to the treatment guidelines, she could have restarted IFX when CD relapsed at the end of TB medication. However, because she had suffered a severe active TB and due to the fear of another severe disease course of active TB when IFX were to be restarted, the patient and parents preferred to start VDZ instead.
VDZ is effective for achieving both clinical remission and mucosal healing in adult patients with UC and CD [5,6,11]. Regarding safety, according to the integrated safety data from six trials, VDZ did not increase the risk of serious infections, progressive multifocal leukoencephalopathy, or malignancy [12]. Among 2,830 patients with 4,811 person-years (PYs) exposure to VDZ, TB was reported in only four patients (0.14%) with an estimated incidence of 0.1/100 PYs [12]. Meanwhile, the estimated incidence of TB during treatment with anti-TNF agents has been reported as 1.34/100 PYs and 0.79/100 PYs for IFX and adalimumab, respectively [13].
Compared with adults, there is limited experience with VDZ therapy in pediatric IBD. In children, VDZ is only available off-label and is used for patients who have already exhausted other treatment options, including anti-TNF agents. According to the ECCO/ESPGHAN (European Crohn’s and Colitis Organisation and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition) guideline, VDZ should be considered in chronically active or steroid-dependent pediatric UC patients as a second-line biologic therapy after anti-TNF failure, even though it has not yet been approved for use in children [7]. In addition, in pediatric CD patients who fail to maintain clinical remission on anti-TNF agents despite dose optimization and immunomodulator use, VDZ can be considered off-label [8]. A multicenter retrospective study showed that VDZ was safe and effective in pediatric IBD patients [14]. In this study, 64 children with IBD who had been previously treated with anti-TNF agents were included. During a median follow-up period of 24 months, corticosteroid-free remission was 37% in UC and 14% in CD at week 14, and 39% in UC and 24% in CD at the last follow-up [14]. Another retrospective study on 52 children with IBD showed clinical remission rates of 76% and 42% for UC and CD, respectively, at week 14 [15]. No serious adverse events were reported in either study [14,15].
In the GEMINI 3 trial, VDZ was not more effective than placebo in inducing clinical remission at week 6 among patients with CD who had failed previous treatment with anti-TNF agents [16]. The clinical benefits of VDZ in these patients were detectable later at week 10 [16]. This slow induction rate of VDZ was also observed in pediatric patients with CD [14]. Contrary to these findings, the patient in this case report showed a fast response to VDZ. Additionally, according to the clinical decision support tool developed for predicting the probability of response to VDZ in adult CD patients [17], the patient’s score in this case report was 16, which applies to an intermediate response probability. However, the patient continuously maintained clinical and biochemical remission, and endoscopic healing was observed at 1-year treatment with VDZ. One reason for this swift and favorable response to VDZ in this case report may be that the patient had not failed IFX due to poor response, but because discontinuation of IFX was inevitable due to active TB infection.
Data regarding TDM in VDZ are limited. An exposure-efficacy relationship does not seem as straightforward as they are for anti-TNF agents, and robust target VDZ trough levels are not well-defined [18]. However, according to data from a TDM study in adult IBD, VDZ trough levels of >30 μg/mL at week 2, >24 μg/mL at week 6, and >14 μg/mL during maintenance therapy have been proposed for achieving clinical remission [19]. In another study in pediatric-onset IBD patients treated with VDZ, the mean VDZ trough level was 29.9 μg/mL at week 6 and 11.5 μg/mL during maintenance therapy [20]. In this case report, VDZ trough levels were lower than the proposed threshold targets; however, the patient responded well. This may be due to variability in the yet to be revealed association between individual pharmacokinetics and the degree of response to VDZ.
In conclusion, we report a case of a pediatric patient with CD who successfully achieved and maintained remission with VDZ after developing active pulmonary TB during treatment with IFX. In cases that require recommencement of treatment with biologics after recovery of active pulmonary TB caused by anti-TNF agents, VDZ may be a good option even in pediatric IBD.
Fig. 1. Images of ileocolonoscopy at the diagnosis of Crohn disease. Multifocal aphthous ulcers are observed in the (A) terminal ileum and (B) colon.
Fig. 2. Images at the diagnosis of Crohn disease. (A) Upper gastrointestinal endoscopy shows multiple ulcers in the duodenum. (B) Magnetic resonance enterography shows multisegmental wall thickening in the ileum.
Fig. 3. Radiologic images at the diagnosis of active pulmonary tuberculosis during infliximab treatment. (A) Chest X-ray shows a marked amount of left pleural effusion. (B) Chest computed tomography shows left pleural effusion with mild pleural thickening and nodularities.
Fig. 4. Images of ileocolonoscopy before and after treatment with vedolizumab. (A) Multiple ulcers with mucosal friability are observed throughout the colon before treatment with vedolizumab. (B) Endoscopic healing is observed 1 year after treatment with vedolizumab.
Fig. 5. Fecal immunochemical test (FIT) and fecal calprotectin (FC) results during vedolizumab treatment.
Table 1. Crohn disease activity, laboratory results, and thickening and nodularities (arrow).
Week VDZ PCDAI CRP (mg/dL) ESR (mm/hr) Albumin (g/dL) VDZ TL (μg/mL) ATV (AU/mL)
0 #1 40.0 2.20 45 3.1
2 #2 12.5 0.04 47 4.1 25.25 1.91
6 #3 5.0 0.12 19 4.1 14.35 4.56
14 #4 0 0.05 15 4.1 3.36 1.76
22 #5 2.5 0.08 24 4.0 3.19 1.62
30 #6 0 0.02 16 4.2 3.59 2.06
38 #7 0 0.03 17 4.4 5.31 2.06
46 #8 2.5 0.09 33 4.5 5.18 1.76
54 #9 0 0.02 8 4.2 4.15 2.06
VDZ, vedolizumab; PCDAI, Pediatric Crohn’s Disease Activity Index; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; TL, trough level; ATV, antibody to VDZ.
Ethical statements
This study was approved by the Institutional Review Board (IRB) of Kyungpook National University Chilgok Hospital (IRB No: 2020-09-013). Informed consent was obtained from the patient and her parents.
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Funding
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2017R1C1B5076980).
Author contributions
Conceptualization, Formal analysis, Investigation: SC, BK; Data curation: All authors; Funding acquisition, Methodology, Resources, Software, Supervision, Validation: BK; Project administration, Visualization: SC; Writing-original draft: SC; Writing-review & editing: BSC, BHC, BK. | AZATHIOPRINE, INFLIXIMAB, MESALAMINE, PREDNISOLONE | DrugsGivenReaction | CC BY-NC | 33601494 | 18,963,545 | 2021-07 |
What was the administration route of drug 'INFLIXIMAB'? | Successful treatment with vedolizumab in an adolescent with Crohn disease who had developed active pulmonary tuberculosis while receiving infliximab.
Vedolizumab (VDZ) has been approved for the treatment of inflammatory bowel diseases (IBDs) in patients aged ≥18 years. We report a case of a pediatric patient with Crohn disease (CD) who was successfully treated with VDZ. A 16-year-old female developed severe active pulmonary tuberculosis (TB) during treatment with infliximab (IFX). IFX was stopped, and TB treatment was started. After a 6-month regimen of standard TB medication, her pulmonary TB was cured; however, gastrointestinal symptoms developed. Due to the concern of the patient and parents regarding TB reactivation on restarting treatment with IFX, VDZ was started off-label. After the second dose of VDZ, the patient was in clinical remission and her remission was continuously sustained. Ileocolonoscopy at 1-year after VDZ initiation revealed endoscopic healing. Therapeutic drug monitoring conducted during VDZ treatment showed negative antibodies to VDZ. No serious adverse events occurred during the VDZ treatment. This is the first case report in Korea demonstrating the safe and effective use of VDZ treatment in a pediatric CD patient. In cases that require recommencement of treatment with biologics after recovery of active pulmonary TB caused by anti-tumor necrosis factor agents, VDZ may be a good option even in pediatric IBD.
Introduction
Crohn disease (CD) is an inflammatory bowel disease (IBD) characterized by ulcers and inflammation that develop anywhere throughout the gastrointestinal (GI) tract [1]. Approximately 25% of patients with CD are diagnosed at <20 years of age, in whom a more aggressive disease course occurs compared with adult-onset disease. Hence, an earlier introduction of immunomodulators and/or anti-tumor necrosis factor (TNF) agents is required [1-3].
Vedolizumab (VDZ) is a humanized monoclonal antibody acting on α4β7 integrin that is present on the surface of lymphocytes and binds to MadCAM-1 on the intestinal endothelium. VDZ selectively inhibits the transmigration of lymphocytes into the inflamed intestinal tissue [4]. This gut-selective mechanism of action of VDZ is advantageous in terms of safety compared to other biologics. VDZ is currently approved for use only in adults with CD and ulcerative colitis (UC) [5,6]. Anti-TNF agents, such as infliximab (IFX) and adalimumab, are the only biological agents approved for use in pediatric IBD, whereas VDZ can be administered only off-label [7,8]. Herein, we report a rare case of a pediatric CD patient who successfully achieved and maintained remission with VDZ after developing severe active pulmonary tuberculosis (TB) during treatment with IFX.
Case
A 16-year-old female was admitted to Kyungpook National University Children’s Hospital with complaints of abdominal pain, diarrhea, and hematochezia for 2 months. The past medical history of the patient was unremarkable. She had completed Bacillus Calmette–Guérin (BCG) vaccination and had no past or family history of pulmonary TB. Initial laboratory tests showed a white blood cell count of 4,500/μL, hemoglobin level of 6.2 g/dL, platelet count of 532,000/μL, albumin level of 3.0 g/dL, erythrocyte sedimentation rate (ESR) of 110 mm/hr, and C-reactive protein (CRP) level of 8.0 mg/dL. The fecal immunochemical test (FIT) was positive, and fecal calprotectin (FC) was >2,000 mg/kg. No pathogens were detected in the stool culture and stool polymerase chain reaction (PCR). Chest X-ray showed no abnormal findings in the lungs, and the interferon-gamma release assay (IGRA) was negative. Ileocolonoscopy showed multifocal ulcers throughout the terminal ileum and colon (Fig. 1). Cryptitis, crypt abscesses, and non-caseating granulomas were observed throughout the terminal ileum and colon on histology; however, the acid-fast bacillus smear and culture and PCR for TB were negative. Upper GI endoscopy revealed ulcers in the duodenum (Fig. 2A). Magnetic resonance enterography showed multisegmental wall thickening in the ileum (Fig. 2B). The patient was diagnosed with CD with a phenotype of A1b, L3+L4ab, B1, G0 according to the Paris classification. Her Pediatric Crohn’s Disease Activity Index (PCDAI) score was 50, and the Simple Endoscopic Score for Crohn’s Disease (SES-CD) was 22.
Treatment began with exclusive enteral nutrition (EEN), mesalazine, and azathioprine, which were effective. One month after treatment, her PCDAI score had decreased to 10. However, 1 month after finishing her 8-week treatment with EEN, the disease relapsed and her PCDAI score elevated to 42.5; hence, prednisolone was started per oral at a dose of 50 mg/day. Despite corticosteroid treatment, symptoms persisted, and IFX was administered. Chest X-ray before the administration of IFX showed no abnormal findings in the lungs, and the IGRA was negative. Symptoms resolved after the second dose of IFX infusion, and her PCDAI score decreased to 7.5. However, during her visit for the third IFX infusion, she complained of fever, cough, and dyspnea on exertion for a week. Radiologic examination of the chest revealed a left pleural effusion with mild pleural thickening and nodularities indicating TB pleurisy on chest X-ray and computed tomography (Fig. 3). Thoracentesis was conducted, and pulmonary TB was confirmed by a positive TB PCR test of the pleural effusion specimen and a positive IGRA test. IFX treatment was discontinued and the standard TB treatment regimen consisting of isoniazid, ethambutol, rifampin, and pyrazinamide for 2 months, followed by isoniazid, ethambutol, and rifampin for 4 months, was started. EEN was restarted and maintained for 8 weeks. Subsequently, mesalazine was administered to treat CD.
Her pulmonary TB was completely cured after 6 months of TB treatment. However, symptoms such as hematochezia, diarrhea, and weight loss began by the end of TB treatment. Laboratory tests showed a white blood cell count of 7,010/μL, hemoglobin level of 6.8 g/dL, platelet count of 477,000/μL, albumin level of 3.1 g/dL, ESR of 45 mm/hr, and CRP of 2.2 mg/dL. FIT was positive, and FC was >2,000 mg/kg. No pathogens were detected in the stool culture and stool PCR. Her PCDAI score was 47.5, and the exacerbation of CD was confirmed by ileocolonoscopy (Fig. 4A). Therefore, we planned to restart IFX. However, due to the fear of another severe disease course of active TB when IFX were to be restarted, the patient and parents preferred to start VDZ off-label instead of restarting IFX. Before starting VDZ, the patient’s weight was 57 kg. VDZ was administered according to the regular regimen approved in adults of 300 mg per dose at weeks 0, 2, and 6 for induction and 8-week intervals for maintenance treatment thereafter. The patient showed a fast response to VDZ treatment. At the week 6 visit for her third VDZ infusion, she was in clinical remission, and inflammatory markers were normalized (Table 1, Fig. 5). Ileocolonoscopy at the 1-year follow-up after VDZ treatment revealed endoscopic healing (Fig. 4B). Therapeutic drug monitoring (TDM) using commercialized enzyme-linked immunosorbent assay kits (Immundiagnostik AG, Bensheim, Germany) was conducted during VDZ treatment. An anti-drug antibody level of ≤10 AU/mL was defined as negative, according to the manufacturer’s manual. TDM results during VDZ treatment showed negative antibodies to VDZ (Table 1). The patient is currently in her second year of VDZ treatment and is maintaining clinical and biochemical remission. No serious adverse events, including TB reactivation, have occurred.
Discussion
With the introduction of anti-TNF agents in the treatment of CD, there is no doubt that treatment outcomes have improved. However, anti-TNF agents are known to increase the risk of serious infections, including TB [9]. It has been reported that anti-TNF agents are associated with a 2- to 8-fold increased risk of developing active TB [9]. Reactivation of latent TB infections (LTBI) rather than a new infection is considered to be the primary cause of active TB, as most of the active TB cases have been reported to occur within 3 to 4 months after starting anti-TNF treatment [9]. Therefore, screening for LTBI prior to anti-TNF treatment is strongly recommended worldwide, and especially in Asia, where the prevalence of LTBI is higher than that of Western countries [9]. In this case report, the patient had completed TB vaccination, did not have any history or exposure to active TB, and TB screening was negative with both chest X-ray and IGRA at both times of diagnostic evaluation of CD and before the commencement of IFX. However, the patient, unfortunately, developed symptoms of active pulmonary TB 5 weeks after starting IFX treatment, indicating that the active TB was probably due to the reactivation of LTBI, which was missed on TB screening.
It is well known that when active TB is diagnosed during anti-TNF treatment, the anti-TNF agent should be withheld, and anti-TB therapy should be started [10]. Regarding when to restart anti-TNF treatment, it is considered safe to delay the resumption of anti-TNF therapy until the completion of anti-TB treatment [10]. However, if an early resumption of anti-TNF treatment is required, anti-TNF treatment may be restarted as early as 2 months after anti-TB treatment in patients who did not have an initially severe active TB, demonstrated a favorable response to anti-TB treatment, and when drug susceptibility was proven [10]. In this case report, the patient’s symptoms of CD were fortunately well controlled without IFX until the end of TB medication. According to the treatment guidelines, she could have restarted IFX when CD relapsed at the end of TB medication. However, because she had suffered a severe active TB and due to the fear of another severe disease course of active TB when IFX were to be restarted, the patient and parents preferred to start VDZ instead.
VDZ is effective for achieving both clinical remission and mucosal healing in adult patients with UC and CD [5,6,11]. Regarding safety, according to the integrated safety data from six trials, VDZ did not increase the risk of serious infections, progressive multifocal leukoencephalopathy, or malignancy [12]. Among 2,830 patients with 4,811 person-years (PYs) exposure to VDZ, TB was reported in only four patients (0.14%) with an estimated incidence of 0.1/100 PYs [12]. Meanwhile, the estimated incidence of TB during treatment with anti-TNF agents has been reported as 1.34/100 PYs and 0.79/100 PYs for IFX and adalimumab, respectively [13].
Compared with adults, there is limited experience with VDZ therapy in pediatric IBD. In children, VDZ is only available off-label and is used for patients who have already exhausted other treatment options, including anti-TNF agents. According to the ECCO/ESPGHAN (European Crohn’s and Colitis Organisation and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition) guideline, VDZ should be considered in chronically active or steroid-dependent pediatric UC patients as a second-line biologic therapy after anti-TNF failure, even though it has not yet been approved for use in children [7]. In addition, in pediatric CD patients who fail to maintain clinical remission on anti-TNF agents despite dose optimization and immunomodulator use, VDZ can be considered off-label [8]. A multicenter retrospective study showed that VDZ was safe and effective in pediatric IBD patients [14]. In this study, 64 children with IBD who had been previously treated with anti-TNF agents were included. During a median follow-up period of 24 months, corticosteroid-free remission was 37% in UC and 14% in CD at week 14, and 39% in UC and 24% in CD at the last follow-up [14]. Another retrospective study on 52 children with IBD showed clinical remission rates of 76% and 42% for UC and CD, respectively, at week 14 [15]. No serious adverse events were reported in either study [14,15].
In the GEMINI 3 trial, VDZ was not more effective than placebo in inducing clinical remission at week 6 among patients with CD who had failed previous treatment with anti-TNF agents [16]. The clinical benefits of VDZ in these patients were detectable later at week 10 [16]. This slow induction rate of VDZ was also observed in pediatric patients with CD [14]. Contrary to these findings, the patient in this case report showed a fast response to VDZ. Additionally, according to the clinical decision support tool developed for predicting the probability of response to VDZ in adult CD patients [17], the patient’s score in this case report was 16, which applies to an intermediate response probability. However, the patient continuously maintained clinical and biochemical remission, and endoscopic healing was observed at 1-year treatment with VDZ. One reason for this swift and favorable response to VDZ in this case report may be that the patient had not failed IFX due to poor response, but because discontinuation of IFX was inevitable due to active TB infection.
Data regarding TDM in VDZ are limited. An exposure-efficacy relationship does not seem as straightforward as they are for anti-TNF agents, and robust target VDZ trough levels are not well-defined [18]. However, according to data from a TDM study in adult IBD, VDZ trough levels of >30 μg/mL at week 2, >24 μg/mL at week 6, and >14 μg/mL during maintenance therapy have been proposed for achieving clinical remission [19]. In another study in pediatric-onset IBD patients treated with VDZ, the mean VDZ trough level was 29.9 μg/mL at week 6 and 11.5 μg/mL during maintenance therapy [20]. In this case report, VDZ trough levels were lower than the proposed threshold targets; however, the patient responded well. This may be due to variability in the yet to be revealed association between individual pharmacokinetics and the degree of response to VDZ.
In conclusion, we report a case of a pediatric patient with CD who successfully achieved and maintained remission with VDZ after developing active pulmonary TB during treatment with IFX. In cases that require recommencement of treatment with biologics after recovery of active pulmonary TB caused by anti-TNF agents, VDZ may be a good option even in pediatric IBD.
Fig. 1. Images of ileocolonoscopy at the diagnosis of Crohn disease. Multifocal aphthous ulcers are observed in the (A) terminal ileum and (B) colon.
Fig. 2. Images at the diagnosis of Crohn disease. (A) Upper gastrointestinal endoscopy shows multiple ulcers in the duodenum. (B) Magnetic resonance enterography shows multisegmental wall thickening in the ileum.
Fig. 3. Radiologic images at the diagnosis of active pulmonary tuberculosis during infliximab treatment. (A) Chest X-ray shows a marked amount of left pleural effusion. (B) Chest computed tomography shows left pleural effusion with mild pleural thickening and nodularities.
Fig. 4. Images of ileocolonoscopy before and after treatment with vedolizumab. (A) Multiple ulcers with mucosal friability are observed throughout the colon before treatment with vedolizumab. (B) Endoscopic healing is observed 1 year after treatment with vedolizumab.
Fig. 5. Fecal immunochemical test (FIT) and fecal calprotectin (FC) results during vedolizumab treatment.
Table 1. Crohn disease activity, laboratory results, and thickening and nodularities (arrow).
Week VDZ PCDAI CRP (mg/dL) ESR (mm/hr) Albumin (g/dL) VDZ TL (μg/mL) ATV (AU/mL)
0 #1 40.0 2.20 45 3.1
2 #2 12.5 0.04 47 4.1 25.25 1.91
6 #3 5.0 0.12 19 4.1 14.35 4.56
14 #4 0 0.05 15 4.1 3.36 1.76
22 #5 2.5 0.08 24 4.0 3.19 1.62
30 #6 0 0.02 16 4.2 3.59 2.06
38 #7 0 0.03 17 4.4 5.31 2.06
46 #8 2.5 0.09 33 4.5 5.18 1.76
54 #9 0 0.02 8 4.2 4.15 2.06
VDZ, vedolizumab; PCDAI, Pediatric Crohn’s Disease Activity Index; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; TL, trough level; ATV, antibody to VDZ.
Ethical statements
This study was approved by the Institutional Review Board (IRB) of Kyungpook National University Chilgok Hospital (IRB No: 2020-09-013). Informed consent was obtained from the patient and her parents.
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Funding
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2017R1C1B5076980).
Author contributions
Conceptualization, Formal analysis, Investigation: SC, BK; Data curation: All authors; Funding acquisition, Methodology, Resources, Software, Supervision, Validation: BK; Project administration, Visualization: SC; Writing-original draft: SC; Writing-review & editing: BSC, BHC, BK. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33601494 | 19,625,958 | 2021-07 |
What was the administration route of drug 'PREDNISOLONE'? | Successful treatment with vedolizumab in an adolescent with Crohn disease who had developed active pulmonary tuberculosis while receiving infliximab.
Vedolizumab (VDZ) has been approved for the treatment of inflammatory bowel diseases (IBDs) in patients aged ≥18 years. We report a case of a pediatric patient with Crohn disease (CD) who was successfully treated with VDZ. A 16-year-old female developed severe active pulmonary tuberculosis (TB) during treatment with infliximab (IFX). IFX was stopped, and TB treatment was started. After a 6-month regimen of standard TB medication, her pulmonary TB was cured; however, gastrointestinal symptoms developed. Due to the concern of the patient and parents regarding TB reactivation on restarting treatment with IFX, VDZ was started off-label. After the second dose of VDZ, the patient was in clinical remission and her remission was continuously sustained. Ileocolonoscopy at 1-year after VDZ initiation revealed endoscopic healing. Therapeutic drug monitoring conducted during VDZ treatment showed negative antibodies to VDZ. No serious adverse events occurred during the VDZ treatment. This is the first case report in Korea demonstrating the safe and effective use of VDZ treatment in a pediatric CD patient. In cases that require recommencement of treatment with biologics after recovery of active pulmonary TB caused by anti-tumor necrosis factor agents, VDZ may be a good option even in pediatric IBD.
Introduction
Crohn disease (CD) is an inflammatory bowel disease (IBD) characterized by ulcers and inflammation that develop anywhere throughout the gastrointestinal (GI) tract [1]. Approximately 25% of patients with CD are diagnosed at <20 years of age, in whom a more aggressive disease course occurs compared with adult-onset disease. Hence, an earlier introduction of immunomodulators and/or anti-tumor necrosis factor (TNF) agents is required [1-3].
Vedolizumab (VDZ) is a humanized monoclonal antibody acting on α4β7 integrin that is present on the surface of lymphocytes and binds to MadCAM-1 on the intestinal endothelium. VDZ selectively inhibits the transmigration of lymphocytes into the inflamed intestinal tissue [4]. This gut-selective mechanism of action of VDZ is advantageous in terms of safety compared to other biologics. VDZ is currently approved for use only in adults with CD and ulcerative colitis (UC) [5,6]. Anti-TNF agents, such as infliximab (IFX) and adalimumab, are the only biological agents approved for use in pediatric IBD, whereas VDZ can be administered only off-label [7,8]. Herein, we report a rare case of a pediatric CD patient who successfully achieved and maintained remission with VDZ after developing severe active pulmonary tuberculosis (TB) during treatment with IFX.
Case
A 16-year-old female was admitted to Kyungpook National University Children’s Hospital with complaints of abdominal pain, diarrhea, and hematochezia for 2 months. The past medical history of the patient was unremarkable. She had completed Bacillus Calmette–Guérin (BCG) vaccination and had no past or family history of pulmonary TB. Initial laboratory tests showed a white blood cell count of 4,500/μL, hemoglobin level of 6.2 g/dL, platelet count of 532,000/μL, albumin level of 3.0 g/dL, erythrocyte sedimentation rate (ESR) of 110 mm/hr, and C-reactive protein (CRP) level of 8.0 mg/dL. The fecal immunochemical test (FIT) was positive, and fecal calprotectin (FC) was >2,000 mg/kg. No pathogens were detected in the stool culture and stool polymerase chain reaction (PCR). Chest X-ray showed no abnormal findings in the lungs, and the interferon-gamma release assay (IGRA) was negative. Ileocolonoscopy showed multifocal ulcers throughout the terminal ileum and colon (Fig. 1). Cryptitis, crypt abscesses, and non-caseating granulomas were observed throughout the terminal ileum and colon on histology; however, the acid-fast bacillus smear and culture and PCR for TB were negative. Upper GI endoscopy revealed ulcers in the duodenum (Fig. 2A). Magnetic resonance enterography showed multisegmental wall thickening in the ileum (Fig. 2B). The patient was diagnosed with CD with a phenotype of A1b, L3+L4ab, B1, G0 according to the Paris classification. Her Pediatric Crohn’s Disease Activity Index (PCDAI) score was 50, and the Simple Endoscopic Score for Crohn’s Disease (SES-CD) was 22.
Treatment began with exclusive enteral nutrition (EEN), mesalazine, and azathioprine, which were effective. One month after treatment, her PCDAI score had decreased to 10. However, 1 month after finishing her 8-week treatment with EEN, the disease relapsed and her PCDAI score elevated to 42.5; hence, prednisolone was started per oral at a dose of 50 mg/day. Despite corticosteroid treatment, symptoms persisted, and IFX was administered. Chest X-ray before the administration of IFX showed no abnormal findings in the lungs, and the IGRA was negative. Symptoms resolved after the second dose of IFX infusion, and her PCDAI score decreased to 7.5. However, during her visit for the third IFX infusion, she complained of fever, cough, and dyspnea on exertion for a week. Radiologic examination of the chest revealed a left pleural effusion with mild pleural thickening and nodularities indicating TB pleurisy on chest X-ray and computed tomography (Fig. 3). Thoracentesis was conducted, and pulmonary TB was confirmed by a positive TB PCR test of the pleural effusion specimen and a positive IGRA test. IFX treatment was discontinued and the standard TB treatment regimen consisting of isoniazid, ethambutol, rifampin, and pyrazinamide for 2 months, followed by isoniazid, ethambutol, and rifampin for 4 months, was started. EEN was restarted and maintained for 8 weeks. Subsequently, mesalazine was administered to treat CD.
Her pulmonary TB was completely cured after 6 months of TB treatment. However, symptoms such as hematochezia, diarrhea, and weight loss began by the end of TB treatment. Laboratory tests showed a white blood cell count of 7,010/μL, hemoglobin level of 6.8 g/dL, platelet count of 477,000/μL, albumin level of 3.1 g/dL, ESR of 45 mm/hr, and CRP of 2.2 mg/dL. FIT was positive, and FC was >2,000 mg/kg. No pathogens were detected in the stool culture and stool PCR. Her PCDAI score was 47.5, and the exacerbation of CD was confirmed by ileocolonoscopy (Fig. 4A). Therefore, we planned to restart IFX. However, due to the fear of another severe disease course of active TB when IFX were to be restarted, the patient and parents preferred to start VDZ off-label instead of restarting IFX. Before starting VDZ, the patient’s weight was 57 kg. VDZ was administered according to the regular regimen approved in adults of 300 mg per dose at weeks 0, 2, and 6 for induction and 8-week intervals for maintenance treatment thereafter. The patient showed a fast response to VDZ treatment. At the week 6 visit for her third VDZ infusion, she was in clinical remission, and inflammatory markers were normalized (Table 1, Fig. 5). Ileocolonoscopy at the 1-year follow-up after VDZ treatment revealed endoscopic healing (Fig. 4B). Therapeutic drug monitoring (TDM) using commercialized enzyme-linked immunosorbent assay kits (Immundiagnostik AG, Bensheim, Germany) was conducted during VDZ treatment. An anti-drug antibody level of ≤10 AU/mL was defined as negative, according to the manufacturer’s manual. TDM results during VDZ treatment showed negative antibodies to VDZ (Table 1). The patient is currently in her second year of VDZ treatment and is maintaining clinical and biochemical remission. No serious adverse events, including TB reactivation, have occurred.
Discussion
With the introduction of anti-TNF agents in the treatment of CD, there is no doubt that treatment outcomes have improved. However, anti-TNF agents are known to increase the risk of serious infections, including TB [9]. It has been reported that anti-TNF agents are associated with a 2- to 8-fold increased risk of developing active TB [9]. Reactivation of latent TB infections (LTBI) rather than a new infection is considered to be the primary cause of active TB, as most of the active TB cases have been reported to occur within 3 to 4 months after starting anti-TNF treatment [9]. Therefore, screening for LTBI prior to anti-TNF treatment is strongly recommended worldwide, and especially in Asia, where the prevalence of LTBI is higher than that of Western countries [9]. In this case report, the patient had completed TB vaccination, did not have any history or exposure to active TB, and TB screening was negative with both chest X-ray and IGRA at both times of diagnostic evaluation of CD and before the commencement of IFX. However, the patient, unfortunately, developed symptoms of active pulmonary TB 5 weeks after starting IFX treatment, indicating that the active TB was probably due to the reactivation of LTBI, which was missed on TB screening.
It is well known that when active TB is diagnosed during anti-TNF treatment, the anti-TNF agent should be withheld, and anti-TB therapy should be started [10]. Regarding when to restart anti-TNF treatment, it is considered safe to delay the resumption of anti-TNF therapy until the completion of anti-TB treatment [10]. However, if an early resumption of anti-TNF treatment is required, anti-TNF treatment may be restarted as early as 2 months after anti-TB treatment in patients who did not have an initially severe active TB, demonstrated a favorable response to anti-TB treatment, and when drug susceptibility was proven [10]. In this case report, the patient’s symptoms of CD were fortunately well controlled without IFX until the end of TB medication. According to the treatment guidelines, she could have restarted IFX when CD relapsed at the end of TB medication. However, because she had suffered a severe active TB and due to the fear of another severe disease course of active TB when IFX were to be restarted, the patient and parents preferred to start VDZ instead.
VDZ is effective for achieving both clinical remission and mucosal healing in adult patients with UC and CD [5,6,11]. Regarding safety, according to the integrated safety data from six trials, VDZ did not increase the risk of serious infections, progressive multifocal leukoencephalopathy, or malignancy [12]. Among 2,830 patients with 4,811 person-years (PYs) exposure to VDZ, TB was reported in only four patients (0.14%) with an estimated incidence of 0.1/100 PYs [12]. Meanwhile, the estimated incidence of TB during treatment with anti-TNF agents has been reported as 1.34/100 PYs and 0.79/100 PYs for IFX and adalimumab, respectively [13].
Compared with adults, there is limited experience with VDZ therapy in pediatric IBD. In children, VDZ is only available off-label and is used for patients who have already exhausted other treatment options, including anti-TNF agents. According to the ECCO/ESPGHAN (European Crohn’s and Colitis Organisation and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition) guideline, VDZ should be considered in chronically active or steroid-dependent pediatric UC patients as a second-line biologic therapy after anti-TNF failure, even though it has not yet been approved for use in children [7]. In addition, in pediatric CD patients who fail to maintain clinical remission on anti-TNF agents despite dose optimization and immunomodulator use, VDZ can be considered off-label [8]. A multicenter retrospective study showed that VDZ was safe and effective in pediatric IBD patients [14]. In this study, 64 children with IBD who had been previously treated with anti-TNF agents were included. During a median follow-up period of 24 months, corticosteroid-free remission was 37% in UC and 14% in CD at week 14, and 39% in UC and 24% in CD at the last follow-up [14]. Another retrospective study on 52 children with IBD showed clinical remission rates of 76% and 42% for UC and CD, respectively, at week 14 [15]. No serious adverse events were reported in either study [14,15].
In the GEMINI 3 trial, VDZ was not more effective than placebo in inducing clinical remission at week 6 among patients with CD who had failed previous treatment with anti-TNF agents [16]. The clinical benefits of VDZ in these patients were detectable later at week 10 [16]. This slow induction rate of VDZ was also observed in pediatric patients with CD [14]. Contrary to these findings, the patient in this case report showed a fast response to VDZ. Additionally, according to the clinical decision support tool developed for predicting the probability of response to VDZ in adult CD patients [17], the patient’s score in this case report was 16, which applies to an intermediate response probability. However, the patient continuously maintained clinical and biochemical remission, and endoscopic healing was observed at 1-year treatment with VDZ. One reason for this swift and favorable response to VDZ in this case report may be that the patient had not failed IFX due to poor response, but because discontinuation of IFX was inevitable due to active TB infection.
Data regarding TDM in VDZ are limited. An exposure-efficacy relationship does not seem as straightforward as they are for anti-TNF agents, and robust target VDZ trough levels are not well-defined [18]. However, according to data from a TDM study in adult IBD, VDZ trough levels of >30 μg/mL at week 2, >24 μg/mL at week 6, and >14 μg/mL during maintenance therapy have been proposed for achieving clinical remission [19]. In another study in pediatric-onset IBD patients treated with VDZ, the mean VDZ trough level was 29.9 μg/mL at week 6 and 11.5 μg/mL during maintenance therapy [20]. In this case report, VDZ trough levels were lower than the proposed threshold targets; however, the patient responded well. This may be due to variability in the yet to be revealed association between individual pharmacokinetics and the degree of response to VDZ.
In conclusion, we report a case of a pediatric patient with CD who successfully achieved and maintained remission with VDZ after developing active pulmonary TB during treatment with IFX. In cases that require recommencement of treatment with biologics after recovery of active pulmonary TB caused by anti-TNF agents, VDZ may be a good option even in pediatric IBD.
Fig. 1. Images of ileocolonoscopy at the diagnosis of Crohn disease. Multifocal aphthous ulcers are observed in the (A) terminal ileum and (B) colon.
Fig. 2. Images at the diagnosis of Crohn disease. (A) Upper gastrointestinal endoscopy shows multiple ulcers in the duodenum. (B) Magnetic resonance enterography shows multisegmental wall thickening in the ileum.
Fig. 3. Radiologic images at the diagnosis of active pulmonary tuberculosis during infliximab treatment. (A) Chest X-ray shows a marked amount of left pleural effusion. (B) Chest computed tomography shows left pleural effusion with mild pleural thickening and nodularities.
Fig. 4. Images of ileocolonoscopy before and after treatment with vedolizumab. (A) Multiple ulcers with mucosal friability are observed throughout the colon before treatment with vedolizumab. (B) Endoscopic healing is observed 1 year after treatment with vedolizumab.
Fig. 5. Fecal immunochemical test (FIT) and fecal calprotectin (FC) results during vedolizumab treatment.
Table 1. Crohn disease activity, laboratory results, and thickening and nodularities (arrow).
Week VDZ PCDAI CRP (mg/dL) ESR (mm/hr) Albumin (g/dL) VDZ TL (μg/mL) ATV (AU/mL)
0 #1 40.0 2.20 45 3.1
2 #2 12.5 0.04 47 4.1 25.25 1.91
6 #3 5.0 0.12 19 4.1 14.35 4.56
14 #4 0 0.05 15 4.1 3.36 1.76
22 #5 2.5 0.08 24 4.0 3.19 1.62
30 #6 0 0.02 16 4.2 3.59 2.06
38 #7 0 0.03 17 4.4 5.31 2.06
46 #8 2.5 0.09 33 4.5 5.18 1.76
54 #9 0 0.02 8 4.2 4.15 2.06
VDZ, vedolizumab; PCDAI, Pediatric Crohn’s Disease Activity Index; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; TL, trough level; ATV, antibody to VDZ.
Ethical statements
This study was approved by the Institutional Review Board (IRB) of Kyungpook National University Chilgok Hospital (IRB No: 2020-09-013). Informed consent was obtained from the patient and her parents.
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Funding
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2017R1C1B5076980).
Author contributions
Conceptualization, Formal analysis, Investigation: SC, BK; Data curation: All authors; Funding acquisition, Methodology, Resources, Software, Supervision, Validation: BK; Project administration, Visualization: SC; Writing-original draft: SC; Writing-review & editing: BSC, BHC, BK. | Oral | DrugAdministrationRoute | CC BY-NC | 33601494 | 18,963,545 | 2021-07 |
What was the dosage of drug 'AZATHIOPRINE'? | Successful treatment with vedolizumab in an adolescent with Crohn disease who had developed active pulmonary tuberculosis while receiving infliximab.
Vedolizumab (VDZ) has been approved for the treatment of inflammatory bowel diseases (IBDs) in patients aged ≥18 years. We report a case of a pediatric patient with Crohn disease (CD) who was successfully treated with VDZ. A 16-year-old female developed severe active pulmonary tuberculosis (TB) during treatment with infliximab (IFX). IFX was stopped, and TB treatment was started. After a 6-month regimen of standard TB medication, her pulmonary TB was cured; however, gastrointestinal symptoms developed. Due to the concern of the patient and parents regarding TB reactivation on restarting treatment with IFX, VDZ was started off-label. After the second dose of VDZ, the patient was in clinical remission and her remission was continuously sustained. Ileocolonoscopy at 1-year after VDZ initiation revealed endoscopic healing. Therapeutic drug monitoring conducted during VDZ treatment showed negative antibodies to VDZ. No serious adverse events occurred during the VDZ treatment. This is the first case report in Korea demonstrating the safe and effective use of VDZ treatment in a pediatric CD patient. In cases that require recommencement of treatment with biologics after recovery of active pulmonary TB caused by anti-tumor necrosis factor agents, VDZ may be a good option even in pediatric IBD.
Introduction
Crohn disease (CD) is an inflammatory bowel disease (IBD) characterized by ulcers and inflammation that develop anywhere throughout the gastrointestinal (GI) tract [1]. Approximately 25% of patients with CD are diagnosed at <20 years of age, in whom a more aggressive disease course occurs compared with adult-onset disease. Hence, an earlier introduction of immunomodulators and/or anti-tumor necrosis factor (TNF) agents is required [1-3].
Vedolizumab (VDZ) is a humanized monoclonal antibody acting on α4β7 integrin that is present on the surface of lymphocytes and binds to MadCAM-1 on the intestinal endothelium. VDZ selectively inhibits the transmigration of lymphocytes into the inflamed intestinal tissue [4]. This gut-selective mechanism of action of VDZ is advantageous in terms of safety compared to other biologics. VDZ is currently approved for use only in adults with CD and ulcerative colitis (UC) [5,6]. Anti-TNF agents, such as infliximab (IFX) and adalimumab, are the only biological agents approved for use in pediatric IBD, whereas VDZ can be administered only off-label [7,8]. Herein, we report a rare case of a pediatric CD patient who successfully achieved and maintained remission with VDZ after developing severe active pulmonary tuberculosis (TB) during treatment with IFX.
Case
A 16-year-old female was admitted to Kyungpook National University Children’s Hospital with complaints of abdominal pain, diarrhea, and hematochezia for 2 months. The past medical history of the patient was unremarkable. She had completed Bacillus Calmette–Guérin (BCG) vaccination and had no past or family history of pulmonary TB. Initial laboratory tests showed a white blood cell count of 4,500/μL, hemoglobin level of 6.2 g/dL, platelet count of 532,000/μL, albumin level of 3.0 g/dL, erythrocyte sedimentation rate (ESR) of 110 mm/hr, and C-reactive protein (CRP) level of 8.0 mg/dL. The fecal immunochemical test (FIT) was positive, and fecal calprotectin (FC) was >2,000 mg/kg. No pathogens were detected in the stool culture and stool polymerase chain reaction (PCR). Chest X-ray showed no abnormal findings in the lungs, and the interferon-gamma release assay (IGRA) was negative. Ileocolonoscopy showed multifocal ulcers throughout the terminal ileum and colon (Fig. 1). Cryptitis, crypt abscesses, and non-caseating granulomas were observed throughout the terminal ileum and colon on histology; however, the acid-fast bacillus smear and culture and PCR for TB were negative. Upper GI endoscopy revealed ulcers in the duodenum (Fig. 2A). Magnetic resonance enterography showed multisegmental wall thickening in the ileum (Fig. 2B). The patient was diagnosed with CD with a phenotype of A1b, L3+L4ab, B1, G0 according to the Paris classification. Her Pediatric Crohn’s Disease Activity Index (PCDAI) score was 50, and the Simple Endoscopic Score for Crohn’s Disease (SES-CD) was 22.
Treatment began with exclusive enteral nutrition (EEN), mesalazine, and azathioprine, which were effective. One month after treatment, her PCDAI score had decreased to 10. However, 1 month after finishing her 8-week treatment with EEN, the disease relapsed and her PCDAI score elevated to 42.5; hence, prednisolone was started per oral at a dose of 50 mg/day. Despite corticosteroid treatment, symptoms persisted, and IFX was administered. Chest X-ray before the administration of IFX showed no abnormal findings in the lungs, and the IGRA was negative. Symptoms resolved after the second dose of IFX infusion, and her PCDAI score decreased to 7.5. However, during her visit for the third IFX infusion, she complained of fever, cough, and dyspnea on exertion for a week. Radiologic examination of the chest revealed a left pleural effusion with mild pleural thickening and nodularities indicating TB pleurisy on chest X-ray and computed tomography (Fig. 3). Thoracentesis was conducted, and pulmonary TB was confirmed by a positive TB PCR test of the pleural effusion specimen and a positive IGRA test. IFX treatment was discontinued and the standard TB treatment regimen consisting of isoniazid, ethambutol, rifampin, and pyrazinamide for 2 months, followed by isoniazid, ethambutol, and rifampin for 4 months, was started. EEN was restarted and maintained for 8 weeks. Subsequently, mesalazine was administered to treat CD.
Her pulmonary TB was completely cured after 6 months of TB treatment. However, symptoms such as hematochezia, diarrhea, and weight loss began by the end of TB treatment. Laboratory tests showed a white blood cell count of 7,010/μL, hemoglobin level of 6.8 g/dL, platelet count of 477,000/μL, albumin level of 3.1 g/dL, ESR of 45 mm/hr, and CRP of 2.2 mg/dL. FIT was positive, and FC was >2,000 mg/kg. No pathogens were detected in the stool culture and stool PCR. Her PCDAI score was 47.5, and the exacerbation of CD was confirmed by ileocolonoscopy (Fig. 4A). Therefore, we planned to restart IFX. However, due to the fear of another severe disease course of active TB when IFX were to be restarted, the patient and parents preferred to start VDZ off-label instead of restarting IFX. Before starting VDZ, the patient’s weight was 57 kg. VDZ was administered according to the regular regimen approved in adults of 300 mg per dose at weeks 0, 2, and 6 for induction and 8-week intervals for maintenance treatment thereafter. The patient showed a fast response to VDZ treatment. At the week 6 visit for her third VDZ infusion, she was in clinical remission, and inflammatory markers were normalized (Table 1, Fig. 5). Ileocolonoscopy at the 1-year follow-up after VDZ treatment revealed endoscopic healing (Fig. 4B). Therapeutic drug monitoring (TDM) using commercialized enzyme-linked immunosorbent assay kits (Immundiagnostik AG, Bensheim, Germany) was conducted during VDZ treatment. An anti-drug antibody level of ≤10 AU/mL was defined as negative, according to the manufacturer’s manual. TDM results during VDZ treatment showed negative antibodies to VDZ (Table 1). The patient is currently in her second year of VDZ treatment and is maintaining clinical and biochemical remission. No serious adverse events, including TB reactivation, have occurred.
Discussion
With the introduction of anti-TNF agents in the treatment of CD, there is no doubt that treatment outcomes have improved. However, anti-TNF agents are known to increase the risk of serious infections, including TB [9]. It has been reported that anti-TNF agents are associated with a 2- to 8-fold increased risk of developing active TB [9]. Reactivation of latent TB infections (LTBI) rather than a new infection is considered to be the primary cause of active TB, as most of the active TB cases have been reported to occur within 3 to 4 months after starting anti-TNF treatment [9]. Therefore, screening for LTBI prior to anti-TNF treatment is strongly recommended worldwide, and especially in Asia, where the prevalence of LTBI is higher than that of Western countries [9]. In this case report, the patient had completed TB vaccination, did not have any history or exposure to active TB, and TB screening was negative with both chest X-ray and IGRA at both times of diagnostic evaluation of CD and before the commencement of IFX. However, the patient, unfortunately, developed symptoms of active pulmonary TB 5 weeks after starting IFX treatment, indicating that the active TB was probably due to the reactivation of LTBI, which was missed on TB screening.
It is well known that when active TB is diagnosed during anti-TNF treatment, the anti-TNF agent should be withheld, and anti-TB therapy should be started [10]. Regarding when to restart anti-TNF treatment, it is considered safe to delay the resumption of anti-TNF therapy until the completion of anti-TB treatment [10]. However, if an early resumption of anti-TNF treatment is required, anti-TNF treatment may be restarted as early as 2 months after anti-TB treatment in patients who did not have an initially severe active TB, demonstrated a favorable response to anti-TB treatment, and when drug susceptibility was proven [10]. In this case report, the patient’s symptoms of CD were fortunately well controlled without IFX until the end of TB medication. According to the treatment guidelines, she could have restarted IFX when CD relapsed at the end of TB medication. However, because she had suffered a severe active TB and due to the fear of another severe disease course of active TB when IFX were to be restarted, the patient and parents preferred to start VDZ instead.
VDZ is effective for achieving both clinical remission and mucosal healing in adult patients with UC and CD [5,6,11]. Regarding safety, according to the integrated safety data from six trials, VDZ did not increase the risk of serious infections, progressive multifocal leukoencephalopathy, or malignancy [12]. Among 2,830 patients with 4,811 person-years (PYs) exposure to VDZ, TB was reported in only four patients (0.14%) with an estimated incidence of 0.1/100 PYs [12]. Meanwhile, the estimated incidence of TB during treatment with anti-TNF agents has been reported as 1.34/100 PYs and 0.79/100 PYs for IFX and adalimumab, respectively [13].
Compared with adults, there is limited experience with VDZ therapy in pediatric IBD. In children, VDZ is only available off-label and is used for patients who have already exhausted other treatment options, including anti-TNF agents. According to the ECCO/ESPGHAN (European Crohn’s and Colitis Organisation and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition) guideline, VDZ should be considered in chronically active or steroid-dependent pediatric UC patients as a second-line biologic therapy after anti-TNF failure, even though it has not yet been approved for use in children [7]. In addition, in pediatric CD patients who fail to maintain clinical remission on anti-TNF agents despite dose optimization and immunomodulator use, VDZ can be considered off-label [8]. A multicenter retrospective study showed that VDZ was safe and effective in pediatric IBD patients [14]. In this study, 64 children with IBD who had been previously treated with anti-TNF agents were included. During a median follow-up period of 24 months, corticosteroid-free remission was 37% in UC and 14% in CD at week 14, and 39% in UC and 24% in CD at the last follow-up [14]. Another retrospective study on 52 children with IBD showed clinical remission rates of 76% and 42% for UC and CD, respectively, at week 14 [15]. No serious adverse events were reported in either study [14,15].
In the GEMINI 3 trial, VDZ was not more effective than placebo in inducing clinical remission at week 6 among patients with CD who had failed previous treatment with anti-TNF agents [16]. The clinical benefits of VDZ in these patients were detectable later at week 10 [16]. This slow induction rate of VDZ was also observed in pediatric patients with CD [14]. Contrary to these findings, the patient in this case report showed a fast response to VDZ. Additionally, according to the clinical decision support tool developed for predicting the probability of response to VDZ in adult CD patients [17], the patient’s score in this case report was 16, which applies to an intermediate response probability. However, the patient continuously maintained clinical and biochemical remission, and endoscopic healing was observed at 1-year treatment with VDZ. One reason for this swift and favorable response to VDZ in this case report may be that the patient had not failed IFX due to poor response, but because discontinuation of IFX was inevitable due to active TB infection.
Data regarding TDM in VDZ are limited. An exposure-efficacy relationship does not seem as straightforward as they are for anti-TNF agents, and robust target VDZ trough levels are not well-defined [18]. However, according to data from a TDM study in adult IBD, VDZ trough levels of >30 μg/mL at week 2, >24 μg/mL at week 6, and >14 μg/mL during maintenance therapy have been proposed for achieving clinical remission [19]. In another study in pediatric-onset IBD patients treated with VDZ, the mean VDZ trough level was 29.9 μg/mL at week 6 and 11.5 μg/mL during maintenance therapy [20]. In this case report, VDZ trough levels were lower than the proposed threshold targets; however, the patient responded well. This may be due to variability in the yet to be revealed association between individual pharmacokinetics and the degree of response to VDZ.
In conclusion, we report a case of a pediatric patient with CD who successfully achieved and maintained remission with VDZ after developing active pulmonary TB during treatment with IFX. In cases that require recommencement of treatment with biologics after recovery of active pulmonary TB caused by anti-TNF agents, VDZ may be a good option even in pediatric IBD.
Fig. 1. Images of ileocolonoscopy at the diagnosis of Crohn disease. Multifocal aphthous ulcers are observed in the (A) terminal ileum and (B) colon.
Fig. 2. Images at the diagnosis of Crohn disease. (A) Upper gastrointestinal endoscopy shows multiple ulcers in the duodenum. (B) Magnetic resonance enterography shows multisegmental wall thickening in the ileum.
Fig. 3. Radiologic images at the diagnosis of active pulmonary tuberculosis during infliximab treatment. (A) Chest X-ray shows a marked amount of left pleural effusion. (B) Chest computed tomography shows left pleural effusion with mild pleural thickening and nodularities.
Fig. 4. Images of ileocolonoscopy before and after treatment with vedolizumab. (A) Multiple ulcers with mucosal friability are observed throughout the colon before treatment with vedolizumab. (B) Endoscopic healing is observed 1 year after treatment with vedolizumab.
Fig. 5. Fecal immunochemical test (FIT) and fecal calprotectin (FC) results during vedolizumab treatment.
Table 1. Crohn disease activity, laboratory results, and thickening and nodularities (arrow).
Week VDZ PCDAI CRP (mg/dL) ESR (mm/hr) Albumin (g/dL) VDZ TL (μg/mL) ATV (AU/mL)
0 #1 40.0 2.20 45 3.1
2 #2 12.5 0.04 47 4.1 25.25 1.91
6 #3 5.0 0.12 19 4.1 14.35 4.56
14 #4 0 0.05 15 4.1 3.36 1.76
22 #5 2.5 0.08 24 4.0 3.19 1.62
30 #6 0 0.02 16 4.2 3.59 2.06
38 #7 0 0.03 17 4.4 5.31 2.06
46 #8 2.5 0.09 33 4.5 5.18 1.76
54 #9 0 0.02 8 4.2 4.15 2.06
VDZ, vedolizumab; PCDAI, Pediatric Crohn’s Disease Activity Index; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; TL, trough level; ATV, antibody to VDZ.
Ethical statements
This study was approved by the Institutional Review Board (IRB) of Kyungpook National University Chilgok Hospital (IRB No: 2020-09-013). Informed consent was obtained from the patient and her parents.
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Funding
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2017R1C1B5076980).
Author contributions
Conceptualization, Formal analysis, Investigation: SC, BK; Data curation: All authors; Funding acquisition, Methodology, Resources, Software, Supervision, Validation: BK; Project administration, Visualization: SC; Writing-original draft: SC; Writing-review & editing: BSC, BHC, BK. | UNKNOWN | DrugDosageText | CC BY-NC | 33601494 | 18,963,545 | 2021-07 |
What was the dosage of drug 'INFLIXIMAB'? | Successful treatment with vedolizumab in an adolescent with Crohn disease who had developed active pulmonary tuberculosis while receiving infliximab.
Vedolizumab (VDZ) has been approved for the treatment of inflammatory bowel diseases (IBDs) in patients aged ≥18 years. We report a case of a pediatric patient with Crohn disease (CD) who was successfully treated with VDZ. A 16-year-old female developed severe active pulmonary tuberculosis (TB) during treatment with infliximab (IFX). IFX was stopped, and TB treatment was started. After a 6-month regimen of standard TB medication, her pulmonary TB was cured; however, gastrointestinal symptoms developed. Due to the concern of the patient and parents regarding TB reactivation on restarting treatment with IFX, VDZ was started off-label. After the second dose of VDZ, the patient was in clinical remission and her remission was continuously sustained. Ileocolonoscopy at 1-year after VDZ initiation revealed endoscopic healing. Therapeutic drug monitoring conducted during VDZ treatment showed negative antibodies to VDZ. No serious adverse events occurred during the VDZ treatment. This is the first case report in Korea demonstrating the safe and effective use of VDZ treatment in a pediatric CD patient. In cases that require recommencement of treatment with biologics after recovery of active pulmonary TB caused by anti-tumor necrosis factor agents, VDZ may be a good option even in pediatric IBD.
Introduction
Crohn disease (CD) is an inflammatory bowel disease (IBD) characterized by ulcers and inflammation that develop anywhere throughout the gastrointestinal (GI) tract [1]. Approximately 25% of patients with CD are diagnosed at <20 years of age, in whom a more aggressive disease course occurs compared with adult-onset disease. Hence, an earlier introduction of immunomodulators and/or anti-tumor necrosis factor (TNF) agents is required [1-3].
Vedolizumab (VDZ) is a humanized monoclonal antibody acting on α4β7 integrin that is present on the surface of lymphocytes and binds to MadCAM-1 on the intestinal endothelium. VDZ selectively inhibits the transmigration of lymphocytes into the inflamed intestinal tissue [4]. This gut-selective mechanism of action of VDZ is advantageous in terms of safety compared to other biologics. VDZ is currently approved for use only in adults with CD and ulcerative colitis (UC) [5,6]. Anti-TNF agents, such as infliximab (IFX) and adalimumab, are the only biological agents approved for use in pediatric IBD, whereas VDZ can be administered only off-label [7,8]. Herein, we report a rare case of a pediatric CD patient who successfully achieved and maintained remission with VDZ after developing severe active pulmonary tuberculosis (TB) during treatment with IFX.
Case
A 16-year-old female was admitted to Kyungpook National University Children’s Hospital with complaints of abdominal pain, diarrhea, and hematochezia for 2 months. The past medical history of the patient was unremarkable. She had completed Bacillus Calmette–Guérin (BCG) vaccination and had no past or family history of pulmonary TB. Initial laboratory tests showed a white blood cell count of 4,500/μL, hemoglobin level of 6.2 g/dL, platelet count of 532,000/μL, albumin level of 3.0 g/dL, erythrocyte sedimentation rate (ESR) of 110 mm/hr, and C-reactive protein (CRP) level of 8.0 mg/dL. The fecal immunochemical test (FIT) was positive, and fecal calprotectin (FC) was >2,000 mg/kg. No pathogens were detected in the stool culture and stool polymerase chain reaction (PCR). Chest X-ray showed no abnormal findings in the lungs, and the interferon-gamma release assay (IGRA) was negative. Ileocolonoscopy showed multifocal ulcers throughout the terminal ileum and colon (Fig. 1). Cryptitis, crypt abscesses, and non-caseating granulomas were observed throughout the terminal ileum and colon on histology; however, the acid-fast bacillus smear and culture and PCR for TB were negative. Upper GI endoscopy revealed ulcers in the duodenum (Fig. 2A). Magnetic resonance enterography showed multisegmental wall thickening in the ileum (Fig. 2B). The patient was diagnosed with CD with a phenotype of A1b, L3+L4ab, B1, G0 according to the Paris classification. Her Pediatric Crohn’s Disease Activity Index (PCDAI) score was 50, and the Simple Endoscopic Score for Crohn’s Disease (SES-CD) was 22.
Treatment began with exclusive enteral nutrition (EEN), mesalazine, and azathioprine, which were effective. One month after treatment, her PCDAI score had decreased to 10. However, 1 month after finishing her 8-week treatment with EEN, the disease relapsed and her PCDAI score elevated to 42.5; hence, prednisolone was started per oral at a dose of 50 mg/day. Despite corticosteroid treatment, symptoms persisted, and IFX was administered. Chest X-ray before the administration of IFX showed no abnormal findings in the lungs, and the IGRA was negative. Symptoms resolved after the second dose of IFX infusion, and her PCDAI score decreased to 7.5. However, during her visit for the third IFX infusion, she complained of fever, cough, and dyspnea on exertion for a week. Radiologic examination of the chest revealed a left pleural effusion with mild pleural thickening and nodularities indicating TB pleurisy on chest X-ray and computed tomography (Fig. 3). Thoracentesis was conducted, and pulmonary TB was confirmed by a positive TB PCR test of the pleural effusion specimen and a positive IGRA test. IFX treatment was discontinued and the standard TB treatment regimen consisting of isoniazid, ethambutol, rifampin, and pyrazinamide for 2 months, followed by isoniazid, ethambutol, and rifampin for 4 months, was started. EEN was restarted and maintained for 8 weeks. Subsequently, mesalazine was administered to treat CD.
Her pulmonary TB was completely cured after 6 months of TB treatment. However, symptoms such as hematochezia, diarrhea, and weight loss began by the end of TB treatment. Laboratory tests showed a white blood cell count of 7,010/μL, hemoglobin level of 6.8 g/dL, platelet count of 477,000/μL, albumin level of 3.1 g/dL, ESR of 45 mm/hr, and CRP of 2.2 mg/dL. FIT was positive, and FC was >2,000 mg/kg. No pathogens were detected in the stool culture and stool PCR. Her PCDAI score was 47.5, and the exacerbation of CD was confirmed by ileocolonoscopy (Fig. 4A). Therefore, we planned to restart IFX. However, due to the fear of another severe disease course of active TB when IFX were to be restarted, the patient and parents preferred to start VDZ off-label instead of restarting IFX. Before starting VDZ, the patient’s weight was 57 kg. VDZ was administered according to the regular regimen approved in adults of 300 mg per dose at weeks 0, 2, and 6 for induction and 8-week intervals for maintenance treatment thereafter. The patient showed a fast response to VDZ treatment. At the week 6 visit for her third VDZ infusion, she was in clinical remission, and inflammatory markers were normalized (Table 1, Fig. 5). Ileocolonoscopy at the 1-year follow-up after VDZ treatment revealed endoscopic healing (Fig. 4B). Therapeutic drug monitoring (TDM) using commercialized enzyme-linked immunosorbent assay kits (Immundiagnostik AG, Bensheim, Germany) was conducted during VDZ treatment. An anti-drug antibody level of ≤10 AU/mL was defined as negative, according to the manufacturer’s manual. TDM results during VDZ treatment showed negative antibodies to VDZ (Table 1). The patient is currently in her second year of VDZ treatment and is maintaining clinical and biochemical remission. No serious adverse events, including TB reactivation, have occurred.
Discussion
With the introduction of anti-TNF agents in the treatment of CD, there is no doubt that treatment outcomes have improved. However, anti-TNF agents are known to increase the risk of serious infections, including TB [9]. It has been reported that anti-TNF agents are associated with a 2- to 8-fold increased risk of developing active TB [9]. Reactivation of latent TB infections (LTBI) rather than a new infection is considered to be the primary cause of active TB, as most of the active TB cases have been reported to occur within 3 to 4 months after starting anti-TNF treatment [9]. Therefore, screening for LTBI prior to anti-TNF treatment is strongly recommended worldwide, and especially in Asia, where the prevalence of LTBI is higher than that of Western countries [9]. In this case report, the patient had completed TB vaccination, did not have any history or exposure to active TB, and TB screening was negative with both chest X-ray and IGRA at both times of diagnostic evaluation of CD and before the commencement of IFX. However, the patient, unfortunately, developed symptoms of active pulmonary TB 5 weeks after starting IFX treatment, indicating that the active TB was probably due to the reactivation of LTBI, which was missed on TB screening.
It is well known that when active TB is diagnosed during anti-TNF treatment, the anti-TNF agent should be withheld, and anti-TB therapy should be started [10]. Regarding when to restart anti-TNF treatment, it is considered safe to delay the resumption of anti-TNF therapy until the completion of anti-TB treatment [10]. However, if an early resumption of anti-TNF treatment is required, anti-TNF treatment may be restarted as early as 2 months after anti-TB treatment in patients who did not have an initially severe active TB, demonstrated a favorable response to anti-TB treatment, and when drug susceptibility was proven [10]. In this case report, the patient’s symptoms of CD were fortunately well controlled without IFX until the end of TB medication. According to the treatment guidelines, she could have restarted IFX when CD relapsed at the end of TB medication. However, because she had suffered a severe active TB and due to the fear of another severe disease course of active TB when IFX were to be restarted, the patient and parents preferred to start VDZ instead.
VDZ is effective for achieving both clinical remission and mucosal healing in adult patients with UC and CD [5,6,11]. Regarding safety, according to the integrated safety data from six trials, VDZ did not increase the risk of serious infections, progressive multifocal leukoencephalopathy, or malignancy [12]. Among 2,830 patients with 4,811 person-years (PYs) exposure to VDZ, TB was reported in only four patients (0.14%) with an estimated incidence of 0.1/100 PYs [12]. Meanwhile, the estimated incidence of TB during treatment with anti-TNF agents has been reported as 1.34/100 PYs and 0.79/100 PYs for IFX and adalimumab, respectively [13].
Compared with adults, there is limited experience with VDZ therapy in pediatric IBD. In children, VDZ is only available off-label and is used for patients who have already exhausted other treatment options, including anti-TNF agents. According to the ECCO/ESPGHAN (European Crohn’s and Colitis Organisation and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition) guideline, VDZ should be considered in chronically active or steroid-dependent pediatric UC patients as a second-line biologic therapy after anti-TNF failure, even though it has not yet been approved for use in children [7]. In addition, in pediatric CD patients who fail to maintain clinical remission on anti-TNF agents despite dose optimization and immunomodulator use, VDZ can be considered off-label [8]. A multicenter retrospective study showed that VDZ was safe and effective in pediatric IBD patients [14]. In this study, 64 children with IBD who had been previously treated with anti-TNF agents were included. During a median follow-up period of 24 months, corticosteroid-free remission was 37% in UC and 14% in CD at week 14, and 39% in UC and 24% in CD at the last follow-up [14]. Another retrospective study on 52 children with IBD showed clinical remission rates of 76% and 42% for UC and CD, respectively, at week 14 [15]. No serious adverse events were reported in either study [14,15].
In the GEMINI 3 trial, VDZ was not more effective than placebo in inducing clinical remission at week 6 among patients with CD who had failed previous treatment with anti-TNF agents [16]. The clinical benefits of VDZ in these patients were detectable later at week 10 [16]. This slow induction rate of VDZ was also observed in pediatric patients with CD [14]. Contrary to these findings, the patient in this case report showed a fast response to VDZ. Additionally, according to the clinical decision support tool developed for predicting the probability of response to VDZ in adult CD patients [17], the patient’s score in this case report was 16, which applies to an intermediate response probability. However, the patient continuously maintained clinical and biochemical remission, and endoscopic healing was observed at 1-year treatment with VDZ. One reason for this swift and favorable response to VDZ in this case report may be that the patient had not failed IFX due to poor response, but because discontinuation of IFX was inevitable due to active TB infection.
Data regarding TDM in VDZ are limited. An exposure-efficacy relationship does not seem as straightforward as they are for anti-TNF agents, and robust target VDZ trough levels are not well-defined [18]. However, according to data from a TDM study in adult IBD, VDZ trough levels of >30 μg/mL at week 2, >24 μg/mL at week 6, and >14 μg/mL during maintenance therapy have been proposed for achieving clinical remission [19]. In another study in pediatric-onset IBD patients treated with VDZ, the mean VDZ trough level was 29.9 μg/mL at week 6 and 11.5 μg/mL during maintenance therapy [20]. In this case report, VDZ trough levels were lower than the proposed threshold targets; however, the patient responded well. This may be due to variability in the yet to be revealed association between individual pharmacokinetics and the degree of response to VDZ.
In conclusion, we report a case of a pediatric patient with CD who successfully achieved and maintained remission with VDZ after developing active pulmonary TB during treatment with IFX. In cases that require recommencement of treatment with biologics after recovery of active pulmonary TB caused by anti-TNF agents, VDZ may be a good option even in pediatric IBD.
Fig. 1. Images of ileocolonoscopy at the diagnosis of Crohn disease. Multifocal aphthous ulcers are observed in the (A) terminal ileum and (B) colon.
Fig. 2. Images at the diagnosis of Crohn disease. (A) Upper gastrointestinal endoscopy shows multiple ulcers in the duodenum. (B) Magnetic resonance enterography shows multisegmental wall thickening in the ileum.
Fig. 3. Radiologic images at the diagnosis of active pulmonary tuberculosis during infliximab treatment. (A) Chest X-ray shows a marked amount of left pleural effusion. (B) Chest computed tomography shows left pleural effusion with mild pleural thickening and nodularities.
Fig. 4. Images of ileocolonoscopy before and after treatment with vedolizumab. (A) Multiple ulcers with mucosal friability are observed throughout the colon before treatment with vedolizumab. (B) Endoscopic healing is observed 1 year after treatment with vedolizumab.
Fig. 5. Fecal immunochemical test (FIT) and fecal calprotectin (FC) results during vedolizumab treatment.
Table 1. Crohn disease activity, laboratory results, and thickening and nodularities (arrow).
Week VDZ PCDAI CRP (mg/dL) ESR (mm/hr) Albumin (g/dL) VDZ TL (μg/mL) ATV (AU/mL)
0 #1 40.0 2.20 45 3.1
2 #2 12.5 0.04 47 4.1 25.25 1.91
6 #3 5.0 0.12 19 4.1 14.35 4.56
14 #4 0 0.05 15 4.1 3.36 1.76
22 #5 2.5 0.08 24 4.0 3.19 1.62
30 #6 0 0.02 16 4.2 3.59 2.06
38 #7 0 0.03 17 4.4 5.31 2.06
46 #8 2.5 0.09 33 4.5 5.18 1.76
54 #9 0 0.02 8 4.2 4.15 2.06
VDZ, vedolizumab; PCDAI, Pediatric Crohn’s Disease Activity Index; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; TL, trough level; ATV, antibody to VDZ.
Ethical statements
This study was approved by the Institutional Review Board (IRB) of Kyungpook National University Chilgok Hospital (IRB No: 2020-09-013). Informed consent was obtained from the patient and her parents.
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Funding
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2017R1C1B5076980).
Author contributions
Conceptualization, Formal analysis, Investigation: SC, BK; Data curation: All authors; Funding acquisition, Methodology, Resources, Software, Supervision, Validation: BK; Project administration, Visualization: SC; Writing-original draft: SC; Writing-review & editing: BSC, BHC, BK. | UNKNOWN | DrugDosageText | CC BY-NC | 33601494 | 18,963,545 | 2021-07 |
What was the dosage of drug 'MESALAMINE'? | Successful treatment with vedolizumab in an adolescent with Crohn disease who had developed active pulmonary tuberculosis while receiving infliximab.
Vedolizumab (VDZ) has been approved for the treatment of inflammatory bowel diseases (IBDs) in patients aged ≥18 years. We report a case of a pediatric patient with Crohn disease (CD) who was successfully treated with VDZ. A 16-year-old female developed severe active pulmonary tuberculosis (TB) during treatment with infliximab (IFX). IFX was stopped, and TB treatment was started. After a 6-month regimen of standard TB medication, her pulmonary TB was cured; however, gastrointestinal symptoms developed. Due to the concern of the patient and parents regarding TB reactivation on restarting treatment with IFX, VDZ was started off-label. After the second dose of VDZ, the patient was in clinical remission and her remission was continuously sustained. Ileocolonoscopy at 1-year after VDZ initiation revealed endoscopic healing. Therapeutic drug monitoring conducted during VDZ treatment showed negative antibodies to VDZ. No serious adverse events occurred during the VDZ treatment. This is the first case report in Korea demonstrating the safe and effective use of VDZ treatment in a pediatric CD patient. In cases that require recommencement of treatment with biologics after recovery of active pulmonary TB caused by anti-tumor necrosis factor agents, VDZ may be a good option even in pediatric IBD.
Introduction
Crohn disease (CD) is an inflammatory bowel disease (IBD) characterized by ulcers and inflammation that develop anywhere throughout the gastrointestinal (GI) tract [1]. Approximately 25% of patients with CD are diagnosed at <20 years of age, in whom a more aggressive disease course occurs compared with adult-onset disease. Hence, an earlier introduction of immunomodulators and/or anti-tumor necrosis factor (TNF) agents is required [1-3].
Vedolizumab (VDZ) is a humanized monoclonal antibody acting on α4β7 integrin that is present on the surface of lymphocytes and binds to MadCAM-1 on the intestinal endothelium. VDZ selectively inhibits the transmigration of lymphocytes into the inflamed intestinal tissue [4]. This gut-selective mechanism of action of VDZ is advantageous in terms of safety compared to other biologics. VDZ is currently approved for use only in adults with CD and ulcerative colitis (UC) [5,6]. Anti-TNF agents, such as infliximab (IFX) and adalimumab, are the only biological agents approved for use in pediatric IBD, whereas VDZ can be administered only off-label [7,8]. Herein, we report a rare case of a pediatric CD patient who successfully achieved and maintained remission with VDZ after developing severe active pulmonary tuberculosis (TB) during treatment with IFX.
Case
A 16-year-old female was admitted to Kyungpook National University Children’s Hospital with complaints of abdominal pain, diarrhea, and hematochezia for 2 months. The past medical history of the patient was unremarkable. She had completed Bacillus Calmette–Guérin (BCG) vaccination and had no past or family history of pulmonary TB. Initial laboratory tests showed a white blood cell count of 4,500/μL, hemoglobin level of 6.2 g/dL, platelet count of 532,000/μL, albumin level of 3.0 g/dL, erythrocyte sedimentation rate (ESR) of 110 mm/hr, and C-reactive protein (CRP) level of 8.0 mg/dL. The fecal immunochemical test (FIT) was positive, and fecal calprotectin (FC) was >2,000 mg/kg. No pathogens were detected in the stool culture and stool polymerase chain reaction (PCR). Chest X-ray showed no abnormal findings in the lungs, and the interferon-gamma release assay (IGRA) was negative. Ileocolonoscopy showed multifocal ulcers throughout the terminal ileum and colon (Fig. 1). Cryptitis, crypt abscesses, and non-caseating granulomas were observed throughout the terminal ileum and colon on histology; however, the acid-fast bacillus smear and culture and PCR for TB were negative. Upper GI endoscopy revealed ulcers in the duodenum (Fig. 2A). Magnetic resonance enterography showed multisegmental wall thickening in the ileum (Fig. 2B). The patient was diagnosed with CD with a phenotype of A1b, L3+L4ab, B1, G0 according to the Paris classification. Her Pediatric Crohn’s Disease Activity Index (PCDAI) score was 50, and the Simple Endoscopic Score for Crohn’s Disease (SES-CD) was 22.
Treatment began with exclusive enteral nutrition (EEN), mesalazine, and azathioprine, which were effective. One month after treatment, her PCDAI score had decreased to 10. However, 1 month after finishing her 8-week treatment with EEN, the disease relapsed and her PCDAI score elevated to 42.5; hence, prednisolone was started per oral at a dose of 50 mg/day. Despite corticosteroid treatment, symptoms persisted, and IFX was administered. Chest X-ray before the administration of IFX showed no abnormal findings in the lungs, and the IGRA was negative. Symptoms resolved after the second dose of IFX infusion, and her PCDAI score decreased to 7.5. However, during her visit for the third IFX infusion, she complained of fever, cough, and dyspnea on exertion for a week. Radiologic examination of the chest revealed a left pleural effusion with mild pleural thickening and nodularities indicating TB pleurisy on chest X-ray and computed tomography (Fig. 3). Thoracentesis was conducted, and pulmonary TB was confirmed by a positive TB PCR test of the pleural effusion specimen and a positive IGRA test. IFX treatment was discontinued and the standard TB treatment regimen consisting of isoniazid, ethambutol, rifampin, and pyrazinamide for 2 months, followed by isoniazid, ethambutol, and rifampin for 4 months, was started. EEN was restarted and maintained for 8 weeks. Subsequently, mesalazine was administered to treat CD.
Her pulmonary TB was completely cured after 6 months of TB treatment. However, symptoms such as hematochezia, diarrhea, and weight loss began by the end of TB treatment. Laboratory tests showed a white blood cell count of 7,010/μL, hemoglobin level of 6.8 g/dL, platelet count of 477,000/μL, albumin level of 3.1 g/dL, ESR of 45 mm/hr, and CRP of 2.2 mg/dL. FIT was positive, and FC was >2,000 mg/kg. No pathogens were detected in the stool culture and stool PCR. Her PCDAI score was 47.5, and the exacerbation of CD was confirmed by ileocolonoscopy (Fig. 4A). Therefore, we planned to restart IFX. However, due to the fear of another severe disease course of active TB when IFX were to be restarted, the patient and parents preferred to start VDZ off-label instead of restarting IFX. Before starting VDZ, the patient’s weight was 57 kg. VDZ was administered according to the regular regimen approved in adults of 300 mg per dose at weeks 0, 2, and 6 for induction and 8-week intervals for maintenance treatment thereafter. The patient showed a fast response to VDZ treatment. At the week 6 visit for her third VDZ infusion, she was in clinical remission, and inflammatory markers were normalized (Table 1, Fig. 5). Ileocolonoscopy at the 1-year follow-up after VDZ treatment revealed endoscopic healing (Fig. 4B). Therapeutic drug monitoring (TDM) using commercialized enzyme-linked immunosorbent assay kits (Immundiagnostik AG, Bensheim, Germany) was conducted during VDZ treatment. An anti-drug antibody level of ≤10 AU/mL was defined as negative, according to the manufacturer’s manual. TDM results during VDZ treatment showed negative antibodies to VDZ (Table 1). The patient is currently in her second year of VDZ treatment and is maintaining clinical and biochemical remission. No serious adverse events, including TB reactivation, have occurred.
Discussion
With the introduction of anti-TNF agents in the treatment of CD, there is no doubt that treatment outcomes have improved. However, anti-TNF agents are known to increase the risk of serious infections, including TB [9]. It has been reported that anti-TNF agents are associated with a 2- to 8-fold increased risk of developing active TB [9]. Reactivation of latent TB infections (LTBI) rather than a new infection is considered to be the primary cause of active TB, as most of the active TB cases have been reported to occur within 3 to 4 months after starting anti-TNF treatment [9]. Therefore, screening for LTBI prior to anti-TNF treatment is strongly recommended worldwide, and especially in Asia, where the prevalence of LTBI is higher than that of Western countries [9]. In this case report, the patient had completed TB vaccination, did not have any history or exposure to active TB, and TB screening was negative with both chest X-ray and IGRA at both times of diagnostic evaluation of CD and before the commencement of IFX. However, the patient, unfortunately, developed symptoms of active pulmonary TB 5 weeks after starting IFX treatment, indicating that the active TB was probably due to the reactivation of LTBI, which was missed on TB screening.
It is well known that when active TB is diagnosed during anti-TNF treatment, the anti-TNF agent should be withheld, and anti-TB therapy should be started [10]. Regarding when to restart anti-TNF treatment, it is considered safe to delay the resumption of anti-TNF therapy until the completion of anti-TB treatment [10]. However, if an early resumption of anti-TNF treatment is required, anti-TNF treatment may be restarted as early as 2 months after anti-TB treatment in patients who did not have an initially severe active TB, demonstrated a favorable response to anti-TB treatment, and when drug susceptibility was proven [10]. In this case report, the patient’s symptoms of CD were fortunately well controlled without IFX until the end of TB medication. According to the treatment guidelines, she could have restarted IFX when CD relapsed at the end of TB medication. However, because she had suffered a severe active TB and due to the fear of another severe disease course of active TB when IFX were to be restarted, the patient and parents preferred to start VDZ instead.
VDZ is effective for achieving both clinical remission and mucosal healing in adult patients with UC and CD [5,6,11]. Regarding safety, according to the integrated safety data from six trials, VDZ did not increase the risk of serious infections, progressive multifocal leukoencephalopathy, or malignancy [12]. Among 2,830 patients with 4,811 person-years (PYs) exposure to VDZ, TB was reported in only four patients (0.14%) with an estimated incidence of 0.1/100 PYs [12]. Meanwhile, the estimated incidence of TB during treatment with anti-TNF agents has been reported as 1.34/100 PYs and 0.79/100 PYs for IFX and adalimumab, respectively [13].
Compared with adults, there is limited experience with VDZ therapy in pediatric IBD. In children, VDZ is only available off-label and is used for patients who have already exhausted other treatment options, including anti-TNF agents. According to the ECCO/ESPGHAN (European Crohn’s and Colitis Organisation and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition) guideline, VDZ should be considered in chronically active or steroid-dependent pediatric UC patients as a second-line biologic therapy after anti-TNF failure, even though it has not yet been approved for use in children [7]. In addition, in pediatric CD patients who fail to maintain clinical remission on anti-TNF agents despite dose optimization and immunomodulator use, VDZ can be considered off-label [8]. A multicenter retrospective study showed that VDZ was safe and effective in pediatric IBD patients [14]. In this study, 64 children with IBD who had been previously treated with anti-TNF agents were included. During a median follow-up period of 24 months, corticosteroid-free remission was 37% in UC and 14% in CD at week 14, and 39% in UC and 24% in CD at the last follow-up [14]. Another retrospective study on 52 children with IBD showed clinical remission rates of 76% and 42% for UC and CD, respectively, at week 14 [15]. No serious adverse events were reported in either study [14,15].
In the GEMINI 3 trial, VDZ was not more effective than placebo in inducing clinical remission at week 6 among patients with CD who had failed previous treatment with anti-TNF agents [16]. The clinical benefits of VDZ in these patients were detectable later at week 10 [16]. This slow induction rate of VDZ was also observed in pediatric patients with CD [14]. Contrary to these findings, the patient in this case report showed a fast response to VDZ. Additionally, according to the clinical decision support tool developed for predicting the probability of response to VDZ in adult CD patients [17], the patient’s score in this case report was 16, which applies to an intermediate response probability. However, the patient continuously maintained clinical and biochemical remission, and endoscopic healing was observed at 1-year treatment with VDZ. One reason for this swift and favorable response to VDZ in this case report may be that the patient had not failed IFX due to poor response, but because discontinuation of IFX was inevitable due to active TB infection.
Data regarding TDM in VDZ are limited. An exposure-efficacy relationship does not seem as straightforward as they are for anti-TNF agents, and robust target VDZ trough levels are not well-defined [18]. However, according to data from a TDM study in adult IBD, VDZ trough levels of >30 μg/mL at week 2, >24 μg/mL at week 6, and >14 μg/mL during maintenance therapy have been proposed for achieving clinical remission [19]. In another study in pediatric-onset IBD patients treated with VDZ, the mean VDZ trough level was 29.9 μg/mL at week 6 and 11.5 μg/mL during maintenance therapy [20]. In this case report, VDZ trough levels were lower than the proposed threshold targets; however, the patient responded well. This may be due to variability in the yet to be revealed association between individual pharmacokinetics and the degree of response to VDZ.
In conclusion, we report a case of a pediatric patient with CD who successfully achieved and maintained remission with VDZ after developing active pulmonary TB during treatment with IFX. In cases that require recommencement of treatment with biologics after recovery of active pulmonary TB caused by anti-TNF agents, VDZ may be a good option even in pediatric IBD.
Fig. 1. Images of ileocolonoscopy at the diagnosis of Crohn disease. Multifocal aphthous ulcers are observed in the (A) terminal ileum and (B) colon.
Fig. 2. Images at the diagnosis of Crohn disease. (A) Upper gastrointestinal endoscopy shows multiple ulcers in the duodenum. (B) Magnetic resonance enterography shows multisegmental wall thickening in the ileum.
Fig. 3. Radiologic images at the diagnosis of active pulmonary tuberculosis during infliximab treatment. (A) Chest X-ray shows a marked amount of left pleural effusion. (B) Chest computed tomography shows left pleural effusion with mild pleural thickening and nodularities.
Fig. 4. Images of ileocolonoscopy before and after treatment with vedolizumab. (A) Multiple ulcers with mucosal friability are observed throughout the colon before treatment with vedolizumab. (B) Endoscopic healing is observed 1 year after treatment with vedolizumab.
Fig. 5. Fecal immunochemical test (FIT) and fecal calprotectin (FC) results during vedolizumab treatment.
Table 1. Crohn disease activity, laboratory results, and thickening and nodularities (arrow).
Week VDZ PCDAI CRP (mg/dL) ESR (mm/hr) Albumin (g/dL) VDZ TL (μg/mL) ATV (AU/mL)
0 #1 40.0 2.20 45 3.1
2 #2 12.5 0.04 47 4.1 25.25 1.91
6 #3 5.0 0.12 19 4.1 14.35 4.56
14 #4 0 0.05 15 4.1 3.36 1.76
22 #5 2.5 0.08 24 4.0 3.19 1.62
30 #6 0 0.02 16 4.2 3.59 2.06
38 #7 0 0.03 17 4.4 5.31 2.06
46 #8 2.5 0.09 33 4.5 5.18 1.76
54 #9 0 0.02 8 4.2 4.15 2.06
VDZ, vedolizumab; PCDAI, Pediatric Crohn’s Disease Activity Index; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; TL, trough level; ATV, antibody to VDZ.
Ethical statements
This study was approved by the Institutional Review Board (IRB) of Kyungpook National University Chilgok Hospital (IRB No: 2020-09-013). Informed consent was obtained from the patient and her parents.
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Funding
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2017R1C1B5076980).
Author contributions
Conceptualization, Formal analysis, Investigation: SC, BK; Data curation: All authors; Funding acquisition, Methodology, Resources, Software, Supervision, Validation: BK; Project administration, Visualization: SC; Writing-original draft: SC; Writing-review & editing: BSC, BHC, BK. | UNKNOWN | DrugDosageText | CC BY-NC | 33601494 | 18,963,545 | 2021-07 |
What was the dosage of drug 'PREDNISOLONE'? | Successful treatment with vedolizumab in an adolescent with Crohn disease who had developed active pulmonary tuberculosis while receiving infliximab.
Vedolizumab (VDZ) has been approved for the treatment of inflammatory bowel diseases (IBDs) in patients aged ≥18 years. We report a case of a pediatric patient with Crohn disease (CD) who was successfully treated with VDZ. A 16-year-old female developed severe active pulmonary tuberculosis (TB) during treatment with infliximab (IFX). IFX was stopped, and TB treatment was started. After a 6-month regimen of standard TB medication, her pulmonary TB was cured; however, gastrointestinal symptoms developed. Due to the concern of the patient and parents regarding TB reactivation on restarting treatment with IFX, VDZ was started off-label. After the second dose of VDZ, the patient was in clinical remission and her remission was continuously sustained. Ileocolonoscopy at 1-year after VDZ initiation revealed endoscopic healing. Therapeutic drug monitoring conducted during VDZ treatment showed negative antibodies to VDZ. No serious adverse events occurred during the VDZ treatment. This is the first case report in Korea demonstrating the safe and effective use of VDZ treatment in a pediatric CD patient. In cases that require recommencement of treatment with biologics after recovery of active pulmonary TB caused by anti-tumor necrosis factor agents, VDZ may be a good option even in pediatric IBD.
Introduction
Crohn disease (CD) is an inflammatory bowel disease (IBD) characterized by ulcers and inflammation that develop anywhere throughout the gastrointestinal (GI) tract [1]. Approximately 25% of patients with CD are diagnosed at <20 years of age, in whom a more aggressive disease course occurs compared with adult-onset disease. Hence, an earlier introduction of immunomodulators and/or anti-tumor necrosis factor (TNF) agents is required [1-3].
Vedolizumab (VDZ) is a humanized monoclonal antibody acting on α4β7 integrin that is present on the surface of lymphocytes and binds to MadCAM-1 on the intestinal endothelium. VDZ selectively inhibits the transmigration of lymphocytes into the inflamed intestinal tissue [4]. This gut-selective mechanism of action of VDZ is advantageous in terms of safety compared to other biologics. VDZ is currently approved for use only in adults with CD and ulcerative colitis (UC) [5,6]. Anti-TNF agents, such as infliximab (IFX) and adalimumab, are the only biological agents approved for use in pediatric IBD, whereas VDZ can be administered only off-label [7,8]. Herein, we report a rare case of a pediatric CD patient who successfully achieved and maintained remission with VDZ after developing severe active pulmonary tuberculosis (TB) during treatment with IFX.
Case
A 16-year-old female was admitted to Kyungpook National University Children’s Hospital with complaints of abdominal pain, diarrhea, and hematochezia for 2 months. The past medical history of the patient was unremarkable. She had completed Bacillus Calmette–Guérin (BCG) vaccination and had no past or family history of pulmonary TB. Initial laboratory tests showed a white blood cell count of 4,500/μL, hemoglobin level of 6.2 g/dL, platelet count of 532,000/μL, albumin level of 3.0 g/dL, erythrocyte sedimentation rate (ESR) of 110 mm/hr, and C-reactive protein (CRP) level of 8.0 mg/dL. The fecal immunochemical test (FIT) was positive, and fecal calprotectin (FC) was >2,000 mg/kg. No pathogens were detected in the stool culture and stool polymerase chain reaction (PCR). Chest X-ray showed no abnormal findings in the lungs, and the interferon-gamma release assay (IGRA) was negative. Ileocolonoscopy showed multifocal ulcers throughout the terminal ileum and colon (Fig. 1). Cryptitis, crypt abscesses, and non-caseating granulomas were observed throughout the terminal ileum and colon on histology; however, the acid-fast bacillus smear and culture and PCR for TB were negative. Upper GI endoscopy revealed ulcers in the duodenum (Fig. 2A). Magnetic resonance enterography showed multisegmental wall thickening in the ileum (Fig. 2B). The patient was diagnosed with CD with a phenotype of A1b, L3+L4ab, B1, G0 according to the Paris classification. Her Pediatric Crohn’s Disease Activity Index (PCDAI) score was 50, and the Simple Endoscopic Score for Crohn’s Disease (SES-CD) was 22.
Treatment began with exclusive enteral nutrition (EEN), mesalazine, and azathioprine, which were effective. One month after treatment, her PCDAI score had decreased to 10. However, 1 month after finishing her 8-week treatment with EEN, the disease relapsed and her PCDAI score elevated to 42.5; hence, prednisolone was started per oral at a dose of 50 mg/day. Despite corticosteroid treatment, symptoms persisted, and IFX was administered. Chest X-ray before the administration of IFX showed no abnormal findings in the lungs, and the IGRA was negative. Symptoms resolved after the second dose of IFX infusion, and her PCDAI score decreased to 7.5. However, during her visit for the third IFX infusion, she complained of fever, cough, and dyspnea on exertion for a week. Radiologic examination of the chest revealed a left pleural effusion with mild pleural thickening and nodularities indicating TB pleurisy on chest X-ray and computed tomography (Fig. 3). Thoracentesis was conducted, and pulmonary TB was confirmed by a positive TB PCR test of the pleural effusion specimen and a positive IGRA test. IFX treatment was discontinued and the standard TB treatment regimen consisting of isoniazid, ethambutol, rifampin, and pyrazinamide for 2 months, followed by isoniazid, ethambutol, and rifampin for 4 months, was started. EEN was restarted and maintained for 8 weeks. Subsequently, mesalazine was administered to treat CD.
Her pulmonary TB was completely cured after 6 months of TB treatment. However, symptoms such as hematochezia, diarrhea, and weight loss began by the end of TB treatment. Laboratory tests showed a white blood cell count of 7,010/μL, hemoglobin level of 6.8 g/dL, platelet count of 477,000/μL, albumin level of 3.1 g/dL, ESR of 45 mm/hr, and CRP of 2.2 mg/dL. FIT was positive, and FC was >2,000 mg/kg. No pathogens were detected in the stool culture and stool PCR. Her PCDAI score was 47.5, and the exacerbation of CD was confirmed by ileocolonoscopy (Fig. 4A). Therefore, we planned to restart IFX. However, due to the fear of another severe disease course of active TB when IFX were to be restarted, the patient and parents preferred to start VDZ off-label instead of restarting IFX. Before starting VDZ, the patient’s weight was 57 kg. VDZ was administered according to the regular regimen approved in adults of 300 mg per dose at weeks 0, 2, and 6 for induction and 8-week intervals for maintenance treatment thereafter. The patient showed a fast response to VDZ treatment. At the week 6 visit for her third VDZ infusion, she was in clinical remission, and inflammatory markers were normalized (Table 1, Fig. 5). Ileocolonoscopy at the 1-year follow-up after VDZ treatment revealed endoscopic healing (Fig. 4B). Therapeutic drug monitoring (TDM) using commercialized enzyme-linked immunosorbent assay kits (Immundiagnostik AG, Bensheim, Germany) was conducted during VDZ treatment. An anti-drug antibody level of ≤10 AU/mL was defined as negative, according to the manufacturer’s manual. TDM results during VDZ treatment showed negative antibodies to VDZ (Table 1). The patient is currently in her second year of VDZ treatment and is maintaining clinical and biochemical remission. No serious adverse events, including TB reactivation, have occurred.
Discussion
With the introduction of anti-TNF agents in the treatment of CD, there is no doubt that treatment outcomes have improved. However, anti-TNF agents are known to increase the risk of serious infections, including TB [9]. It has been reported that anti-TNF agents are associated with a 2- to 8-fold increased risk of developing active TB [9]. Reactivation of latent TB infections (LTBI) rather than a new infection is considered to be the primary cause of active TB, as most of the active TB cases have been reported to occur within 3 to 4 months after starting anti-TNF treatment [9]. Therefore, screening for LTBI prior to anti-TNF treatment is strongly recommended worldwide, and especially in Asia, where the prevalence of LTBI is higher than that of Western countries [9]. In this case report, the patient had completed TB vaccination, did not have any history or exposure to active TB, and TB screening was negative with both chest X-ray and IGRA at both times of diagnostic evaluation of CD and before the commencement of IFX. However, the patient, unfortunately, developed symptoms of active pulmonary TB 5 weeks after starting IFX treatment, indicating that the active TB was probably due to the reactivation of LTBI, which was missed on TB screening.
It is well known that when active TB is diagnosed during anti-TNF treatment, the anti-TNF agent should be withheld, and anti-TB therapy should be started [10]. Regarding when to restart anti-TNF treatment, it is considered safe to delay the resumption of anti-TNF therapy until the completion of anti-TB treatment [10]. However, if an early resumption of anti-TNF treatment is required, anti-TNF treatment may be restarted as early as 2 months after anti-TB treatment in patients who did not have an initially severe active TB, demonstrated a favorable response to anti-TB treatment, and when drug susceptibility was proven [10]. In this case report, the patient’s symptoms of CD were fortunately well controlled without IFX until the end of TB medication. According to the treatment guidelines, she could have restarted IFX when CD relapsed at the end of TB medication. However, because she had suffered a severe active TB and due to the fear of another severe disease course of active TB when IFX were to be restarted, the patient and parents preferred to start VDZ instead.
VDZ is effective for achieving both clinical remission and mucosal healing in adult patients with UC and CD [5,6,11]. Regarding safety, according to the integrated safety data from six trials, VDZ did not increase the risk of serious infections, progressive multifocal leukoencephalopathy, or malignancy [12]. Among 2,830 patients with 4,811 person-years (PYs) exposure to VDZ, TB was reported in only four patients (0.14%) with an estimated incidence of 0.1/100 PYs [12]. Meanwhile, the estimated incidence of TB during treatment with anti-TNF agents has been reported as 1.34/100 PYs and 0.79/100 PYs for IFX and adalimumab, respectively [13].
Compared with adults, there is limited experience with VDZ therapy in pediatric IBD. In children, VDZ is only available off-label and is used for patients who have already exhausted other treatment options, including anti-TNF agents. According to the ECCO/ESPGHAN (European Crohn’s and Colitis Organisation and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition) guideline, VDZ should be considered in chronically active or steroid-dependent pediatric UC patients as a second-line biologic therapy after anti-TNF failure, even though it has not yet been approved for use in children [7]. In addition, in pediatric CD patients who fail to maintain clinical remission on anti-TNF agents despite dose optimization and immunomodulator use, VDZ can be considered off-label [8]. A multicenter retrospective study showed that VDZ was safe and effective in pediatric IBD patients [14]. In this study, 64 children with IBD who had been previously treated with anti-TNF agents were included. During a median follow-up period of 24 months, corticosteroid-free remission was 37% in UC and 14% in CD at week 14, and 39% in UC and 24% in CD at the last follow-up [14]. Another retrospective study on 52 children with IBD showed clinical remission rates of 76% and 42% for UC and CD, respectively, at week 14 [15]. No serious adverse events were reported in either study [14,15].
In the GEMINI 3 trial, VDZ was not more effective than placebo in inducing clinical remission at week 6 among patients with CD who had failed previous treatment with anti-TNF agents [16]. The clinical benefits of VDZ in these patients were detectable later at week 10 [16]. This slow induction rate of VDZ was also observed in pediatric patients with CD [14]. Contrary to these findings, the patient in this case report showed a fast response to VDZ. Additionally, according to the clinical decision support tool developed for predicting the probability of response to VDZ in adult CD patients [17], the patient’s score in this case report was 16, which applies to an intermediate response probability. However, the patient continuously maintained clinical and biochemical remission, and endoscopic healing was observed at 1-year treatment with VDZ. One reason for this swift and favorable response to VDZ in this case report may be that the patient had not failed IFX due to poor response, but because discontinuation of IFX was inevitable due to active TB infection.
Data regarding TDM in VDZ are limited. An exposure-efficacy relationship does not seem as straightforward as they are for anti-TNF agents, and robust target VDZ trough levels are not well-defined [18]. However, according to data from a TDM study in adult IBD, VDZ trough levels of >30 μg/mL at week 2, >24 μg/mL at week 6, and >14 μg/mL during maintenance therapy have been proposed for achieving clinical remission [19]. In another study in pediatric-onset IBD patients treated with VDZ, the mean VDZ trough level was 29.9 μg/mL at week 6 and 11.5 μg/mL during maintenance therapy [20]. In this case report, VDZ trough levels were lower than the proposed threshold targets; however, the patient responded well. This may be due to variability in the yet to be revealed association between individual pharmacokinetics and the degree of response to VDZ.
In conclusion, we report a case of a pediatric patient with CD who successfully achieved and maintained remission with VDZ after developing active pulmonary TB during treatment with IFX. In cases that require recommencement of treatment with biologics after recovery of active pulmonary TB caused by anti-TNF agents, VDZ may be a good option even in pediatric IBD.
Fig. 1. Images of ileocolonoscopy at the diagnosis of Crohn disease. Multifocal aphthous ulcers are observed in the (A) terminal ileum and (B) colon.
Fig. 2. Images at the diagnosis of Crohn disease. (A) Upper gastrointestinal endoscopy shows multiple ulcers in the duodenum. (B) Magnetic resonance enterography shows multisegmental wall thickening in the ileum.
Fig. 3. Radiologic images at the diagnosis of active pulmonary tuberculosis during infliximab treatment. (A) Chest X-ray shows a marked amount of left pleural effusion. (B) Chest computed tomography shows left pleural effusion with mild pleural thickening and nodularities.
Fig. 4. Images of ileocolonoscopy before and after treatment with vedolizumab. (A) Multiple ulcers with mucosal friability are observed throughout the colon before treatment with vedolizumab. (B) Endoscopic healing is observed 1 year after treatment with vedolizumab.
Fig. 5. Fecal immunochemical test (FIT) and fecal calprotectin (FC) results during vedolizumab treatment.
Table 1. Crohn disease activity, laboratory results, and thickening and nodularities (arrow).
Week VDZ PCDAI CRP (mg/dL) ESR (mm/hr) Albumin (g/dL) VDZ TL (μg/mL) ATV (AU/mL)
0 #1 40.0 2.20 45 3.1
2 #2 12.5 0.04 47 4.1 25.25 1.91
6 #3 5.0 0.12 19 4.1 14.35 4.56
14 #4 0 0.05 15 4.1 3.36 1.76
22 #5 2.5 0.08 24 4.0 3.19 1.62
30 #6 0 0.02 16 4.2 3.59 2.06
38 #7 0 0.03 17 4.4 5.31 2.06
46 #8 2.5 0.09 33 4.5 5.18 1.76
54 #9 0 0.02 8 4.2 4.15 2.06
VDZ, vedolizumab; PCDAI, Pediatric Crohn’s Disease Activity Index; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; TL, trough level; ATV, antibody to VDZ.
Ethical statements
This study was approved by the Institutional Review Board (IRB) of Kyungpook National University Chilgok Hospital (IRB No: 2020-09-013). Informed consent was obtained from the patient and her parents.
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Funding
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2017R1C1B5076980).
Author contributions
Conceptualization, Formal analysis, Investigation: SC, BK; Data curation: All authors; Funding acquisition, Methodology, Resources, Software, Supervision, Validation: BK; Project administration, Visualization: SC; Writing-original draft: SC; Writing-review & editing: BSC, BHC, BK. | 50 mg (milligrams). | DrugDosage | CC BY-NC | 33601494 | 18,963,545 | 2021-07 |
What was the outcome of reaction 'Crohn^s disease'? | Successful treatment with vedolizumab in an adolescent with Crohn disease who had developed active pulmonary tuberculosis while receiving infliximab.
Vedolizumab (VDZ) has been approved for the treatment of inflammatory bowel diseases (IBDs) in patients aged ≥18 years. We report a case of a pediatric patient with Crohn disease (CD) who was successfully treated with VDZ. A 16-year-old female developed severe active pulmonary tuberculosis (TB) during treatment with infliximab (IFX). IFX was stopped, and TB treatment was started. After a 6-month regimen of standard TB medication, her pulmonary TB was cured; however, gastrointestinal symptoms developed. Due to the concern of the patient and parents regarding TB reactivation on restarting treatment with IFX, VDZ was started off-label. After the second dose of VDZ, the patient was in clinical remission and her remission was continuously sustained. Ileocolonoscopy at 1-year after VDZ initiation revealed endoscopic healing. Therapeutic drug monitoring conducted during VDZ treatment showed negative antibodies to VDZ. No serious adverse events occurred during the VDZ treatment. This is the first case report in Korea demonstrating the safe and effective use of VDZ treatment in a pediatric CD patient. In cases that require recommencement of treatment with biologics after recovery of active pulmonary TB caused by anti-tumor necrosis factor agents, VDZ may be a good option even in pediatric IBD.
Introduction
Crohn disease (CD) is an inflammatory bowel disease (IBD) characterized by ulcers and inflammation that develop anywhere throughout the gastrointestinal (GI) tract [1]. Approximately 25% of patients with CD are diagnosed at <20 years of age, in whom a more aggressive disease course occurs compared with adult-onset disease. Hence, an earlier introduction of immunomodulators and/or anti-tumor necrosis factor (TNF) agents is required [1-3].
Vedolizumab (VDZ) is a humanized monoclonal antibody acting on α4β7 integrin that is present on the surface of lymphocytes and binds to MadCAM-1 on the intestinal endothelium. VDZ selectively inhibits the transmigration of lymphocytes into the inflamed intestinal tissue [4]. This gut-selective mechanism of action of VDZ is advantageous in terms of safety compared to other biologics. VDZ is currently approved for use only in adults with CD and ulcerative colitis (UC) [5,6]. Anti-TNF agents, such as infliximab (IFX) and adalimumab, are the only biological agents approved for use in pediatric IBD, whereas VDZ can be administered only off-label [7,8]. Herein, we report a rare case of a pediatric CD patient who successfully achieved and maintained remission with VDZ after developing severe active pulmonary tuberculosis (TB) during treatment with IFX.
Case
A 16-year-old female was admitted to Kyungpook National University Children’s Hospital with complaints of abdominal pain, diarrhea, and hematochezia for 2 months. The past medical history of the patient was unremarkable. She had completed Bacillus Calmette–Guérin (BCG) vaccination and had no past or family history of pulmonary TB. Initial laboratory tests showed a white blood cell count of 4,500/μL, hemoglobin level of 6.2 g/dL, platelet count of 532,000/μL, albumin level of 3.0 g/dL, erythrocyte sedimentation rate (ESR) of 110 mm/hr, and C-reactive protein (CRP) level of 8.0 mg/dL. The fecal immunochemical test (FIT) was positive, and fecal calprotectin (FC) was >2,000 mg/kg. No pathogens were detected in the stool culture and stool polymerase chain reaction (PCR). Chest X-ray showed no abnormal findings in the lungs, and the interferon-gamma release assay (IGRA) was negative. Ileocolonoscopy showed multifocal ulcers throughout the terminal ileum and colon (Fig. 1). Cryptitis, crypt abscesses, and non-caseating granulomas were observed throughout the terminal ileum and colon on histology; however, the acid-fast bacillus smear and culture and PCR for TB were negative. Upper GI endoscopy revealed ulcers in the duodenum (Fig. 2A). Magnetic resonance enterography showed multisegmental wall thickening in the ileum (Fig. 2B). The patient was diagnosed with CD with a phenotype of A1b, L3+L4ab, B1, G0 according to the Paris classification. Her Pediatric Crohn’s Disease Activity Index (PCDAI) score was 50, and the Simple Endoscopic Score for Crohn’s Disease (SES-CD) was 22.
Treatment began with exclusive enteral nutrition (EEN), mesalazine, and azathioprine, which were effective. One month after treatment, her PCDAI score had decreased to 10. However, 1 month after finishing her 8-week treatment with EEN, the disease relapsed and her PCDAI score elevated to 42.5; hence, prednisolone was started per oral at a dose of 50 mg/day. Despite corticosteroid treatment, symptoms persisted, and IFX was administered. Chest X-ray before the administration of IFX showed no abnormal findings in the lungs, and the IGRA was negative. Symptoms resolved after the second dose of IFX infusion, and her PCDAI score decreased to 7.5. However, during her visit for the third IFX infusion, she complained of fever, cough, and dyspnea on exertion for a week. Radiologic examination of the chest revealed a left pleural effusion with mild pleural thickening and nodularities indicating TB pleurisy on chest X-ray and computed tomography (Fig. 3). Thoracentesis was conducted, and pulmonary TB was confirmed by a positive TB PCR test of the pleural effusion specimen and a positive IGRA test. IFX treatment was discontinued and the standard TB treatment regimen consisting of isoniazid, ethambutol, rifampin, and pyrazinamide for 2 months, followed by isoniazid, ethambutol, and rifampin for 4 months, was started. EEN was restarted and maintained for 8 weeks. Subsequently, mesalazine was administered to treat CD.
Her pulmonary TB was completely cured after 6 months of TB treatment. However, symptoms such as hematochezia, diarrhea, and weight loss began by the end of TB treatment. Laboratory tests showed a white blood cell count of 7,010/μL, hemoglobin level of 6.8 g/dL, platelet count of 477,000/μL, albumin level of 3.1 g/dL, ESR of 45 mm/hr, and CRP of 2.2 mg/dL. FIT was positive, and FC was >2,000 mg/kg. No pathogens were detected in the stool culture and stool PCR. Her PCDAI score was 47.5, and the exacerbation of CD was confirmed by ileocolonoscopy (Fig. 4A). Therefore, we planned to restart IFX. However, due to the fear of another severe disease course of active TB when IFX were to be restarted, the patient and parents preferred to start VDZ off-label instead of restarting IFX. Before starting VDZ, the patient’s weight was 57 kg. VDZ was administered according to the regular regimen approved in adults of 300 mg per dose at weeks 0, 2, and 6 for induction and 8-week intervals for maintenance treatment thereafter. The patient showed a fast response to VDZ treatment. At the week 6 visit for her third VDZ infusion, she was in clinical remission, and inflammatory markers were normalized (Table 1, Fig. 5). Ileocolonoscopy at the 1-year follow-up after VDZ treatment revealed endoscopic healing (Fig. 4B). Therapeutic drug monitoring (TDM) using commercialized enzyme-linked immunosorbent assay kits (Immundiagnostik AG, Bensheim, Germany) was conducted during VDZ treatment. An anti-drug antibody level of ≤10 AU/mL was defined as negative, according to the manufacturer’s manual. TDM results during VDZ treatment showed negative antibodies to VDZ (Table 1). The patient is currently in her second year of VDZ treatment and is maintaining clinical and biochemical remission. No serious adverse events, including TB reactivation, have occurred.
Discussion
With the introduction of anti-TNF agents in the treatment of CD, there is no doubt that treatment outcomes have improved. However, anti-TNF agents are known to increase the risk of serious infections, including TB [9]. It has been reported that anti-TNF agents are associated with a 2- to 8-fold increased risk of developing active TB [9]. Reactivation of latent TB infections (LTBI) rather than a new infection is considered to be the primary cause of active TB, as most of the active TB cases have been reported to occur within 3 to 4 months after starting anti-TNF treatment [9]. Therefore, screening for LTBI prior to anti-TNF treatment is strongly recommended worldwide, and especially in Asia, where the prevalence of LTBI is higher than that of Western countries [9]. In this case report, the patient had completed TB vaccination, did not have any history or exposure to active TB, and TB screening was negative with both chest X-ray and IGRA at both times of diagnostic evaluation of CD and before the commencement of IFX. However, the patient, unfortunately, developed symptoms of active pulmonary TB 5 weeks after starting IFX treatment, indicating that the active TB was probably due to the reactivation of LTBI, which was missed on TB screening.
It is well known that when active TB is diagnosed during anti-TNF treatment, the anti-TNF agent should be withheld, and anti-TB therapy should be started [10]. Regarding when to restart anti-TNF treatment, it is considered safe to delay the resumption of anti-TNF therapy until the completion of anti-TB treatment [10]. However, if an early resumption of anti-TNF treatment is required, anti-TNF treatment may be restarted as early as 2 months after anti-TB treatment in patients who did not have an initially severe active TB, demonstrated a favorable response to anti-TB treatment, and when drug susceptibility was proven [10]. In this case report, the patient’s symptoms of CD were fortunately well controlled without IFX until the end of TB medication. According to the treatment guidelines, she could have restarted IFX when CD relapsed at the end of TB medication. However, because she had suffered a severe active TB and due to the fear of another severe disease course of active TB when IFX were to be restarted, the patient and parents preferred to start VDZ instead.
VDZ is effective for achieving both clinical remission and mucosal healing in adult patients with UC and CD [5,6,11]. Regarding safety, according to the integrated safety data from six trials, VDZ did not increase the risk of serious infections, progressive multifocal leukoencephalopathy, or malignancy [12]. Among 2,830 patients with 4,811 person-years (PYs) exposure to VDZ, TB was reported in only four patients (0.14%) with an estimated incidence of 0.1/100 PYs [12]. Meanwhile, the estimated incidence of TB during treatment with anti-TNF agents has been reported as 1.34/100 PYs and 0.79/100 PYs for IFX and adalimumab, respectively [13].
Compared with adults, there is limited experience with VDZ therapy in pediatric IBD. In children, VDZ is only available off-label and is used for patients who have already exhausted other treatment options, including anti-TNF agents. According to the ECCO/ESPGHAN (European Crohn’s and Colitis Organisation and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition) guideline, VDZ should be considered in chronically active or steroid-dependent pediatric UC patients as a second-line biologic therapy after anti-TNF failure, even though it has not yet been approved for use in children [7]. In addition, in pediatric CD patients who fail to maintain clinical remission on anti-TNF agents despite dose optimization and immunomodulator use, VDZ can be considered off-label [8]. A multicenter retrospective study showed that VDZ was safe and effective in pediatric IBD patients [14]. In this study, 64 children with IBD who had been previously treated with anti-TNF agents were included. During a median follow-up period of 24 months, corticosteroid-free remission was 37% in UC and 14% in CD at week 14, and 39% in UC and 24% in CD at the last follow-up [14]. Another retrospective study on 52 children with IBD showed clinical remission rates of 76% and 42% for UC and CD, respectively, at week 14 [15]. No serious adverse events were reported in either study [14,15].
In the GEMINI 3 trial, VDZ was not more effective than placebo in inducing clinical remission at week 6 among patients with CD who had failed previous treatment with anti-TNF agents [16]. The clinical benefits of VDZ in these patients were detectable later at week 10 [16]. This slow induction rate of VDZ was also observed in pediatric patients with CD [14]. Contrary to these findings, the patient in this case report showed a fast response to VDZ. Additionally, according to the clinical decision support tool developed for predicting the probability of response to VDZ in adult CD patients [17], the patient’s score in this case report was 16, which applies to an intermediate response probability. However, the patient continuously maintained clinical and biochemical remission, and endoscopic healing was observed at 1-year treatment with VDZ. One reason for this swift and favorable response to VDZ in this case report may be that the patient had not failed IFX due to poor response, but because discontinuation of IFX was inevitable due to active TB infection.
Data regarding TDM in VDZ are limited. An exposure-efficacy relationship does not seem as straightforward as they are for anti-TNF agents, and robust target VDZ trough levels are not well-defined [18]. However, according to data from a TDM study in adult IBD, VDZ trough levels of >30 μg/mL at week 2, >24 μg/mL at week 6, and >14 μg/mL during maintenance therapy have been proposed for achieving clinical remission [19]. In another study in pediatric-onset IBD patients treated with VDZ, the mean VDZ trough level was 29.9 μg/mL at week 6 and 11.5 μg/mL during maintenance therapy [20]. In this case report, VDZ trough levels were lower than the proposed threshold targets; however, the patient responded well. This may be due to variability in the yet to be revealed association between individual pharmacokinetics and the degree of response to VDZ.
In conclusion, we report a case of a pediatric patient with CD who successfully achieved and maintained remission with VDZ after developing active pulmonary TB during treatment with IFX. In cases that require recommencement of treatment with biologics after recovery of active pulmonary TB caused by anti-TNF agents, VDZ may be a good option even in pediatric IBD.
Fig. 1. Images of ileocolonoscopy at the diagnosis of Crohn disease. Multifocal aphthous ulcers are observed in the (A) terminal ileum and (B) colon.
Fig. 2. Images at the diagnosis of Crohn disease. (A) Upper gastrointestinal endoscopy shows multiple ulcers in the duodenum. (B) Magnetic resonance enterography shows multisegmental wall thickening in the ileum.
Fig. 3. Radiologic images at the diagnosis of active pulmonary tuberculosis during infliximab treatment. (A) Chest X-ray shows a marked amount of left pleural effusion. (B) Chest computed tomography shows left pleural effusion with mild pleural thickening and nodularities.
Fig. 4. Images of ileocolonoscopy before and after treatment with vedolizumab. (A) Multiple ulcers with mucosal friability are observed throughout the colon before treatment with vedolizumab. (B) Endoscopic healing is observed 1 year after treatment with vedolizumab.
Fig. 5. Fecal immunochemical test (FIT) and fecal calprotectin (FC) results during vedolizumab treatment.
Table 1. Crohn disease activity, laboratory results, and thickening and nodularities (arrow).
Week VDZ PCDAI CRP (mg/dL) ESR (mm/hr) Albumin (g/dL) VDZ TL (μg/mL) ATV (AU/mL)
0 #1 40.0 2.20 45 3.1
2 #2 12.5 0.04 47 4.1 25.25 1.91
6 #3 5.0 0.12 19 4.1 14.35 4.56
14 #4 0 0.05 15 4.1 3.36 1.76
22 #5 2.5 0.08 24 4.0 3.19 1.62
30 #6 0 0.02 16 4.2 3.59 2.06
38 #7 0 0.03 17 4.4 5.31 2.06
46 #8 2.5 0.09 33 4.5 5.18 1.76
54 #9 0 0.02 8 4.2 4.15 2.06
VDZ, vedolizumab; PCDAI, Pediatric Crohn’s Disease Activity Index; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; TL, trough level; ATV, antibody to VDZ.
Ethical statements
This study was approved by the Institutional Review Board (IRB) of Kyungpook National University Chilgok Hospital (IRB No: 2020-09-013). Informed consent was obtained from the patient and her parents.
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Funding
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2017R1C1B5076980).
Author contributions
Conceptualization, Formal analysis, Investigation: SC, BK; Data curation: All authors; Funding acquisition, Methodology, Resources, Software, Supervision, Validation: BK; Project administration, Visualization: SC; Writing-original draft: SC; Writing-review & editing: BSC, BHC, BK. | Recovering | ReactionOutcome | CC BY-NC | 33601494 | 18,963,545 | 2021-07 |
What was the outcome of reaction 'Pulmonary tuberculosis'? | Successful treatment with vedolizumab in an adolescent with Crohn disease who had developed active pulmonary tuberculosis while receiving infliximab.
Vedolizumab (VDZ) has been approved for the treatment of inflammatory bowel diseases (IBDs) in patients aged ≥18 years. We report a case of a pediatric patient with Crohn disease (CD) who was successfully treated with VDZ. A 16-year-old female developed severe active pulmonary tuberculosis (TB) during treatment with infliximab (IFX). IFX was stopped, and TB treatment was started. After a 6-month regimen of standard TB medication, her pulmonary TB was cured; however, gastrointestinal symptoms developed. Due to the concern of the patient and parents regarding TB reactivation on restarting treatment with IFX, VDZ was started off-label. After the second dose of VDZ, the patient was in clinical remission and her remission was continuously sustained. Ileocolonoscopy at 1-year after VDZ initiation revealed endoscopic healing. Therapeutic drug monitoring conducted during VDZ treatment showed negative antibodies to VDZ. No serious adverse events occurred during the VDZ treatment. This is the first case report in Korea demonstrating the safe and effective use of VDZ treatment in a pediatric CD patient. In cases that require recommencement of treatment with biologics after recovery of active pulmonary TB caused by anti-tumor necrosis factor agents, VDZ may be a good option even in pediatric IBD.
Introduction
Crohn disease (CD) is an inflammatory bowel disease (IBD) characterized by ulcers and inflammation that develop anywhere throughout the gastrointestinal (GI) tract [1]. Approximately 25% of patients with CD are diagnosed at <20 years of age, in whom a more aggressive disease course occurs compared with adult-onset disease. Hence, an earlier introduction of immunomodulators and/or anti-tumor necrosis factor (TNF) agents is required [1-3].
Vedolizumab (VDZ) is a humanized monoclonal antibody acting on α4β7 integrin that is present on the surface of lymphocytes and binds to MadCAM-1 on the intestinal endothelium. VDZ selectively inhibits the transmigration of lymphocytes into the inflamed intestinal tissue [4]. This gut-selective mechanism of action of VDZ is advantageous in terms of safety compared to other biologics. VDZ is currently approved for use only in adults with CD and ulcerative colitis (UC) [5,6]. Anti-TNF agents, such as infliximab (IFX) and adalimumab, are the only biological agents approved for use in pediatric IBD, whereas VDZ can be administered only off-label [7,8]. Herein, we report a rare case of a pediatric CD patient who successfully achieved and maintained remission with VDZ after developing severe active pulmonary tuberculosis (TB) during treatment with IFX.
Case
A 16-year-old female was admitted to Kyungpook National University Children’s Hospital with complaints of abdominal pain, diarrhea, and hematochezia for 2 months. The past medical history of the patient was unremarkable. She had completed Bacillus Calmette–Guérin (BCG) vaccination and had no past or family history of pulmonary TB. Initial laboratory tests showed a white blood cell count of 4,500/μL, hemoglobin level of 6.2 g/dL, platelet count of 532,000/μL, albumin level of 3.0 g/dL, erythrocyte sedimentation rate (ESR) of 110 mm/hr, and C-reactive protein (CRP) level of 8.0 mg/dL. The fecal immunochemical test (FIT) was positive, and fecal calprotectin (FC) was >2,000 mg/kg. No pathogens were detected in the stool culture and stool polymerase chain reaction (PCR). Chest X-ray showed no abnormal findings in the lungs, and the interferon-gamma release assay (IGRA) was negative. Ileocolonoscopy showed multifocal ulcers throughout the terminal ileum and colon (Fig. 1). Cryptitis, crypt abscesses, and non-caseating granulomas were observed throughout the terminal ileum and colon on histology; however, the acid-fast bacillus smear and culture and PCR for TB were negative. Upper GI endoscopy revealed ulcers in the duodenum (Fig. 2A). Magnetic resonance enterography showed multisegmental wall thickening in the ileum (Fig. 2B). The patient was diagnosed with CD with a phenotype of A1b, L3+L4ab, B1, G0 according to the Paris classification. Her Pediatric Crohn’s Disease Activity Index (PCDAI) score was 50, and the Simple Endoscopic Score for Crohn’s Disease (SES-CD) was 22.
Treatment began with exclusive enteral nutrition (EEN), mesalazine, and azathioprine, which were effective. One month after treatment, her PCDAI score had decreased to 10. However, 1 month after finishing her 8-week treatment with EEN, the disease relapsed and her PCDAI score elevated to 42.5; hence, prednisolone was started per oral at a dose of 50 mg/day. Despite corticosteroid treatment, symptoms persisted, and IFX was administered. Chest X-ray before the administration of IFX showed no abnormal findings in the lungs, and the IGRA was negative. Symptoms resolved after the second dose of IFX infusion, and her PCDAI score decreased to 7.5. However, during her visit for the third IFX infusion, she complained of fever, cough, and dyspnea on exertion for a week. Radiologic examination of the chest revealed a left pleural effusion with mild pleural thickening and nodularities indicating TB pleurisy on chest X-ray and computed tomography (Fig. 3). Thoracentesis was conducted, and pulmonary TB was confirmed by a positive TB PCR test of the pleural effusion specimen and a positive IGRA test. IFX treatment was discontinued and the standard TB treatment regimen consisting of isoniazid, ethambutol, rifampin, and pyrazinamide for 2 months, followed by isoniazid, ethambutol, and rifampin for 4 months, was started. EEN was restarted and maintained for 8 weeks. Subsequently, mesalazine was administered to treat CD.
Her pulmonary TB was completely cured after 6 months of TB treatment. However, symptoms such as hematochezia, diarrhea, and weight loss began by the end of TB treatment. Laboratory tests showed a white blood cell count of 7,010/μL, hemoglobin level of 6.8 g/dL, platelet count of 477,000/μL, albumin level of 3.1 g/dL, ESR of 45 mm/hr, and CRP of 2.2 mg/dL. FIT was positive, and FC was >2,000 mg/kg. No pathogens were detected in the stool culture and stool PCR. Her PCDAI score was 47.5, and the exacerbation of CD was confirmed by ileocolonoscopy (Fig. 4A). Therefore, we planned to restart IFX. However, due to the fear of another severe disease course of active TB when IFX were to be restarted, the patient and parents preferred to start VDZ off-label instead of restarting IFX. Before starting VDZ, the patient’s weight was 57 kg. VDZ was administered according to the regular regimen approved in adults of 300 mg per dose at weeks 0, 2, and 6 for induction and 8-week intervals for maintenance treatment thereafter. The patient showed a fast response to VDZ treatment. At the week 6 visit for her third VDZ infusion, she was in clinical remission, and inflammatory markers were normalized (Table 1, Fig. 5). Ileocolonoscopy at the 1-year follow-up after VDZ treatment revealed endoscopic healing (Fig. 4B). Therapeutic drug monitoring (TDM) using commercialized enzyme-linked immunosorbent assay kits (Immundiagnostik AG, Bensheim, Germany) was conducted during VDZ treatment. An anti-drug antibody level of ≤10 AU/mL was defined as negative, according to the manufacturer’s manual. TDM results during VDZ treatment showed negative antibodies to VDZ (Table 1). The patient is currently in her second year of VDZ treatment and is maintaining clinical and biochemical remission. No serious adverse events, including TB reactivation, have occurred.
Discussion
With the introduction of anti-TNF agents in the treatment of CD, there is no doubt that treatment outcomes have improved. However, anti-TNF agents are known to increase the risk of serious infections, including TB [9]. It has been reported that anti-TNF agents are associated with a 2- to 8-fold increased risk of developing active TB [9]. Reactivation of latent TB infections (LTBI) rather than a new infection is considered to be the primary cause of active TB, as most of the active TB cases have been reported to occur within 3 to 4 months after starting anti-TNF treatment [9]. Therefore, screening for LTBI prior to anti-TNF treatment is strongly recommended worldwide, and especially in Asia, where the prevalence of LTBI is higher than that of Western countries [9]. In this case report, the patient had completed TB vaccination, did not have any history or exposure to active TB, and TB screening was negative with both chest X-ray and IGRA at both times of diagnostic evaluation of CD and before the commencement of IFX. However, the patient, unfortunately, developed symptoms of active pulmonary TB 5 weeks after starting IFX treatment, indicating that the active TB was probably due to the reactivation of LTBI, which was missed on TB screening.
It is well known that when active TB is diagnosed during anti-TNF treatment, the anti-TNF agent should be withheld, and anti-TB therapy should be started [10]. Regarding when to restart anti-TNF treatment, it is considered safe to delay the resumption of anti-TNF therapy until the completion of anti-TB treatment [10]. However, if an early resumption of anti-TNF treatment is required, anti-TNF treatment may be restarted as early as 2 months after anti-TB treatment in patients who did not have an initially severe active TB, demonstrated a favorable response to anti-TB treatment, and when drug susceptibility was proven [10]. In this case report, the patient’s symptoms of CD were fortunately well controlled without IFX until the end of TB medication. According to the treatment guidelines, she could have restarted IFX when CD relapsed at the end of TB medication. However, because she had suffered a severe active TB and due to the fear of another severe disease course of active TB when IFX were to be restarted, the patient and parents preferred to start VDZ instead.
VDZ is effective for achieving both clinical remission and mucosal healing in adult patients with UC and CD [5,6,11]. Regarding safety, according to the integrated safety data from six trials, VDZ did not increase the risk of serious infections, progressive multifocal leukoencephalopathy, or malignancy [12]. Among 2,830 patients with 4,811 person-years (PYs) exposure to VDZ, TB was reported in only four patients (0.14%) with an estimated incidence of 0.1/100 PYs [12]. Meanwhile, the estimated incidence of TB during treatment with anti-TNF agents has been reported as 1.34/100 PYs and 0.79/100 PYs for IFX and adalimumab, respectively [13].
Compared with adults, there is limited experience with VDZ therapy in pediatric IBD. In children, VDZ is only available off-label and is used for patients who have already exhausted other treatment options, including anti-TNF agents. According to the ECCO/ESPGHAN (European Crohn’s and Colitis Organisation and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition) guideline, VDZ should be considered in chronically active or steroid-dependent pediatric UC patients as a second-line biologic therapy after anti-TNF failure, even though it has not yet been approved for use in children [7]. In addition, in pediatric CD patients who fail to maintain clinical remission on anti-TNF agents despite dose optimization and immunomodulator use, VDZ can be considered off-label [8]. A multicenter retrospective study showed that VDZ was safe and effective in pediatric IBD patients [14]. In this study, 64 children with IBD who had been previously treated with anti-TNF agents were included. During a median follow-up period of 24 months, corticosteroid-free remission was 37% in UC and 14% in CD at week 14, and 39% in UC and 24% in CD at the last follow-up [14]. Another retrospective study on 52 children with IBD showed clinical remission rates of 76% and 42% for UC and CD, respectively, at week 14 [15]. No serious adverse events were reported in either study [14,15].
In the GEMINI 3 trial, VDZ was not more effective than placebo in inducing clinical remission at week 6 among patients with CD who had failed previous treatment with anti-TNF agents [16]. The clinical benefits of VDZ in these patients were detectable later at week 10 [16]. This slow induction rate of VDZ was also observed in pediatric patients with CD [14]. Contrary to these findings, the patient in this case report showed a fast response to VDZ. Additionally, according to the clinical decision support tool developed for predicting the probability of response to VDZ in adult CD patients [17], the patient’s score in this case report was 16, which applies to an intermediate response probability. However, the patient continuously maintained clinical and biochemical remission, and endoscopic healing was observed at 1-year treatment with VDZ. One reason for this swift and favorable response to VDZ in this case report may be that the patient had not failed IFX due to poor response, but because discontinuation of IFX was inevitable due to active TB infection.
Data regarding TDM in VDZ are limited. An exposure-efficacy relationship does not seem as straightforward as they are for anti-TNF agents, and robust target VDZ trough levels are not well-defined [18]. However, according to data from a TDM study in adult IBD, VDZ trough levels of >30 μg/mL at week 2, >24 μg/mL at week 6, and >14 μg/mL during maintenance therapy have been proposed for achieving clinical remission [19]. In another study in pediatric-onset IBD patients treated with VDZ, the mean VDZ trough level was 29.9 μg/mL at week 6 and 11.5 μg/mL during maintenance therapy [20]. In this case report, VDZ trough levels were lower than the proposed threshold targets; however, the patient responded well. This may be due to variability in the yet to be revealed association between individual pharmacokinetics and the degree of response to VDZ.
In conclusion, we report a case of a pediatric patient with CD who successfully achieved and maintained remission with VDZ after developing active pulmonary TB during treatment with IFX. In cases that require recommencement of treatment with biologics after recovery of active pulmonary TB caused by anti-TNF agents, VDZ may be a good option even in pediatric IBD.
Fig. 1. Images of ileocolonoscopy at the diagnosis of Crohn disease. Multifocal aphthous ulcers are observed in the (A) terminal ileum and (B) colon.
Fig. 2. Images at the diagnosis of Crohn disease. (A) Upper gastrointestinal endoscopy shows multiple ulcers in the duodenum. (B) Magnetic resonance enterography shows multisegmental wall thickening in the ileum.
Fig. 3. Radiologic images at the diagnosis of active pulmonary tuberculosis during infliximab treatment. (A) Chest X-ray shows a marked amount of left pleural effusion. (B) Chest computed tomography shows left pleural effusion with mild pleural thickening and nodularities.
Fig. 4. Images of ileocolonoscopy before and after treatment with vedolizumab. (A) Multiple ulcers with mucosal friability are observed throughout the colon before treatment with vedolizumab. (B) Endoscopic healing is observed 1 year after treatment with vedolizumab.
Fig. 5. Fecal immunochemical test (FIT) and fecal calprotectin (FC) results during vedolizumab treatment.
Table 1. Crohn disease activity, laboratory results, and thickening and nodularities (arrow).
Week VDZ PCDAI CRP (mg/dL) ESR (mm/hr) Albumin (g/dL) VDZ TL (μg/mL) ATV (AU/mL)
0 #1 40.0 2.20 45 3.1
2 #2 12.5 0.04 47 4.1 25.25 1.91
6 #3 5.0 0.12 19 4.1 14.35 4.56
14 #4 0 0.05 15 4.1 3.36 1.76
22 #5 2.5 0.08 24 4.0 3.19 1.62
30 #6 0 0.02 16 4.2 3.59 2.06
38 #7 0 0.03 17 4.4 5.31 2.06
46 #8 2.5 0.09 33 4.5 5.18 1.76
54 #9 0 0.02 8 4.2 4.15 2.06
VDZ, vedolizumab; PCDAI, Pediatric Crohn’s Disease Activity Index; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; TL, trough level; ATV, antibody to VDZ.
Ethical statements
This study was approved by the Institutional Review Board (IRB) of Kyungpook National University Chilgok Hospital (IRB No: 2020-09-013). Informed consent was obtained from the patient and her parents.
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Funding
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2017R1C1B5076980).
Author contributions
Conceptualization, Formal analysis, Investigation: SC, BK; Data curation: All authors; Funding acquisition, Methodology, Resources, Software, Supervision, Validation: BK; Project administration, Visualization: SC; Writing-original draft: SC; Writing-review & editing: BSC, BHC, BK. | Recovered | ReactionOutcome | CC BY-NC | 33601494 | 19,625,958 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Angiocentric lymphoma'. | Chronic lymphocytic infiltration with pontine perivascular enhancement responsive to steroids (CLIPPERS) and its association with Epstein-Barr Virus (EBV)-related lymphomatoid granulomatosis: a case report.
BACKGROUND
Chronic lymphocytic infiltration with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a neuro-inflammatory syndrome first described in 2010. It has a relationship with lymphoproliferative disorders that has not been fully elucidated. This case represents an unusual progression of CLIPPERS to Epstein-Barr Virus (EBV)-related lymphomatoid granulomatosis (LYG). The exact connection between CLIPPERS and LYG remains poorly understood.
METHODS
We present a case of a 75-year-old man who was diagnosed with CLIPPERS with initial response to immunosuppression but later progressed to EBV-related LYG. EBV polymerase chain reaction (PCR) was detected in his cerebrospinal fluid (CSF), and repeat imaging revealed findings that were uncharacteristic for CLIPPERS; thereby prompting a brain biopsy which led to a diagnosis of EBV-related LYG. This case highlights the following learning points: 1) CLIPPERS cases are often part of a spectrum of lymphomatous disease, 2) CLIPPERS can be associated with EBV-related lymphoproliferative disorders such as LYG, and 3) EBV detection in CSF should prompt earlier consideration for brain biopsy in patients.
CONCLUSIONS
Our case highlights the difficulty in distinguishing CLIPPERS from other steroid-responsive conditions such as neoplastic and granulomatous diseases. Given the association of CLIPPERS with EBV-related LYG as demonstrated in this case, we recommend testing for EBV in CSF for all patients with suspected CLIPPERS. An early referral for brain biopsy and treatment with rituximab should be considered for patients with suspected CLIPPERS who test positive for EBV in their CSF.
Background
Chronic lymphocytic infiltration with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory central nervous system disorder first described in 2010 with a predilection for pontine involvement [1]. Since its description, increased awareness of this condition has led to more cases being diagnosed.
It remains unclear whether CLIPPERS represents a discrete disease entity or a spectrum of clinical conditions sharing a common neuroimmunological basis. We describe a case of a patient who initially presented with clinical and imaging features of CLIPPERS but later progressed to a diagnosis of Epstein-Barr virus (EBV) related-lymphomatoid granulomatosis (LYG). The exact association between CLIPPERS and LYG remains poorly understood.
Case presentation
A 75-year-old man presented with a 3-week history of progressive vertigo, ataxia, dysarthria, dysphagia and hiccups; on the background of a 3-month history of fatigue, anorexia and 8 kilograms of unintentional weight loss. He had no significant past medical history and there was no history of taking immunosuppressive agents.
On examination, his Glasgow Coma Scale (GCS) was 15. There was significant truncal ataxia, bulbar dysarthria and direction-changing gaze-evoked horizontal nystagmus. Power was normal in the limbs, but there was severe ataxia and brisk deep tendon reflexes in both upper limbs. Heel–shin coordination was preserved, and lower limb reflexes and plantar responses were normal. He had an Expanded Disability Status Scale (EDSS) score of 6.5.
Routine bloods were unremarkable. An infective screen including a tuberculosis interferon gamma release assay, and viral (hepatitis A/B/C, herpes simplex), schistosomal and strongyloides serology were all negative. Testing for human immunodeficiency virus which causes an immunocompromised state returned negative. Vasculitic, autoimmune and antineuronal antibody panels were also negative. Computed tomography (CT) of the brain was normal. A chest, abdomen and pelvis CT scan did not demonstrate any evidence of systemic malignancy. Cerebrospinal fluid (CSF) examination revealed elevated protein 0.76 g/L (0.15–0.40 g/L), glucose 4.6 mmol/L (2.5–4.5 mmol/L), 0 polymorphonuclear cells, 11 mononuclear cells, and 0 erythrocytes. Cytopathology revealed increased lymphocytes with no evidence of atypia. Flow cytometry was not possible due to low cell recovery. There were no bacteria seen; CSF culture was negative and Mycobacterium tuberculosis polymerase chain reaction (PCR) was negative. Matched oligoclonal immunoglobulin G (IgG) bands were detected in the CSF and serum. Magnetic resonance imaging (MRI) of the brain revealed diffuse signal change within the pons, cerebellar peduncles and pontomedullary junction with some mass effect, and characteristic punctate and linear enhancement typical for CLIPPERS (Fig. 1).
Fig. 1 MRI brain at initial presentation. a Axial T2-weighted image of the brainstem shows diffuse signal change within the pons and right middle cerebellar peduncle (arrow). b Axial T1-weighted post-contrast image showing punctate and linear areas of enhancement (arrows) in the pons and right cerebellar peduncle. c Sagittal T1-weighted post-contrast image shows patchy enhancement in the pons and pontomedullary junction
Treatment with high-dose intravenous methylprednisolone (1 g/day) for five days, followed by a tapered dose of oral prednisolone (down to 20 mg/day) and an introduction of oral mycophenolate mofetil (500 mg BD), resulted in marked clinical improvement including restoration of normal mobility. His EDSS score improved to 1. A follow-up MRI brain revealed corresponding radiological resolution (Fig. 2). No atypical imaging features as previously described by Taieb et al. in their series [2] were evident on the baseline presentation and follow-up MRI brain studies. A diagnosis of CLIPPERS was made in view of the clinical presentation, radiological findings and exquisite response to steroid treatment.
Fig. 2 Follow-up MRI brain 4 months post commencing treatment. a Axial and b sagittal T1-weighted post-contrast images showing normal appearance of the pons, cerebellar peduncles and pontomedullary junction with no residual enhancement
Nine months later, our patient presented with a GCS of 10 (E3 V2 M5) and dysphasia after a 1-week history of lethargy. On examination, he had bilateral sixth nerve palsies and hyperreflexia in both upper limbs. His EDSS score worsened to 7. A lumbar puncture revealed elevated protein 0.57 g/L (0.15–0.40 g/L), normal glucose, 6 mononuclear cells, 0 polymorphs and 66 erythrocytes. No blasts or malignant cells were present. Flow cytometry was not performed due to low cell counts. CSF herpes simplex and enterovirus PCR were negative. John Cunningham virus serology was also negative. Notably, EBV PCR was positive in the CSF, with negative plasma EBV PCR. Oligoclonal IgG bands were detected in both CSF and serum; however, there were additional bands detected only in the CSF which were consistent with intrathecal synthesis.
MRI of the brain revealed new peripherally enhancing lesions in the left frontal and parietal lobes (Fig. 3a-c). In addition, there were confluent T2 hyperintense changes in the bilateral periventricular white matter. Importantly, no new lesions were demonstrated in the pons or infratentorial compartment. These imaging findings are atypical for the progression of CLIPPERS and thus prompted a brain biopsy.
Fig. 3 a Axial T2-weighted and b axial T1-weighted post-contrast images show a new rim-enhancing mass with vasogenic oedema in the left parietal lobe (arrow) and c patchy cortical enhancement in the left cingulate gyrus (arrow). Post-treatment MRI brain d axial T2-weighted and e T1-weighted post-contrast images show decrease in vasogenic oedema and reduced enhancement in the left parietal lobe compatible with treatment response
Biopsy of the left parietal lesion showed an angiocentric infiltrate of epithelioid histiocytes, lymphocytes and large atypical lymphoid cells with large areas of necrosis. The large atypical lymphoid cells were B-cells (CD20+, PAX5+, Epstein-Barr Encoding Region In Situ Hybridisation +) and the lymphocytes were predominantly small T-cells (CD3+) (Fig. 4a-d). The features were those of lymphomatoid granulomatosis grade III.
Fig. 4 a High power magnification of angiocentric infiltrate of abnormal lymphoid cells and histiocytes in the brain, Haematoxylin and eosin. b High power magnification showing numbers of large B-cells with PAX5 immunohistochemistry. c Numbers of EBV+ large B-cells with Epstein-Barr Encoding Region In Situ Hybridisation (EBER ISH) on high power magnification. d Numerous small T-cells in the angiocentric infiltrate with CD3 immunohistochemistry
There was no evidence of any skin or pulmonary involvement of LYG. Our patient was enrolled in a treatment trial for lymphoma, and has since commenced treatment with ibrutinib, rituximab and EBV-specific cytotoxic T-cells (EBV-CTLs). He is tolerating his treatment well and has made significant clinical improvement. His GCS improved to 15 and he had an EDSS score of 2. His dysphasia has resolved and is fully independent with mobility. Similarly, his repeat MRI Brain six months post treatment also demonstrated a decrease in vasogenic oedema and reduced enhancement in the left parietal lobe compatible with treatment response (Fig. 3d-e).
Discussion and conclusions
LYG is a rare angiocentric and angiodestructive B-cell lymphoproliferative disorder characterised histologically by a predominance of reactive T-cells and fewer neoplastic EBV-positive B-cells [3]. LYG range from an indolent process with no B-cell atypia (grade I) to an aggressive B-cell lymphoma (grade III) [3].
The exact connection between CLIPPERS and LYG is poorly understood. Possibilities include:
CLIPPERS representing an early phase of LYG. Some of these cases progress due to T-cell dysfunction inherent in CLIPPERS, resulting in reduced T-cell immunosurveillance [4].
CLIPPERS reflecting a host immune response against a primary central nervous system lymphoma, which could then remit spontaneously or with steroid therapy. Transformation to LYG happens when the host immune response is suppressed [5].
LYG represents an EBV-associated lymphoproliferative disorder which is usually associated with an underlying immunodeficiency [6]. Therefore, immunosuppression used in the treatment of CLIPPERS may contribute to the pathogenesis of LYG.
The association of EBV with LYG suggests a transformative role of EBV in LYG pathogenesis [6]. LYG is hypothesised to result from a defective immune surveillance of EBV [7]. In two published cases of CLIPPERS to LYG, both patients had EBV-positive cells in the second brain biopsy four months and three months after the first brain biopsies that were negative for EBV [4, 8]. However, one of these patients had received high dose IV methylprednisolone prior to the first biopsy [8], which is known to partly treat high grade B-cell lymphoma of the CNS. The other patient [4] had cerebellum biopsied first and then a necrotic pontine lesion biopsied second. The short time interval between two biopsies suggests that prior treatment or sampling may have obscured underlying LYG. One of these patients had CLIPPERS red flags on the initial episode with the “brain on fire” changes on MRI in the corpus callosum [4] and the other only showed atypical CLIPPERS clinical signs of peripheral nerve facial palsy on the second episode [8]. Of the three patients reported by Taieb et al., with non-CLIPPERS with LYG [2], their cases 3 and 4 had non-CLIPPERS MRI findings in the first episode, whereas their case 10 had probable CLIPPERS until developing relapse with large pontine mass on 80 mg /day of prednisolone and LYG on brain biopsy at four months. Interestingly, Taieb et al’s case 4 had suffered an EBV-related macrophage activation syndrome one year prior to presentation with CLIPPERS [2]. The transformative role of EBV has also been highlighted in a recent case report which reflects latent EBV infection’s role in converting CLIPPERS to EBV-positive diffuse large B cell lymphoma especially in the setting of chronic immunosuppression [9].
In our case, our patient did not have a brain biopsy at initial presentation, nor EBV testing on the initial CSF sample. However, during his second presentation, EBV was detected by PCR of the CSF and by Epstein-Barr Encoding Region in situ hybridization in the brain biopsy. but was undetectable in plasma. The presence of EBV in CSF or brain biopsy samples should prompt a search for alternative diagnoses such as EBV-related lymphoproliferative diseases. This is important given the risk of transformation to lymphomatoid granulomatosis in EBV positive patients [6], especially in the setting of immunosuppression as treatment for CLIPPERS. We recommend testing for EBV in CSF for patients with suspected CLIPPERS; and in those patients who test positive for EBV in their CSF, an early referral for brain biopsy should be considered.
Given the rarity of CLIPPERS, there is a lack of randomised controlled treatment trials. The evidence for the use of various steroid regimens and steroid-sparing agents remain anecdotal. Rituximab has proven efficacy in maintaining remission in CLIPPERS [10], and in the treatment and prevention of EBV-related lymphoproliferative disorders [11]. Rituximab should therefore be considered as a steroid-sparing agent for the management of patients with CLIPPERS and EBV positivity at the outset.
Although various clinical, radiological and pathological characteristics have been proposed to aid the diagnosis of CLIPPERS [12], distinguishing CLIPPERS from other steroid-responsive conditions such as neoplastic and granulomatous diseases remains challenging [13]. Patients with CLIPPERS associated with lymphoma have a worse prognosis compared to those without lymphoma [14]. Therefore, early consideration of CLIPPERS associated lymphoproliferative disorders is important. Given the association of CLIPPERS with EBV-related LYG, as demonstrated in this case, we recommend testing for EBV in CSF for all patients with suspected CLIPPERS. An early referral for brain biopsy and treatment with rituximab should be considered for patients with suspected CLIPPERS who test positive for EBV in their CSF.
Abbreviations
CLIPPERSChronic lymphocytic infiltration with pontine perivascular enhancement responsive to steroids.
CSFCerebrospinal fluid
CTComputed tomography
EBVEpstein-Barr Virus
EDSSExpanded Disability Severity Scale
EBEREpstein-Barr Encoding Region
GCSGlasgow Coma Scale
IgGImmunoglobulin G
ISHIn situ hybridisation
LYGLymphomatoid granulomatosis
MRIMagnetic resonance imaging
PCRPolymerase chain reaction
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
None.
Authors’ contributions
YLD: study initiation, study conception, data collection, manuscript writing, manuscript revision. HKK: data collection, manuscript writing, manuscript revision. PM: manuscript writing, manuscript revision. ML: data collection, manuscript revision. LM: manuscript revision. DAB: data collection, manuscript revision. DEC: study conception, manuscript writing, manuscript revision. All authors have read and approved the manuscript.
Funding
None.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author upon request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained for publication.
Competing interests
None. | METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISOLONE | DrugsGivenReaction | CC BY | 33602163 | 19,840,581 | 2021-02-18 |
What was the administration route of drug 'PREDNISOLONE'? | Chronic lymphocytic infiltration with pontine perivascular enhancement responsive to steroids (CLIPPERS) and its association with Epstein-Barr Virus (EBV)-related lymphomatoid granulomatosis: a case report.
BACKGROUND
Chronic lymphocytic infiltration with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a neuro-inflammatory syndrome first described in 2010. It has a relationship with lymphoproliferative disorders that has not been fully elucidated. This case represents an unusual progression of CLIPPERS to Epstein-Barr Virus (EBV)-related lymphomatoid granulomatosis (LYG). The exact connection between CLIPPERS and LYG remains poorly understood.
METHODS
We present a case of a 75-year-old man who was diagnosed with CLIPPERS with initial response to immunosuppression but later progressed to EBV-related LYG. EBV polymerase chain reaction (PCR) was detected in his cerebrospinal fluid (CSF), and repeat imaging revealed findings that were uncharacteristic for CLIPPERS; thereby prompting a brain biopsy which led to a diagnosis of EBV-related LYG. This case highlights the following learning points: 1) CLIPPERS cases are often part of a spectrum of lymphomatous disease, 2) CLIPPERS can be associated with EBV-related lymphoproliferative disorders such as LYG, and 3) EBV detection in CSF should prompt earlier consideration for brain biopsy in patients.
CONCLUSIONS
Our case highlights the difficulty in distinguishing CLIPPERS from other steroid-responsive conditions such as neoplastic and granulomatous diseases. Given the association of CLIPPERS with EBV-related LYG as demonstrated in this case, we recommend testing for EBV in CSF for all patients with suspected CLIPPERS. An early referral for brain biopsy and treatment with rituximab should be considered for patients with suspected CLIPPERS who test positive for EBV in their CSF.
Background
Chronic lymphocytic infiltration with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory central nervous system disorder first described in 2010 with a predilection for pontine involvement [1]. Since its description, increased awareness of this condition has led to more cases being diagnosed.
It remains unclear whether CLIPPERS represents a discrete disease entity or a spectrum of clinical conditions sharing a common neuroimmunological basis. We describe a case of a patient who initially presented with clinical and imaging features of CLIPPERS but later progressed to a diagnosis of Epstein-Barr virus (EBV) related-lymphomatoid granulomatosis (LYG). The exact association between CLIPPERS and LYG remains poorly understood.
Case presentation
A 75-year-old man presented with a 3-week history of progressive vertigo, ataxia, dysarthria, dysphagia and hiccups; on the background of a 3-month history of fatigue, anorexia and 8 kilograms of unintentional weight loss. He had no significant past medical history and there was no history of taking immunosuppressive agents.
On examination, his Glasgow Coma Scale (GCS) was 15. There was significant truncal ataxia, bulbar dysarthria and direction-changing gaze-evoked horizontal nystagmus. Power was normal in the limbs, but there was severe ataxia and brisk deep tendon reflexes in both upper limbs. Heel–shin coordination was preserved, and lower limb reflexes and plantar responses were normal. He had an Expanded Disability Status Scale (EDSS) score of 6.5.
Routine bloods were unremarkable. An infective screen including a tuberculosis interferon gamma release assay, and viral (hepatitis A/B/C, herpes simplex), schistosomal and strongyloides serology were all negative. Testing for human immunodeficiency virus which causes an immunocompromised state returned negative. Vasculitic, autoimmune and antineuronal antibody panels were also negative. Computed tomography (CT) of the brain was normal. A chest, abdomen and pelvis CT scan did not demonstrate any evidence of systemic malignancy. Cerebrospinal fluid (CSF) examination revealed elevated protein 0.76 g/L (0.15–0.40 g/L), glucose 4.6 mmol/L (2.5–4.5 mmol/L), 0 polymorphonuclear cells, 11 mononuclear cells, and 0 erythrocytes. Cytopathology revealed increased lymphocytes with no evidence of atypia. Flow cytometry was not possible due to low cell recovery. There were no bacteria seen; CSF culture was negative and Mycobacterium tuberculosis polymerase chain reaction (PCR) was negative. Matched oligoclonal immunoglobulin G (IgG) bands were detected in the CSF and serum. Magnetic resonance imaging (MRI) of the brain revealed diffuse signal change within the pons, cerebellar peduncles and pontomedullary junction with some mass effect, and characteristic punctate and linear enhancement typical for CLIPPERS (Fig. 1).
Fig. 1 MRI brain at initial presentation. a Axial T2-weighted image of the brainstem shows diffuse signal change within the pons and right middle cerebellar peduncle (arrow). b Axial T1-weighted post-contrast image showing punctate and linear areas of enhancement (arrows) in the pons and right cerebellar peduncle. c Sagittal T1-weighted post-contrast image shows patchy enhancement in the pons and pontomedullary junction
Treatment with high-dose intravenous methylprednisolone (1 g/day) for five days, followed by a tapered dose of oral prednisolone (down to 20 mg/day) and an introduction of oral mycophenolate mofetil (500 mg BD), resulted in marked clinical improvement including restoration of normal mobility. His EDSS score improved to 1. A follow-up MRI brain revealed corresponding radiological resolution (Fig. 2). No atypical imaging features as previously described by Taieb et al. in their series [2] were evident on the baseline presentation and follow-up MRI brain studies. A diagnosis of CLIPPERS was made in view of the clinical presentation, radiological findings and exquisite response to steroid treatment.
Fig. 2 Follow-up MRI brain 4 months post commencing treatment. a Axial and b sagittal T1-weighted post-contrast images showing normal appearance of the pons, cerebellar peduncles and pontomedullary junction with no residual enhancement
Nine months later, our patient presented with a GCS of 10 (E3 V2 M5) and dysphasia after a 1-week history of lethargy. On examination, he had bilateral sixth nerve palsies and hyperreflexia in both upper limbs. His EDSS score worsened to 7. A lumbar puncture revealed elevated protein 0.57 g/L (0.15–0.40 g/L), normal glucose, 6 mononuclear cells, 0 polymorphs and 66 erythrocytes. No blasts or malignant cells were present. Flow cytometry was not performed due to low cell counts. CSF herpes simplex and enterovirus PCR were negative. John Cunningham virus serology was also negative. Notably, EBV PCR was positive in the CSF, with negative plasma EBV PCR. Oligoclonal IgG bands were detected in both CSF and serum; however, there were additional bands detected only in the CSF which were consistent with intrathecal synthesis.
MRI of the brain revealed new peripherally enhancing lesions in the left frontal and parietal lobes (Fig. 3a-c). In addition, there were confluent T2 hyperintense changes in the bilateral periventricular white matter. Importantly, no new lesions were demonstrated in the pons or infratentorial compartment. These imaging findings are atypical for the progression of CLIPPERS and thus prompted a brain biopsy.
Fig. 3 a Axial T2-weighted and b axial T1-weighted post-contrast images show a new rim-enhancing mass with vasogenic oedema in the left parietal lobe (arrow) and c patchy cortical enhancement in the left cingulate gyrus (arrow). Post-treatment MRI brain d axial T2-weighted and e T1-weighted post-contrast images show decrease in vasogenic oedema and reduced enhancement in the left parietal lobe compatible with treatment response
Biopsy of the left parietal lesion showed an angiocentric infiltrate of epithelioid histiocytes, lymphocytes and large atypical lymphoid cells with large areas of necrosis. The large atypical lymphoid cells were B-cells (CD20+, PAX5+, Epstein-Barr Encoding Region In Situ Hybridisation +) and the lymphocytes were predominantly small T-cells (CD3+) (Fig. 4a-d). The features were those of lymphomatoid granulomatosis grade III.
Fig. 4 a High power magnification of angiocentric infiltrate of abnormal lymphoid cells and histiocytes in the brain, Haematoxylin and eosin. b High power magnification showing numbers of large B-cells with PAX5 immunohistochemistry. c Numbers of EBV+ large B-cells with Epstein-Barr Encoding Region In Situ Hybridisation (EBER ISH) on high power magnification. d Numerous small T-cells in the angiocentric infiltrate with CD3 immunohistochemistry
There was no evidence of any skin or pulmonary involvement of LYG. Our patient was enrolled in a treatment trial for lymphoma, and has since commenced treatment with ibrutinib, rituximab and EBV-specific cytotoxic T-cells (EBV-CTLs). He is tolerating his treatment well and has made significant clinical improvement. His GCS improved to 15 and he had an EDSS score of 2. His dysphasia has resolved and is fully independent with mobility. Similarly, his repeat MRI Brain six months post treatment also demonstrated a decrease in vasogenic oedema and reduced enhancement in the left parietal lobe compatible with treatment response (Fig. 3d-e).
Discussion and conclusions
LYG is a rare angiocentric and angiodestructive B-cell lymphoproliferative disorder characterised histologically by a predominance of reactive T-cells and fewer neoplastic EBV-positive B-cells [3]. LYG range from an indolent process with no B-cell atypia (grade I) to an aggressive B-cell lymphoma (grade III) [3].
The exact connection between CLIPPERS and LYG is poorly understood. Possibilities include:
CLIPPERS representing an early phase of LYG. Some of these cases progress due to T-cell dysfunction inherent in CLIPPERS, resulting in reduced T-cell immunosurveillance [4].
CLIPPERS reflecting a host immune response against a primary central nervous system lymphoma, which could then remit spontaneously or with steroid therapy. Transformation to LYG happens when the host immune response is suppressed [5].
LYG represents an EBV-associated lymphoproliferative disorder which is usually associated with an underlying immunodeficiency [6]. Therefore, immunosuppression used in the treatment of CLIPPERS may contribute to the pathogenesis of LYG.
The association of EBV with LYG suggests a transformative role of EBV in LYG pathogenesis [6]. LYG is hypothesised to result from a defective immune surveillance of EBV [7]. In two published cases of CLIPPERS to LYG, both patients had EBV-positive cells in the second brain biopsy four months and three months after the first brain biopsies that were negative for EBV [4, 8]. However, one of these patients had received high dose IV methylprednisolone prior to the first biopsy [8], which is known to partly treat high grade B-cell lymphoma of the CNS. The other patient [4] had cerebellum biopsied first and then a necrotic pontine lesion biopsied second. The short time interval between two biopsies suggests that prior treatment or sampling may have obscured underlying LYG. One of these patients had CLIPPERS red flags on the initial episode with the “brain on fire” changes on MRI in the corpus callosum [4] and the other only showed atypical CLIPPERS clinical signs of peripheral nerve facial palsy on the second episode [8]. Of the three patients reported by Taieb et al., with non-CLIPPERS with LYG [2], their cases 3 and 4 had non-CLIPPERS MRI findings in the first episode, whereas their case 10 had probable CLIPPERS until developing relapse with large pontine mass on 80 mg /day of prednisolone and LYG on brain biopsy at four months. Interestingly, Taieb et al’s case 4 had suffered an EBV-related macrophage activation syndrome one year prior to presentation with CLIPPERS [2]. The transformative role of EBV has also been highlighted in a recent case report which reflects latent EBV infection’s role in converting CLIPPERS to EBV-positive diffuse large B cell lymphoma especially in the setting of chronic immunosuppression [9].
In our case, our patient did not have a brain biopsy at initial presentation, nor EBV testing on the initial CSF sample. However, during his second presentation, EBV was detected by PCR of the CSF and by Epstein-Barr Encoding Region in situ hybridization in the brain biopsy. but was undetectable in plasma. The presence of EBV in CSF or brain biopsy samples should prompt a search for alternative diagnoses such as EBV-related lymphoproliferative diseases. This is important given the risk of transformation to lymphomatoid granulomatosis in EBV positive patients [6], especially in the setting of immunosuppression as treatment for CLIPPERS. We recommend testing for EBV in CSF for patients with suspected CLIPPERS; and in those patients who test positive for EBV in their CSF, an early referral for brain biopsy should be considered.
Given the rarity of CLIPPERS, there is a lack of randomised controlled treatment trials. The evidence for the use of various steroid regimens and steroid-sparing agents remain anecdotal. Rituximab has proven efficacy in maintaining remission in CLIPPERS [10], and in the treatment and prevention of EBV-related lymphoproliferative disorders [11]. Rituximab should therefore be considered as a steroid-sparing agent for the management of patients with CLIPPERS and EBV positivity at the outset.
Although various clinical, radiological and pathological characteristics have been proposed to aid the diagnosis of CLIPPERS [12], distinguishing CLIPPERS from other steroid-responsive conditions such as neoplastic and granulomatous diseases remains challenging [13]. Patients with CLIPPERS associated with lymphoma have a worse prognosis compared to those without lymphoma [14]. Therefore, early consideration of CLIPPERS associated lymphoproliferative disorders is important. Given the association of CLIPPERS with EBV-related LYG, as demonstrated in this case, we recommend testing for EBV in CSF for all patients with suspected CLIPPERS. An early referral for brain biopsy and treatment with rituximab should be considered for patients with suspected CLIPPERS who test positive for EBV in their CSF.
Abbreviations
CLIPPERSChronic lymphocytic infiltration with pontine perivascular enhancement responsive to steroids.
CSFCerebrospinal fluid
CTComputed tomography
EBVEpstein-Barr Virus
EDSSExpanded Disability Severity Scale
EBEREpstein-Barr Encoding Region
GCSGlasgow Coma Scale
IgGImmunoglobulin G
ISHIn situ hybridisation
LYGLymphomatoid granulomatosis
MRIMagnetic resonance imaging
PCRPolymerase chain reaction
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
None.
Authors’ contributions
YLD: study initiation, study conception, data collection, manuscript writing, manuscript revision. HKK: data collection, manuscript writing, manuscript revision. PM: manuscript writing, manuscript revision. ML: data collection, manuscript revision. LM: manuscript revision. DAB: data collection, manuscript revision. DEC: study conception, manuscript writing, manuscript revision. All authors have read and approved the manuscript.
Funding
None.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author upon request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained for publication.
Competing interests
None. | Oral | DrugAdministrationRoute | CC BY | 33602163 | 19,840,581 | 2021-02-18 |
What was the dosage of drug 'PREDNISOLONE'? | Chronic lymphocytic infiltration with pontine perivascular enhancement responsive to steroids (CLIPPERS) and its association with Epstein-Barr Virus (EBV)-related lymphomatoid granulomatosis: a case report.
BACKGROUND
Chronic lymphocytic infiltration with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a neuro-inflammatory syndrome first described in 2010. It has a relationship with lymphoproliferative disorders that has not been fully elucidated. This case represents an unusual progression of CLIPPERS to Epstein-Barr Virus (EBV)-related lymphomatoid granulomatosis (LYG). The exact connection between CLIPPERS and LYG remains poorly understood.
METHODS
We present a case of a 75-year-old man who was diagnosed with CLIPPERS with initial response to immunosuppression but later progressed to EBV-related LYG. EBV polymerase chain reaction (PCR) was detected in his cerebrospinal fluid (CSF), and repeat imaging revealed findings that were uncharacteristic for CLIPPERS; thereby prompting a brain biopsy which led to a diagnosis of EBV-related LYG. This case highlights the following learning points: 1) CLIPPERS cases are often part of a spectrum of lymphomatous disease, 2) CLIPPERS can be associated with EBV-related lymphoproliferative disorders such as LYG, and 3) EBV detection in CSF should prompt earlier consideration for brain biopsy in patients.
CONCLUSIONS
Our case highlights the difficulty in distinguishing CLIPPERS from other steroid-responsive conditions such as neoplastic and granulomatous diseases. Given the association of CLIPPERS with EBV-related LYG as demonstrated in this case, we recommend testing for EBV in CSF for all patients with suspected CLIPPERS. An early referral for brain biopsy and treatment with rituximab should be considered for patients with suspected CLIPPERS who test positive for EBV in their CSF.
Background
Chronic lymphocytic infiltration with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory central nervous system disorder first described in 2010 with a predilection for pontine involvement [1]. Since its description, increased awareness of this condition has led to more cases being diagnosed.
It remains unclear whether CLIPPERS represents a discrete disease entity or a spectrum of clinical conditions sharing a common neuroimmunological basis. We describe a case of a patient who initially presented with clinical and imaging features of CLIPPERS but later progressed to a diagnosis of Epstein-Barr virus (EBV) related-lymphomatoid granulomatosis (LYG). The exact association between CLIPPERS and LYG remains poorly understood.
Case presentation
A 75-year-old man presented with a 3-week history of progressive vertigo, ataxia, dysarthria, dysphagia and hiccups; on the background of a 3-month history of fatigue, anorexia and 8 kilograms of unintentional weight loss. He had no significant past medical history and there was no history of taking immunosuppressive agents.
On examination, his Glasgow Coma Scale (GCS) was 15. There was significant truncal ataxia, bulbar dysarthria and direction-changing gaze-evoked horizontal nystagmus. Power was normal in the limbs, but there was severe ataxia and brisk deep tendon reflexes in both upper limbs. Heel–shin coordination was preserved, and lower limb reflexes and plantar responses were normal. He had an Expanded Disability Status Scale (EDSS) score of 6.5.
Routine bloods were unremarkable. An infective screen including a tuberculosis interferon gamma release assay, and viral (hepatitis A/B/C, herpes simplex), schistosomal and strongyloides serology were all negative. Testing for human immunodeficiency virus which causes an immunocompromised state returned negative. Vasculitic, autoimmune and antineuronal antibody panels were also negative. Computed tomography (CT) of the brain was normal. A chest, abdomen and pelvis CT scan did not demonstrate any evidence of systemic malignancy. Cerebrospinal fluid (CSF) examination revealed elevated protein 0.76 g/L (0.15–0.40 g/L), glucose 4.6 mmol/L (2.5–4.5 mmol/L), 0 polymorphonuclear cells, 11 mononuclear cells, and 0 erythrocytes. Cytopathology revealed increased lymphocytes with no evidence of atypia. Flow cytometry was not possible due to low cell recovery. There were no bacteria seen; CSF culture was negative and Mycobacterium tuberculosis polymerase chain reaction (PCR) was negative. Matched oligoclonal immunoglobulin G (IgG) bands were detected in the CSF and serum. Magnetic resonance imaging (MRI) of the brain revealed diffuse signal change within the pons, cerebellar peduncles and pontomedullary junction with some mass effect, and characteristic punctate and linear enhancement typical for CLIPPERS (Fig. 1).
Fig. 1 MRI brain at initial presentation. a Axial T2-weighted image of the brainstem shows diffuse signal change within the pons and right middle cerebellar peduncle (arrow). b Axial T1-weighted post-contrast image showing punctate and linear areas of enhancement (arrows) in the pons and right cerebellar peduncle. c Sagittal T1-weighted post-contrast image shows patchy enhancement in the pons and pontomedullary junction
Treatment with high-dose intravenous methylprednisolone (1 g/day) for five days, followed by a tapered dose of oral prednisolone (down to 20 mg/day) and an introduction of oral mycophenolate mofetil (500 mg BD), resulted in marked clinical improvement including restoration of normal mobility. His EDSS score improved to 1. A follow-up MRI brain revealed corresponding radiological resolution (Fig. 2). No atypical imaging features as previously described by Taieb et al. in their series [2] were evident on the baseline presentation and follow-up MRI brain studies. A diagnosis of CLIPPERS was made in view of the clinical presentation, radiological findings and exquisite response to steroid treatment.
Fig. 2 Follow-up MRI brain 4 months post commencing treatment. a Axial and b sagittal T1-weighted post-contrast images showing normal appearance of the pons, cerebellar peduncles and pontomedullary junction with no residual enhancement
Nine months later, our patient presented with a GCS of 10 (E3 V2 M5) and dysphasia after a 1-week history of lethargy. On examination, he had bilateral sixth nerve palsies and hyperreflexia in both upper limbs. His EDSS score worsened to 7. A lumbar puncture revealed elevated protein 0.57 g/L (0.15–0.40 g/L), normal glucose, 6 mononuclear cells, 0 polymorphs and 66 erythrocytes. No blasts or malignant cells were present. Flow cytometry was not performed due to low cell counts. CSF herpes simplex and enterovirus PCR were negative. John Cunningham virus serology was also negative. Notably, EBV PCR was positive in the CSF, with negative plasma EBV PCR. Oligoclonal IgG bands were detected in both CSF and serum; however, there were additional bands detected only in the CSF which were consistent with intrathecal synthesis.
MRI of the brain revealed new peripherally enhancing lesions in the left frontal and parietal lobes (Fig. 3a-c). In addition, there were confluent T2 hyperintense changes in the bilateral periventricular white matter. Importantly, no new lesions were demonstrated in the pons or infratentorial compartment. These imaging findings are atypical for the progression of CLIPPERS and thus prompted a brain biopsy.
Fig. 3 a Axial T2-weighted and b axial T1-weighted post-contrast images show a new rim-enhancing mass with vasogenic oedema in the left parietal lobe (arrow) and c patchy cortical enhancement in the left cingulate gyrus (arrow). Post-treatment MRI brain d axial T2-weighted and e T1-weighted post-contrast images show decrease in vasogenic oedema and reduced enhancement in the left parietal lobe compatible with treatment response
Biopsy of the left parietal lesion showed an angiocentric infiltrate of epithelioid histiocytes, lymphocytes and large atypical lymphoid cells with large areas of necrosis. The large atypical lymphoid cells were B-cells (CD20+, PAX5+, Epstein-Barr Encoding Region In Situ Hybridisation +) and the lymphocytes were predominantly small T-cells (CD3+) (Fig. 4a-d). The features were those of lymphomatoid granulomatosis grade III.
Fig. 4 a High power magnification of angiocentric infiltrate of abnormal lymphoid cells and histiocytes in the brain, Haematoxylin and eosin. b High power magnification showing numbers of large B-cells with PAX5 immunohistochemistry. c Numbers of EBV+ large B-cells with Epstein-Barr Encoding Region In Situ Hybridisation (EBER ISH) on high power magnification. d Numerous small T-cells in the angiocentric infiltrate with CD3 immunohistochemistry
There was no evidence of any skin or pulmonary involvement of LYG. Our patient was enrolled in a treatment trial for lymphoma, and has since commenced treatment with ibrutinib, rituximab and EBV-specific cytotoxic T-cells (EBV-CTLs). He is tolerating his treatment well and has made significant clinical improvement. His GCS improved to 15 and he had an EDSS score of 2. His dysphasia has resolved and is fully independent with mobility. Similarly, his repeat MRI Brain six months post treatment also demonstrated a decrease in vasogenic oedema and reduced enhancement in the left parietal lobe compatible with treatment response (Fig. 3d-e).
Discussion and conclusions
LYG is a rare angiocentric and angiodestructive B-cell lymphoproliferative disorder characterised histologically by a predominance of reactive T-cells and fewer neoplastic EBV-positive B-cells [3]. LYG range from an indolent process with no B-cell atypia (grade I) to an aggressive B-cell lymphoma (grade III) [3].
The exact connection between CLIPPERS and LYG is poorly understood. Possibilities include:
CLIPPERS representing an early phase of LYG. Some of these cases progress due to T-cell dysfunction inherent in CLIPPERS, resulting in reduced T-cell immunosurveillance [4].
CLIPPERS reflecting a host immune response against a primary central nervous system lymphoma, which could then remit spontaneously or with steroid therapy. Transformation to LYG happens when the host immune response is suppressed [5].
LYG represents an EBV-associated lymphoproliferative disorder which is usually associated with an underlying immunodeficiency [6]. Therefore, immunosuppression used in the treatment of CLIPPERS may contribute to the pathogenesis of LYG.
The association of EBV with LYG suggests a transformative role of EBV in LYG pathogenesis [6]. LYG is hypothesised to result from a defective immune surveillance of EBV [7]. In two published cases of CLIPPERS to LYG, both patients had EBV-positive cells in the second brain biopsy four months and three months after the first brain biopsies that were negative for EBV [4, 8]. However, one of these patients had received high dose IV methylprednisolone prior to the first biopsy [8], which is known to partly treat high grade B-cell lymphoma of the CNS. The other patient [4] had cerebellum biopsied first and then a necrotic pontine lesion biopsied second. The short time interval between two biopsies suggests that prior treatment or sampling may have obscured underlying LYG. One of these patients had CLIPPERS red flags on the initial episode with the “brain on fire” changes on MRI in the corpus callosum [4] and the other only showed atypical CLIPPERS clinical signs of peripheral nerve facial palsy on the second episode [8]. Of the three patients reported by Taieb et al., with non-CLIPPERS with LYG [2], their cases 3 and 4 had non-CLIPPERS MRI findings in the first episode, whereas their case 10 had probable CLIPPERS until developing relapse with large pontine mass on 80 mg /day of prednisolone and LYG on brain biopsy at four months. Interestingly, Taieb et al’s case 4 had suffered an EBV-related macrophage activation syndrome one year prior to presentation with CLIPPERS [2]. The transformative role of EBV has also been highlighted in a recent case report which reflects latent EBV infection’s role in converting CLIPPERS to EBV-positive diffuse large B cell lymphoma especially in the setting of chronic immunosuppression [9].
In our case, our patient did not have a brain biopsy at initial presentation, nor EBV testing on the initial CSF sample. However, during his second presentation, EBV was detected by PCR of the CSF and by Epstein-Barr Encoding Region in situ hybridization in the brain biopsy. but was undetectable in plasma. The presence of EBV in CSF or brain biopsy samples should prompt a search for alternative diagnoses such as EBV-related lymphoproliferative diseases. This is important given the risk of transformation to lymphomatoid granulomatosis in EBV positive patients [6], especially in the setting of immunosuppression as treatment for CLIPPERS. We recommend testing for EBV in CSF for patients with suspected CLIPPERS; and in those patients who test positive for EBV in their CSF, an early referral for brain biopsy should be considered.
Given the rarity of CLIPPERS, there is a lack of randomised controlled treatment trials. The evidence for the use of various steroid regimens and steroid-sparing agents remain anecdotal. Rituximab has proven efficacy in maintaining remission in CLIPPERS [10], and in the treatment and prevention of EBV-related lymphoproliferative disorders [11]. Rituximab should therefore be considered as a steroid-sparing agent for the management of patients with CLIPPERS and EBV positivity at the outset.
Although various clinical, radiological and pathological characteristics have been proposed to aid the diagnosis of CLIPPERS [12], distinguishing CLIPPERS from other steroid-responsive conditions such as neoplastic and granulomatous diseases remains challenging [13]. Patients with CLIPPERS associated with lymphoma have a worse prognosis compared to those without lymphoma [14]. Therefore, early consideration of CLIPPERS associated lymphoproliferative disorders is important. Given the association of CLIPPERS with EBV-related LYG, as demonstrated in this case, we recommend testing for EBV in CSF for all patients with suspected CLIPPERS. An early referral for brain biopsy and treatment with rituximab should be considered for patients with suspected CLIPPERS who test positive for EBV in their CSF.
Abbreviations
CLIPPERSChronic lymphocytic infiltration with pontine perivascular enhancement responsive to steroids.
CSFCerebrospinal fluid
CTComputed tomography
EBVEpstein-Barr Virus
EDSSExpanded Disability Severity Scale
EBEREpstein-Barr Encoding Region
GCSGlasgow Coma Scale
IgGImmunoglobulin G
ISHIn situ hybridisation
LYGLymphomatoid granulomatosis
MRIMagnetic resonance imaging
PCRPolymerase chain reaction
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
None.
Authors’ contributions
YLD: study initiation, study conception, data collection, manuscript writing, manuscript revision. HKK: data collection, manuscript writing, manuscript revision. PM: manuscript writing, manuscript revision. ML: data collection, manuscript revision. LM: manuscript revision. DAB: data collection, manuscript revision. DEC: study conception, manuscript writing, manuscript revision. All authors have read and approved the manuscript.
Funding
None.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author upon request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained for publication.
Competing interests
None. | DOWN TO 20 MG/DAY | DrugDosageText | CC BY | 33602163 | 19,840,581 | 2021-02-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood creatine phosphokinase increased'. | Catatonia associated with late-life psychosis successfully treated with lithium: a case report.
BACKGROUND
Catatonia is a psychomotor syndrome that presents various symptoms ranging from stupor to agitation, with prominent disturbances of volition. Its pathogenesis is poorly understood. Benzodiazepines and electroconvulsive therapy (ECT) are safe and effective standard treatments for catatonia; however, alternative treatment strategies have not been established in cases where these treatments are either ineffective or unavailable. Here, we report a case of catatonia associated with late-life psychosis, which was successfully treated with lithium.
METHODS
A 66-year-old single man with hearing impairment developed hallucination and delusions and presented with catatonic stupor after a fall. He initially responded to benzodiazepine therapy; however, his psychotic symptoms became clinically evident and benzodiazepine provided limited efficacy. Blonanserin was ineffective, and ECT was unavailable. His catatonic and psychotic symptoms were finally relieved by lithium monotherapy.
CONCLUSIONS
Catatonic symptoms are common in patients with mood disorders, suggesting that lithium may be effective in these cases. Moreover, lithium may be effective for both catatonic and psychotic symptoms, as it normalizes imbalances of excitatory and inhibitory systems in the brain, which underlies major psychosis. Cumulative evidence from further cases is needed to validate our findings.
Background
Catatonia is a psychomotor syndrome that presents various symptoms ranging from stupor to agitation, with prominent disturbances of volition; its pathogenesis is poorly understood [1]. Catatonia was once recognized as a subtype of schizophrenia; however, the Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) removed it from all schizophrenia subtypes, and defined it as a specifier of various psychiatric disorders or medical conditions [2]. Indeed, catatonia has been reported to be associated with a variety of medical conditions [3, 4]. Moreover, a previous study has reported that catatonic symptoms were more common in patients with manic or mixed episodes (28–31%) than in those with schizophrenia (10–15%) [5]. A prospective cohort study has also reported the incidence of catatonia to be only 7.6% in patients with schizophrenia [6].
Benzodiazepines and electroconvulsive therapy (ECT) are safe and effective standard treatments for catatonia, particularly in acute cases; however, benzodiazepines show limited efficacy in a considerable number of patients [7], and available facilities for ECT are limited. In cases where benzodiazepines are ineffective and ECT is unavailable, a systematic review of alternative treatment strategies proposed glutamate antagonists, antiepileptic drugs, and atypical antipsychotics as first-, second-, and third-line treatments for catatonia, respectively [8]. The proper alternative treatment of catatonia may differ depending on the underlying disease; however, as its pathogenesis is unclear, the pharmacological action of each drug is therefore unknown.
Here, we report a case of catatonia associated with late-life psychosis that was successfully treated with lithium.
Case presentation
The patient was a 66-year-old single man, who worked for a cleaning company, and had hearing impairment; however, there was no evident medical history of psychiatric disorders. He was found lying in front of his apartment and was sent to the emergency room. A physical examination revealed fracture of the left patella and calcaneus, which appeared to be related to trauma. He kept his eyes closed for most of the day and demonstrated no spontaneous speech or reaction. Although his blood tests showed inflammatory reaction, his vital signs were normal, and computed tomography and electroencephalography of his brain showed no significant findings. He had no relatives and there was no life history information of him. According to the information of the neighboring residents, he had exhibited strange behaviors since about 2 months before admission and often annoyed the neighbors. Before his arrival to the emergency department, a neighbor called the police because the patient had stood in front of his apartment for a long time. While in detention, he did not respond to the police interrogations at all; he was found lying in front of his apartment a few hours after police released him. After admission to the emergency department, he was consulted with our department for the assessment of psychotic symptoms by his physician. Including the process leading to hospitalization, he was diagnosed with catatonia based on the presence of stupor, mutism, and negativism which was detected from the information by the police about the patients’ uncooperative behavior during detention. He was started on intravenous administration of 5 mg/day midazolam, which was switched to lorazepam, administered through a feeding tube. He then gradually opened his eyes and started speaking. He stated that “someone was trying to kill me, so I jumped to escape. I don’t want to talk about anything because I am being seen and heard by someone.” He was, therefore, suspected to have hallucinations and delusions. He subsequently developed fever, and the blood tests showed an inflammatory reaction with creatine kinase (CK) elevation; antibiotics were accordingly administered for infection at the injury site. The dose of lorazepam was tapered to 2 mg/day because he developed delirium; after normalization of CK levels, a blonanserin patch at a dose of 20 mg/day was added for his underlying psychotic symptoms. His delirium improved, and he was able to eat by himself; however, he spent more time lying down with his eyes closed. Considering the possibility of oversedation, lorazepam was tapered to a dose of 1 mg/day. Since he appeared to have improved slightly, the dose of blonanserin patch was increased to 40 mg/day, and lorazepam was terminated. However, he spent most of his time in bed, and eating became difficult. Although he was a suitable candidate for ECT, it was unavailable in our facility. We tried to transfer the facility where ECT was available; however, it was full. Lithium was, therefore, added, and blonanserin patch was terminated; he opened his eyes and began to move after the dose of lithium was increased to 400 mg/day, and he began to eat and talk. He said that “I have always been able to hear hallucinations, but now I cannot. I want to recover from the injury and go home immediately.” Although the dose of lithium was temporarily increased to 600 mg/day, the dose of 400 mg/day was maintained after obtaining informed consent, based on the blood concentration results (Fig. 1). He mentioned that he had graduated from high school and had no history of alcohol or drug abuse. At age 60, he moved to his present apartment after changing jobs, and had developed hallucinations approximately a year before hospitalization. On examination, his mini-mental state examination (MMSE) score was 26; some points were lost on 3-step command (minus 2) and delayed recall (minus 2) tasks, suggesting that there was no remarkable cognitive dysfunction. He was, therefore, transferred to a rehabilitation facility.Fig. 1 Clinical course of a case of catatonia associated with late paraphrenia. A 66-year-old man with catatonic stupor initially responded to benzodiazepine therapy, and his psychotic symptoms became clinically evident because he stated that “someone was trying to kill me, so I jumped to escape. I don’t want to talk about anything because I am being seen and heard by someone.” He subsequently developed delirium with fever and creatine kinase (CK) level elevation and the dose of lorazepam was tapered to 2 mg/day. After normalization of CK levels, a blonanserin patch at a dose of 20 mg/day was added for his underlying psychotic symptoms. The dose of the blonanserin patch was increased to 40 mg/day, and lorazepam was terminated; however, it was not effective. Although he was a suitable candidate for ECT, it was unavailable in our facility. Lithium was, therefore, added, and the blonanserin patch was terminated; his catatonic and psychotic symptoms were finally relieved by lithium monotherapy. He said that “I have always been able to hear hallucinations, but now I cannot. I want to recover from the injury and go home immediately.” Although the dose of lithium was temporarily increased to 600 mg/day (0.86 mEq/ml), the dose of 400 mg/day (0.50 mEq/ml) was maintained after obtaining informed consent, based on the blood concentration results. Li blood concentration of lithium, CK creatine kinase
Discussion and conclusions
This report describes the case of a single elderly man with hearing impairment, who developed hallucination and delusions and presented with catatonia at the last minute before his fall. There were no remarkable brain organic abnormalities which possibly cause catatonic symptoms, suggesting that his psychotic and catatonic symptoms were not derived from either trauma or drugs used after admission. His premorbid social function was almost normal enough to work for cleaning company, and the results of cognitive function tests performed after his psychiatric symptoms improved showed that he did not have remarkable neurocognitive impairment leading to social dysfunction. He had sensory deficit, which is common in late paraphrenia [9], and developed psychotic symptoms after 60 years of age without any evident history of psychiatric disorders. This suggested that his catatonia occurred because of late-life psychosis called as late paraphrenia, which has been recognized to be independent of schizophrenia [10]. Although the patient showed no remarkable cognitive dysfunction in MMSE, we could not rule out the possibility of neurocognitive deficit of the patient because there was no other neurocognitive examination of the patient to assess cognitive impairment. A previous review of paraphrenia has reported that the pathology of paraphrenia is similar to that of the neurofibrillary tangles, which are the predominant form of senile dementia [11]. His psychotic episode could have represented the prodromal symptoms of dementia; he therefore needs to be followed up closely for the progressive of cognitive dysfunction in the future.
The patient had initially responded to benzodiazepine therapy, and his psychotic symptoms became clinically evident; however, its efficacy was limited. Some patients with catatonia fail to respond to benzodiazepines, with approximately 30% of patients showing only partial response [12, 13]; in particular, cases that occur secondary to schizophrenia have been reported to be less likely to respond to benzodiazepines [14, 15]. Moreover, benzodiazepine use is not suitable for elderly patients, considering the risk of delirium. Atypical antipsychotics have been recommended as one of the alternative treatment strategies for catatonia [8]; however, blonanserin did not improve his catatonia. Finally, both his catatonic and psychotic symptoms were completely resolved by lithium monotherapy. Catatonic symptoms are more common in patients with mood disorders than in those with schizophrenia [5], suggesting that lithium may be effective for catatonia. Although previous case reports advocate the effectiveness of lithium in preventing recurrence of catatonia [16, 17], there is no evidence of its effectiveness in the acute phase.
Although the pathogenesis of catatonia remains poorly understood, the neurochemical hypothesis suggests that alterations in various neurotransmission systems, including gamma-aminobutyric acid (GABA) and glutamate, play a role [18, 19]. Even if the effects of benzodiazepines on the GABA system in the brain are limited, ECT has a high response rate, suggesting that catatonia may be the final common outcome for abnormal brain seizure activity [20]. In the present case, antiepileptic drugs which are candidates of the alternative treatment strategies for catatonia [8] were not administrated due to no remarkable abnormalities of electroencephalography. Finally, lithium was used because the effect of benzodiazepine was limited and ECT was unavailable. A previous study, using induced pluripotent stem cells (iPSCs) derived from neuronal cells of patients with bipolar disorders, has reported that the hyperexcitability phenotype of young neurons was selectively reversed by lithium only in lithium responders [21]. Moreover, a recent study using iPSCs derived from monozygotic twins discordant for major psychosis has suggested that lithium may normalize unbalanced specification of excitatory and inhibitory neurons in major psychosis neural circuits, by activating the Wnt signaling pathway [22]. In the present case of catatonia associated with late-life psychosis, lithium, although not as fast-acting as ECT, was effective for both catatonic and psychotic symptoms, as it normalized unbalanced specification of excitatory and inhibitory systems in the brain.
To the best of our knowledge, this is the first report on the efficacy of lithium in the acute phase of catatonia. There was a previous report of lithium therapy for catatonia features in autism spectrum disorder patients [23] and the another reported the case of catatonia cause by lithium overdose [24], suggesting that the action and effects of lithium on neurons numerous and diverse. Future studies are needed to elucidate the pathogenesis of catatonia to identify the most reliable treatment.
Abbreviations
ECTElectroconvulsive therapy
iPSCsInduced pluripotent stem cells
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank to all staff involved in the medical care of this patient.
Authors’ contributions
HS and JT were involved in the management of the patient. This case report was written by HS. MH and MI revised the manuscript. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
The data used for this case report is available from the corresponding authors on reasonable request.
Ethics approval and consent to participate
Ethics committee in Kansai Rosai Hospital approved for the publication of this case report.
Consent for publication
Written informed consent has been obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests. This edit was made to conform to the format of the journal guidelines. | BLONANSERIN, LITHIUM, LORAZEPAM, MIDAZOLAM | DrugsGivenReaction | CC BY | 33602282 | 19,733,655 | 2021-02-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Delirium'. | Catatonia associated with late-life psychosis successfully treated with lithium: a case report.
BACKGROUND
Catatonia is a psychomotor syndrome that presents various symptoms ranging from stupor to agitation, with prominent disturbances of volition. Its pathogenesis is poorly understood. Benzodiazepines and electroconvulsive therapy (ECT) are safe and effective standard treatments for catatonia; however, alternative treatment strategies have not been established in cases where these treatments are either ineffective or unavailable. Here, we report a case of catatonia associated with late-life psychosis, which was successfully treated with lithium.
METHODS
A 66-year-old single man with hearing impairment developed hallucination and delusions and presented with catatonic stupor after a fall. He initially responded to benzodiazepine therapy; however, his psychotic symptoms became clinically evident and benzodiazepine provided limited efficacy. Blonanserin was ineffective, and ECT was unavailable. His catatonic and psychotic symptoms were finally relieved by lithium monotherapy.
CONCLUSIONS
Catatonic symptoms are common in patients with mood disorders, suggesting that lithium may be effective in these cases. Moreover, lithium may be effective for both catatonic and psychotic symptoms, as it normalizes imbalances of excitatory and inhibitory systems in the brain, which underlies major psychosis. Cumulative evidence from further cases is needed to validate our findings.
Background
Catatonia is a psychomotor syndrome that presents various symptoms ranging from stupor to agitation, with prominent disturbances of volition; its pathogenesis is poorly understood [1]. Catatonia was once recognized as a subtype of schizophrenia; however, the Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) removed it from all schizophrenia subtypes, and defined it as a specifier of various psychiatric disorders or medical conditions [2]. Indeed, catatonia has been reported to be associated with a variety of medical conditions [3, 4]. Moreover, a previous study has reported that catatonic symptoms were more common in patients with manic or mixed episodes (28–31%) than in those with schizophrenia (10–15%) [5]. A prospective cohort study has also reported the incidence of catatonia to be only 7.6% in patients with schizophrenia [6].
Benzodiazepines and electroconvulsive therapy (ECT) are safe and effective standard treatments for catatonia, particularly in acute cases; however, benzodiazepines show limited efficacy in a considerable number of patients [7], and available facilities for ECT are limited. In cases where benzodiazepines are ineffective and ECT is unavailable, a systematic review of alternative treatment strategies proposed glutamate antagonists, antiepileptic drugs, and atypical antipsychotics as first-, second-, and third-line treatments for catatonia, respectively [8]. The proper alternative treatment of catatonia may differ depending on the underlying disease; however, as its pathogenesis is unclear, the pharmacological action of each drug is therefore unknown.
Here, we report a case of catatonia associated with late-life psychosis that was successfully treated with lithium.
Case presentation
The patient was a 66-year-old single man, who worked for a cleaning company, and had hearing impairment; however, there was no evident medical history of psychiatric disorders. He was found lying in front of his apartment and was sent to the emergency room. A physical examination revealed fracture of the left patella and calcaneus, which appeared to be related to trauma. He kept his eyes closed for most of the day and demonstrated no spontaneous speech or reaction. Although his blood tests showed inflammatory reaction, his vital signs were normal, and computed tomography and electroencephalography of his brain showed no significant findings. He had no relatives and there was no life history information of him. According to the information of the neighboring residents, he had exhibited strange behaviors since about 2 months before admission and often annoyed the neighbors. Before his arrival to the emergency department, a neighbor called the police because the patient had stood in front of his apartment for a long time. While in detention, he did not respond to the police interrogations at all; he was found lying in front of his apartment a few hours after police released him. After admission to the emergency department, he was consulted with our department for the assessment of psychotic symptoms by his physician. Including the process leading to hospitalization, he was diagnosed with catatonia based on the presence of stupor, mutism, and negativism which was detected from the information by the police about the patients’ uncooperative behavior during detention. He was started on intravenous administration of 5 mg/day midazolam, which was switched to lorazepam, administered through a feeding tube. He then gradually opened his eyes and started speaking. He stated that “someone was trying to kill me, so I jumped to escape. I don’t want to talk about anything because I am being seen and heard by someone.” He was, therefore, suspected to have hallucinations and delusions. He subsequently developed fever, and the blood tests showed an inflammatory reaction with creatine kinase (CK) elevation; antibiotics were accordingly administered for infection at the injury site. The dose of lorazepam was tapered to 2 mg/day because he developed delirium; after normalization of CK levels, a blonanserin patch at a dose of 20 mg/day was added for his underlying psychotic symptoms. His delirium improved, and he was able to eat by himself; however, he spent more time lying down with his eyes closed. Considering the possibility of oversedation, lorazepam was tapered to a dose of 1 mg/day. Since he appeared to have improved slightly, the dose of blonanserin patch was increased to 40 mg/day, and lorazepam was terminated. However, he spent most of his time in bed, and eating became difficult. Although he was a suitable candidate for ECT, it was unavailable in our facility. We tried to transfer the facility where ECT was available; however, it was full. Lithium was, therefore, added, and blonanserin patch was terminated; he opened his eyes and began to move after the dose of lithium was increased to 400 mg/day, and he began to eat and talk. He said that “I have always been able to hear hallucinations, but now I cannot. I want to recover from the injury and go home immediately.” Although the dose of lithium was temporarily increased to 600 mg/day, the dose of 400 mg/day was maintained after obtaining informed consent, based on the blood concentration results (Fig. 1). He mentioned that he had graduated from high school and had no history of alcohol or drug abuse. At age 60, he moved to his present apartment after changing jobs, and had developed hallucinations approximately a year before hospitalization. On examination, his mini-mental state examination (MMSE) score was 26; some points were lost on 3-step command (minus 2) and delayed recall (minus 2) tasks, suggesting that there was no remarkable cognitive dysfunction. He was, therefore, transferred to a rehabilitation facility.Fig. 1 Clinical course of a case of catatonia associated with late paraphrenia. A 66-year-old man with catatonic stupor initially responded to benzodiazepine therapy, and his psychotic symptoms became clinically evident because he stated that “someone was trying to kill me, so I jumped to escape. I don’t want to talk about anything because I am being seen and heard by someone.” He subsequently developed delirium with fever and creatine kinase (CK) level elevation and the dose of lorazepam was tapered to 2 mg/day. After normalization of CK levels, a blonanserin patch at a dose of 20 mg/day was added for his underlying psychotic symptoms. The dose of the blonanserin patch was increased to 40 mg/day, and lorazepam was terminated; however, it was not effective. Although he was a suitable candidate for ECT, it was unavailable in our facility. Lithium was, therefore, added, and the blonanserin patch was terminated; his catatonic and psychotic symptoms were finally relieved by lithium monotherapy. He said that “I have always been able to hear hallucinations, but now I cannot. I want to recover from the injury and go home immediately.” Although the dose of lithium was temporarily increased to 600 mg/day (0.86 mEq/ml), the dose of 400 mg/day (0.50 mEq/ml) was maintained after obtaining informed consent, based on the blood concentration results. Li blood concentration of lithium, CK creatine kinase
Discussion and conclusions
This report describes the case of a single elderly man with hearing impairment, who developed hallucination and delusions and presented with catatonia at the last minute before his fall. There were no remarkable brain organic abnormalities which possibly cause catatonic symptoms, suggesting that his psychotic and catatonic symptoms were not derived from either trauma or drugs used after admission. His premorbid social function was almost normal enough to work for cleaning company, and the results of cognitive function tests performed after his psychiatric symptoms improved showed that he did not have remarkable neurocognitive impairment leading to social dysfunction. He had sensory deficit, which is common in late paraphrenia [9], and developed psychotic symptoms after 60 years of age without any evident history of psychiatric disorders. This suggested that his catatonia occurred because of late-life psychosis called as late paraphrenia, which has been recognized to be independent of schizophrenia [10]. Although the patient showed no remarkable cognitive dysfunction in MMSE, we could not rule out the possibility of neurocognitive deficit of the patient because there was no other neurocognitive examination of the patient to assess cognitive impairment. A previous review of paraphrenia has reported that the pathology of paraphrenia is similar to that of the neurofibrillary tangles, which are the predominant form of senile dementia [11]. His psychotic episode could have represented the prodromal symptoms of dementia; he therefore needs to be followed up closely for the progressive of cognitive dysfunction in the future.
The patient had initially responded to benzodiazepine therapy, and his psychotic symptoms became clinically evident; however, its efficacy was limited. Some patients with catatonia fail to respond to benzodiazepines, with approximately 30% of patients showing only partial response [12, 13]; in particular, cases that occur secondary to schizophrenia have been reported to be less likely to respond to benzodiazepines [14, 15]. Moreover, benzodiazepine use is not suitable for elderly patients, considering the risk of delirium. Atypical antipsychotics have been recommended as one of the alternative treatment strategies for catatonia [8]; however, blonanserin did not improve his catatonia. Finally, both his catatonic and psychotic symptoms were completely resolved by lithium monotherapy. Catatonic symptoms are more common in patients with mood disorders than in those with schizophrenia [5], suggesting that lithium may be effective for catatonia. Although previous case reports advocate the effectiveness of lithium in preventing recurrence of catatonia [16, 17], there is no evidence of its effectiveness in the acute phase.
Although the pathogenesis of catatonia remains poorly understood, the neurochemical hypothesis suggests that alterations in various neurotransmission systems, including gamma-aminobutyric acid (GABA) and glutamate, play a role [18, 19]. Even if the effects of benzodiazepines on the GABA system in the brain are limited, ECT has a high response rate, suggesting that catatonia may be the final common outcome for abnormal brain seizure activity [20]. In the present case, antiepileptic drugs which are candidates of the alternative treatment strategies for catatonia [8] were not administrated due to no remarkable abnormalities of electroencephalography. Finally, lithium was used because the effect of benzodiazepine was limited and ECT was unavailable. A previous study, using induced pluripotent stem cells (iPSCs) derived from neuronal cells of patients with bipolar disorders, has reported that the hyperexcitability phenotype of young neurons was selectively reversed by lithium only in lithium responders [21]. Moreover, a recent study using iPSCs derived from monozygotic twins discordant for major psychosis has suggested that lithium may normalize unbalanced specification of excitatory and inhibitory neurons in major psychosis neural circuits, by activating the Wnt signaling pathway [22]. In the present case of catatonia associated with late-life psychosis, lithium, although not as fast-acting as ECT, was effective for both catatonic and psychotic symptoms, as it normalized unbalanced specification of excitatory and inhibitory systems in the brain.
To the best of our knowledge, this is the first report on the efficacy of lithium in the acute phase of catatonia. There was a previous report of lithium therapy for catatonia features in autism spectrum disorder patients [23] and the another reported the case of catatonia cause by lithium overdose [24], suggesting that the action and effects of lithium on neurons numerous and diverse. Future studies are needed to elucidate the pathogenesis of catatonia to identify the most reliable treatment.
Abbreviations
ECTElectroconvulsive therapy
iPSCsInduced pluripotent stem cells
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank to all staff involved in the medical care of this patient.
Authors’ contributions
HS and JT were involved in the management of the patient. This case report was written by HS. MH and MI revised the manuscript. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
The data used for this case report is available from the corresponding authors on reasonable request.
Ethics approval and consent to participate
Ethics committee in Kansai Rosai Hospital approved for the publication of this case report.
Consent for publication
Written informed consent has been obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests. This edit was made to conform to the format of the journal guidelines. | LORAZEPAM | DrugsGivenReaction | CC BY | 33602282 | 19,742,073 | 2021-02-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Delusion'. | Catatonia associated with late-life psychosis successfully treated with lithium: a case report.
BACKGROUND
Catatonia is a psychomotor syndrome that presents various symptoms ranging from stupor to agitation, with prominent disturbances of volition. Its pathogenesis is poorly understood. Benzodiazepines and electroconvulsive therapy (ECT) are safe and effective standard treatments for catatonia; however, alternative treatment strategies have not been established in cases where these treatments are either ineffective or unavailable. Here, we report a case of catatonia associated with late-life psychosis, which was successfully treated with lithium.
METHODS
A 66-year-old single man with hearing impairment developed hallucination and delusions and presented with catatonic stupor after a fall. He initially responded to benzodiazepine therapy; however, his psychotic symptoms became clinically evident and benzodiazepine provided limited efficacy. Blonanserin was ineffective, and ECT was unavailable. His catatonic and psychotic symptoms were finally relieved by lithium monotherapy.
CONCLUSIONS
Catatonic symptoms are common in patients with mood disorders, suggesting that lithium may be effective in these cases. Moreover, lithium may be effective for both catatonic and psychotic symptoms, as it normalizes imbalances of excitatory and inhibitory systems in the brain, which underlies major psychosis. Cumulative evidence from further cases is needed to validate our findings.
Background
Catatonia is a psychomotor syndrome that presents various symptoms ranging from stupor to agitation, with prominent disturbances of volition; its pathogenesis is poorly understood [1]. Catatonia was once recognized as a subtype of schizophrenia; however, the Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) removed it from all schizophrenia subtypes, and defined it as a specifier of various psychiatric disorders or medical conditions [2]. Indeed, catatonia has been reported to be associated with a variety of medical conditions [3, 4]. Moreover, a previous study has reported that catatonic symptoms were more common in patients with manic or mixed episodes (28–31%) than in those with schizophrenia (10–15%) [5]. A prospective cohort study has also reported the incidence of catatonia to be only 7.6% in patients with schizophrenia [6].
Benzodiazepines and electroconvulsive therapy (ECT) are safe and effective standard treatments for catatonia, particularly in acute cases; however, benzodiazepines show limited efficacy in a considerable number of patients [7], and available facilities for ECT are limited. In cases where benzodiazepines are ineffective and ECT is unavailable, a systematic review of alternative treatment strategies proposed glutamate antagonists, antiepileptic drugs, and atypical antipsychotics as first-, second-, and third-line treatments for catatonia, respectively [8]. The proper alternative treatment of catatonia may differ depending on the underlying disease; however, as its pathogenesis is unclear, the pharmacological action of each drug is therefore unknown.
Here, we report a case of catatonia associated with late-life psychosis that was successfully treated with lithium.
Case presentation
The patient was a 66-year-old single man, who worked for a cleaning company, and had hearing impairment; however, there was no evident medical history of psychiatric disorders. He was found lying in front of his apartment and was sent to the emergency room. A physical examination revealed fracture of the left patella and calcaneus, which appeared to be related to trauma. He kept his eyes closed for most of the day and demonstrated no spontaneous speech or reaction. Although his blood tests showed inflammatory reaction, his vital signs were normal, and computed tomography and electroencephalography of his brain showed no significant findings. He had no relatives and there was no life history information of him. According to the information of the neighboring residents, he had exhibited strange behaviors since about 2 months before admission and often annoyed the neighbors. Before his arrival to the emergency department, a neighbor called the police because the patient had stood in front of his apartment for a long time. While in detention, he did not respond to the police interrogations at all; he was found lying in front of his apartment a few hours after police released him. After admission to the emergency department, he was consulted with our department for the assessment of psychotic symptoms by his physician. Including the process leading to hospitalization, he was diagnosed with catatonia based on the presence of stupor, mutism, and negativism which was detected from the information by the police about the patients’ uncooperative behavior during detention. He was started on intravenous administration of 5 mg/day midazolam, which was switched to lorazepam, administered through a feeding tube. He then gradually opened his eyes and started speaking. He stated that “someone was trying to kill me, so I jumped to escape. I don’t want to talk about anything because I am being seen and heard by someone.” He was, therefore, suspected to have hallucinations and delusions. He subsequently developed fever, and the blood tests showed an inflammatory reaction with creatine kinase (CK) elevation; antibiotics were accordingly administered for infection at the injury site. The dose of lorazepam was tapered to 2 mg/day because he developed delirium; after normalization of CK levels, a blonanserin patch at a dose of 20 mg/day was added for his underlying psychotic symptoms. His delirium improved, and he was able to eat by himself; however, he spent more time lying down with his eyes closed. Considering the possibility of oversedation, lorazepam was tapered to a dose of 1 mg/day. Since he appeared to have improved slightly, the dose of blonanserin patch was increased to 40 mg/day, and lorazepam was terminated. However, he spent most of his time in bed, and eating became difficult. Although he was a suitable candidate for ECT, it was unavailable in our facility. We tried to transfer the facility where ECT was available; however, it was full. Lithium was, therefore, added, and blonanserin patch was terminated; he opened his eyes and began to move after the dose of lithium was increased to 400 mg/day, and he began to eat and talk. He said that “I have always been able to hear hallucinations, but now I cannot. I want to recover from the injury and go home immediately.” Although the dose of lithium was temporarily increased to 600 mg/day, the dose of 400 mg/day was maintained after obtaining informed consent, based on the blood concentration results (Fig. 1). He mentioned that he had graduated from high school and had no history of alcohol or drug abuse. At age 60, he moved to his present apartment after changing jobs, and had developed hallucinations approximately a year before hospitalization. On examination, his mini-mental state examination (MMSE) score was 26; some points were lost on 3-step command (minus 2) and delayed recall (minus 2) tasks, suggesting that there was no remarkable cognitive dysfunction. He was, therefore, transferred to a rehabilitation facility.Fig. 1 Clinical course of a case of catatonia associated with late paraphrenia. A 66-year-old man with catatonic stupor initially responded to benzodiazepine therapy, and his psychotic symptoms became clinically evident because he stated that “someone was trying to kill me, so I jumped to escape. I don’t want to talk about anything because I am being seen and heard by someone.” He subsequently developed delirium with fever and creatine kinase (CK) level elevation and the dose of lorazepam was tapered to 2 mg/day. After normalization of CK levels, a blonanserin patch at a dose of 20 mg/day was added for his underlying psychotic symptoms. The dose of the blonanserin patch was increased to 40 mg/day, and lorazepam was terminated; however, it was not effective. Although he was a suitable candidate for ECT, it was unavailable in our facility. Lithium was, therefore, added, and the blonanserin patch was terminated; his catatonic and psychotic symptoms were finally relieved by lithium monotherapy. He said that “I have always been able to hear hallucinations, but now I cannot. I want to recover from the injury and go home immediately.” Although the dose of lithium was temporarily increased to 600 mg/day (0.86 mEq/ml), the dose of 400 mg/day (0.50 mEq/ml) was maintained after obtaining informed consent, based on the blood concentration results. Li blood concentration of lithium, CK creatine kinase
Discussion and conclusions
This report describes the case of a single elderly man with hearing impairment, who developed hallucination and delusions and presented with catatonia at the last minute before his fall. There were no remarkable brain organic abnormalities which possibly cause catatonic symptoms, suggesting that his psychotic and catatonic symptoms were not derived from either trauma or drugs used after admission. His premorbid social function was almost normal enough to work for cleaning company, and the results of cognitive function tests performed after his psychiatric symptoms improved showed that he did not have remarkable neurocognitive impairment leading to social dysfunction. He had sensory deficit, which is common in late paraphrenia [9], and developed psychotic symptoms after 60 years of age without any evident history of psychiatric disorders. This suggested that his catatonia occurred because of late-life psychosis called as late paraphrenia, which has been recognized to be independent of schizophrenia [10]. Although the patient showed no remarkable cognitive dysfunction in MMSE, we could not rule out the possibility of neurocognitive deficit of the patient because there was no other neurocognitive examination of the patient to assess cognitive impairment. A previous review of paraphrenia has reported that the pathology of paraphrenia is similar to that of the neurofibrillary tangles, which are the predominant form of senile dementia [11]. His psychotic episode could have represented the prodromal symptoms of dementia; he therefore needs to be followed up closely for the progressive of cognitive dysfunction in the future.
The patient had initially responded to benzodiazepine therapy, and his psychotic symptoms became clinically evident; however, its efficacy was limited. Some patients with catatonia fail to respond to benzodiazepines, with approximately 30% of patients showing only partial response [12, 13]; in particular, cases that occur secondary to schizophrenia have been reported to be less likely to respond to benzodiazepines [14, 15]. Moreover, benzodiazepine use is not suitable for elderly patients, considering the risk of delirium. Atypical antipsychotics have been recommended as one of the alternative treatment strategies for catatonia [8]; however, blonanserin did not improve his catatonia. Finally, both his catatonic and psychotic symptoms were completely resolved by lithium monotherapy. Catatonic symptoms are more common in patients with mood disorders than in those with schizophrenia [5], suggesting that lithium may be effective for catatonia. Although previous case reports advocate the effectiveness of lithium in preventing recurrence of catatonia [16, 17], there is no evidence of its effectiveness in the acute phase.
Although the pathogenesis of catatonia remains poorly understood, the neurochemical hypothesis suggests that alterations in various neurotransmission systems, including gamma-aminobutyric acid (GABA) and glutamate, play a role [18, 19]. Even if the effects of benzodiazepines on the GABA system in the brain are limited, ECT has a high response rate, suggesting that catatonia may be the final common outcome for abnormal brain seizure activity [20]. In the present case, antiepileptic drugs which are candidates of the alternative treatment strategies for catatonia [8] were not administrated due to no remarkable abnormalities of electroencephalography. Finally, lithium was used because the effect of benzodiazepine was limited and ECT was unavailable. A previous study, using induced pluripotent stem cells (iPSCs) derived from neuronal cells of patients with bipolar disorders, has reported that the hyperexcitability phenotype of young neurons was selectively reversed by lithium only in lithium responders [21]. Moreover, a recent study using iPSCs derived from monozygotic twins discordant for major psychosis has suggested that lithium may normalize unbalanced specification of excitatory and inhibitory neurons in major psychosis neural circuits, by activating the Wnt signaling pathway [22]. In the present case of catatonia associated with late-life psychosis, lithium, although not as fast-acting as ECT, was effective for both catatonic and psychotic symptoms, as it normalized unbalanced specification of excitatory and inhibitory systems in the brain.
To the best of our knowledge, this is the first report on the efficacy of lithium in the acute phase of catatonia. There was a previous report of lithium therapy for catatonia features in autism spectrum disorder patients [23] and the another reported the case of catatonia cause by lithium overdose [24], suggesting that the action and effects of lithium on neurons numerous and diverse. Future studies are needed to elucidate the pathogenesis of catatonia to identify the most reliable treatment.
Abbreviations
ECTElectroconvulsive therapy
iPSCsInduced pluripotent stem cells
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank to all staff involved in the medical care of this patient.
Authors’ contributions
HS and JT were involved in the management of the patient. This case report was written by HS. MH and MI revised the manuscript. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
The data used for this case report is available from the corresponding authors on reasonable request.
Ethics approval and consent to participate
Ethics committee in Kansai Rosai Hospital approved for the publication of this case report.
Consent for publication
Written informed consent has been obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests. This edit was made to conform to the format of the journal guidelines. | BLONANSERIN, LITHIUM, LORAZEPAM, MIDAZOLAM | DrugsGivenReaction | CC BY | 33602282 | 19,733,655 | 2021-02-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hallucination'. | Catatonia associated with late-life psychosis successfully treated with lithium: a case report.
BACKGROUND
Catatonia is a psychomotor syndrome that presents various symptoms ranging from stupor to agitation, with prominent disturbances of volition. Its pathogenesis is poorly understood. Benzodiazepines and electroconvulsive therapy (ECT) are safe and effective standard treatments for catatonia; however, alternative treatment strategies have not been established in cases where these treatments are either ineffective or unavailable. Here, we report a case of catatonia associated with late-life psychosis, which was successfully treated with lithium.
METHODS
A 66-year-old single man with hearing impairment developed hallucination and delusions and presented with catatonic stupor after a fall. He initially responded to benzodiazepine therapy; however, his psychotic symptoms became clinically evident and benzodiazepine provided limited efficacy. Blonanserin was ineffective, and ECT was unavailable. His catatonic and psychotic symptoms were finally relieved by lithium monotherapy.
CONCLUSIONS
Catatonic symptoms are common in patients with mood disorders, suggesting that lithium may be effective in these cases. Moreover, lithium may be effective for both catatonic and psychotic symptoms, as it normalizes imbalances of excitatory and inhibitory systems in the brain, which underlies major psychosis. Cumulative evidence from further cases is needed to validate our findings.
Background
Catatonia is a psychomotor syndrome that presents various symptoms ranging from stupor to agitation, with prominent disturbances of volition; its pathogenesis is poorly understood [1]. Catatonia was once recognized as a subtype of schizophrenia; however, the Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) removed it from all schizophrenia subtypes, and defined it as a specifier of various psychiatric disorders or medical conditions [2]. Indeed, catatonia has been reported to be associated with a variety of medical conditions [3, 4]. Moreover, a previous study has reported that catatonic symptoms were more common in patients with manic or mixed episodes (28–31%) than in those with schizophrenia (10–15%) [5]. A prospective cohort study has also reported the incidence of catatonia to be only 7.6% in patients with schizophrenia [6].
Benzodiazepines and electroconvulsive therapy (ECT) are safe and effective standard treatments for catatonia, particularly in acute cases; however, benzodiazepines show limited efficacy in a considerable number of patients [7], and available facilities for ECT are limited. In cases where benzodiazepines are ineffective and ECT is unavailable, a systematic review of alternative treatment strategies proposed glutamate antagonists, antiepileptic drugs, and atypical antipsychotics as first-, second-, and third-line treatments for catatonia, respectively [8]. The proper alternative treatment of catatonia may differ depending on the underlying disease; however, as its pathogenesis is unclear, the pharmacological action of each drug is therefore unknown.
Here, we report a case of catatonia associated with late-life psychosis that was successfully treated with lithium.
Case presentation
The patient was a 66-year-old single man, who worked for a cleaning company, and had hearing impairment; however, there was no evident medical history of psychiatric disorders. He was found lying in front of his apartment and was sent to the emergency room. A physical examination revealed fracture of the left patella and calcaneus, which appeared to be related to trauma. He kept his eyes closed for most of the day and demonstrated no spontaneous speech or reaction. Although his blood tests showed inflammatory reaction, his vital signs were normal, and computed tomography and electroencephalography of his brain showed no significant findings. He had no relatives and there was no life history information of him. According to the information of the neighboring residents, he had exhibited strange behaviors since about 2 months before admission and often annoyed the neighbors. Before his arrival to the emergency department, a neighbor called the police because the patient had stood in front of his apartment for a long time. While in detention, he did not respond to the police interrogations at all; he was found lying in front of his apartment a few hours after police released him. After admission to the emergency department, he was consulted with our department for the assessment of psychotic symptoms by his physician. Including the process leading to hospitalization, he was diagnosed with catatonia based on the presence of stupor, mutism, and negativism which was detected from the information by the police about the patients’ uncooperative behavior during detention. He was started on intravenous administration of 5 mg/day midazolam, which was switched to lorazepam, administered through a feeding tube. He then gradually opened his eyes and started speaking. He stated that “someone was trying to kill me, so I jumped to escape. I don’t want to talk about anything because I am being seen and heard by someone.” He was, therefore, suspected to have hallucinations and delusions. He subsequently developed fever, and the blood tests showed an inflammatory reaction with creatine kinase (CK) elevation; antibiotics were accordingly administered for infection at the injury site. The dose of lorazepam was tapered to 2 mg/day because he developed delirium; after normalization of CK levels, a blonanserin patch at a dose of 20 mg/day was added for his underlying psychotic symptoms. His delirium improved, and he was able to eat by himself; however, he spent more time lying down with his eyes closed. Considering the possibility of oversedation, lorazepam was tapered to a dose of 1 mg/day. Since he appeared to have improved slightly, the dose of blonanserin patch was increased to 40 mg/day, and lorazepam was terminated. However, he spent most of his time in bed, and eating became difficult. Although he was a suitable candidate for ECT, it was unavailable in our facility. We tried to transfer the facility where ECT was available; however, it was full. Lithium was, therefore, added, and blonanserin patch was terminated; he opened his eyes and began to move after the dose of lithium was increased to 400 mg/day, and he began to eat and talk. He said that “I have always been able to hear hallucinations, but now I cannot. I want to recover from the injury and go home immediately.” Although the dose of lithium was temporarily increased to 600 mg/day, the dose of 400 mg/day was maintained after obtaining informed consent, based on the blood concentration results (Fig. 1). He mentioned that he had graduated from high school and had no history of alcohol or drug abuse. At age 60, he moved to his present apartment after changing jobs, and had developed hallucinations approximately a year before hospitalization. On examination, his mini-mental state examination (MMSE) score was 26; some points were lost on 3-step command (minus 2) and delayed recall (minus 2) tasks, suggesting that there was no remarkable cognitive dysfunction. He was, therefore, transferred to a rehabilitation facility.Fig. 1 Clinical course of a case of catatonia associated with late paraphrenia. A 66-year-old man with catatonic stupor initially responded to benzodiazepine therapy, and his psychotic symptoms became clinically evident because he stated that “someone was trying to kill me, so I jumped to escape. I don’t want to talk about anything because I am being seen and heard by someone.” He subsequently developed delirium with fever and creatine kinase (CK) level elevation and the dose of lorazepam was tapered to 2 mg/day. After normalization of CK levels, a blonanserin patch at a dose of 20 mg/day was added for his underlying psychotic symptoms. The dose of the blonanserin patch was increased to 40 mg/day, and lorazepam was terminated; however, it was not effective. Although he was a suitable candidate for ECT, it was unavailable in our facility. Lithium was, therefore, added, and the blonanserin patch was terminated; his catatonic and psychotic symptoms were finally relieved by lithium monotherapy. He said that “I have always been able to hear hallucinations, but now I cannot. I want to recover from the injury and go home immediately.” Although the dose of lithium was temporarily increased to 600 mg/day (0.86 mEq/ml), the dose of 400 mg/day (0.50 mEq/ml) was maintained after obtaining informed consent, based on the blood concentration results. Li blood concentration of lithium, CK creatine kinase
Discussion and conclusions
This report describes the case of a single elderly man with hearing impairment, who developed hallucination and delusions and presented with catatonia at the last minute before his fall. There were no remarkable brain organic abnormalities which possibly cause catatonic symptoms, suggesting that his psychotic and catatonic symptoms were not derived from either trauma or drugs used after admission. His premorbid social function was almost normal enough to work for cleaning company, and the results of cognitive function tests performed after his psychiatric symptoms improved showed that he did not have remarkable neurocognitive impairment leading to social dysfunction. He had sensory deficit, which is common in late paraphrenia [9], and developed psychotic symptoms after 60 years of age without any evident history of psychiatric disorders. This suggested that his catatonia occurred because of late-life psychosis called as late paraphrenia, which has been recognized to be independent of schizophrenia [10]. Although the patient showed no remarkable cognitive dysfunction in MMSE, we could not rule out the possibility of neurocognitive deficit of the patient because there was no other neurocognitive examination of the patient to assess cognitive impairment. A previous review of paraphrenia has reported that the pathology of paraphrenia is similar to that of the neurofibrillary tangles, which are the predominant form of senile dementia [11]. His psychotic episode could have represented the prodromal symptoms of dementia; he therefore needs to be followed up closely for the progressive of cognitive dysfunction in the future.
The patient had initially responded to benzodiazepine therapy, and his psychotic symptoms became clinically evident; however, its efficacy was limited. Some patients with catatonia fail to respond to benzodiazepines, with approximately 30% of patients showing only partial response [12, 13]; in particular, cases that occur secondary to schizophrenia have been reported to be less likely to respond to benzodiazepines [14, 15]. Moreover, benzodiazepine use is not suitable for elderly patients, considering the risk of delirium. Atypical antipsychotics have been recommended as one of the alternative treatment strategies for catatonia [8]; however, blonanserin did not improve his catatonia. Finally, both his catatonic and psychotic symptoms were completely resolved by lithium monotherapy. Catatonic symptoms are more common in patients with mood disorders than in those with schizophrenia [5], suggesting that lithium may be effective for catatonia. Although previous case reports advocate the effectiveness of lithium in preventing recurrence of catatonia [16, 17], there is no evidence of its effectiveness in the acute phase.
Although the pathogenesis of catatonia remains poorly understood, the neurochemical hypothesis suggests that alterations in various neurotransmission systems, including gamma-aminobutyric acid (GABA) and glutamate, play a role [18, 19]. Even if the effects of benzodiazepines on the GABA system in the brain are limited, ECT has a high response rate, suggesting that catatonia may be the final common outcome for abnormal brain seizure activity [20]. In the present case, antiepileptic drugs which are candidates of the alternative treatment strategies for catatonia [8] were not administrated due to no remarkable abnormalities of electroencephalography. Finally, lithium was used because the effect of benzodiazepine was limited and ECT was unavailable. A previous study, using induced pluripotent stem cells (iPSCs) derived from neuronal cells of patients with bipolar disorders, has reported that the hyperexcitability phenotype of young neurons was selectively reversed by lithium only in lithium responders [21]. Moreover, a recent study using iPSCs derived from monozygotic twins discordant for major psychosis has suggested that lithium may normalize unbalanced specification of excitatory and inhibitory neurons in major psychosis neural circuits, by activating the Wnt signaling pathway [22]. In the present case of catatonia associated with late-life psychosis, lithium, although not as fast-acting as ECT, was effective for both catatonic and psychotic symptoms, as it normalized unbalanced specification of excitatory and inhibitory systems in the brain.
To the best of our knowledge, this is the first report on the efficacy of lithium in the acute phase of catatonia. There was a previous report of lithium therapy for catatonia features in autism spectrum disorder patients [23] and the another reported the case of catatonia cause by lithium overdose [24], suggesting that the action and effects of lithium on neurons numerous and diverse. Future studies are needed to elucidate the pathogenesis of catatonia to identify the most reliable treatment.
Abbreviations
ECTElectroconvulsive therapy
iPSCsInduced pluripotent stem cells
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank to all staff involved in the medical care of this patient.
Authors’ contributions
HS and JT were involved in the management of the patient. This case report was written by HS. MH and MI revised the manuscript. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
The data used for this case report is available from the corresponding authors on reasonable request.
Ethics approval and consent to participate
Ethics committee in Kansai Rosai Hospital approved for the publication of this case report.
Consent for publication
Written informed consent has been obtained from the patient for the publication of this case report.
Competing interests
The authors declare that they have no competing interests. This edit was made to conform to the format of the journal guidelines. | BLONANSERIN, LITHIUM, LORAZEPAM, MIDAZOLAM | DrugsGivenReaction | CC BY | 33602282 | 19,733,655 | 2021-02-18 |
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