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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Primary undifferentiated pleomorphic cardiac sarcoma presenting as right heart failure.
Right-sided heart failure is a common sequela of left heart failure and seldom presents as a primary disorder. The differential diagnosis of right heart failure includes a cardiac tumor. Cardiac malignancies are rare tumors with an overall poor prognosis. We evaluated a 69-year-old man who presented with a 3-week history of progressive lower extremity swelling, ascites, and scrotal swelling. Laboratory studies were significant only for mildly elevated liver function tests. CT scan of the abdomen and pelvis showed ascites, hepatic swelling, and a bland clot in the inferior vena cava extending from the level of the kidneys to the right atrium. A large mass originating from the right atrium was identified, and biopsy confirmed an undifferentiated pleomorphic cardiac sarcoma. Given the extensive tumor and clot burden, he was not an operative candidate. He developed portal hypertension with esophageal varices and expired due to variceal bleeding.
Background
Right-sided heart failure usually does not occur in isolation. Most often it presents as a manifestation of either left-sided heart failure or pulmonary pathology such as obstructive sleep apnea or pulmonary embolism. The potential for accumulation of significant amounts of fluid below the diaphragm may result in dramatic presentations of ascites, marked scrotal swelling, and lower extremity edema. Hepatic congestion from right heart failure leads to the complications of portal hypertension including esophageal varices and clotting disorders.
While the majority of right heart failure is caused by left heart failure, valvular disorders, and portal hypertension, it is incumbent on the medical team to ensure that other, less common conditions do not exist. Since the potential causes of right heart failure are extensive, primary right atrial malignancy is seldom considered. The current case was illustrative of the importance of a thorough differential diagnosis.
Case presentation
A 69-year-old male with a past medical history of diabetes mellitus type 2 presented to the emergency department with a 2-week history of progressively worsening bilateral lower extremity swelling and abdominal distention associated with mild weight loss and dyspnea on exertion. There was no previous history of cardiac, hepatic, or renal disease, and no history of hepatitis or alcohol abuse. He had recently been on a trip out of the country when his symptoms progressed to the point where he was no longer able to walk. He was evaluated at a local medical facility where he was started on several diuretics. Once his swelling receded, he returned back to the USA to be further evaluated. On initial clinical examination, he was found to be hypertensive (170/101) and tachycardic (104 beats per minute) with normal respirations and an oxygen saturation of 97% on room air. Physical examination was notable for bitemporal wasting, jugular venous distention, a tense distended abdomen, and 3+ pitting edema up to his bilateral hips.
Upon admission, a complete blood count was normal, and electrolytes were significant only for mildly decreased sodium at 131 millimoles (mmol) per liter. Creatinine clearance was normal and hemoglobin A1c was elevated at 7.3% (normal <5.7%). Alanine aminotransferase (ALT) was elevated at 174 International Units/liter (IU/L) (normal <55 IU/L), aspartate aminotransferase (AST) was high at 134 IU/L (normal 5-34 IU/L), and alkaline phosphatase was abnormal at 207 IU/L (normal 38-126 IU/L). Albumin was low at 3.2 grams/deciliter (g/dL) (normal 3.5-5.0 g/dL). Troponin I was negative. Prothrombin time (PT) was elevated at 20.9 seconds (normal ≤ 14.6 seconds) and International Normalized Ratio (INR) was 1.9 (normal 0.8-1.2). Hepatitis serologies were negative for hepatitis A, B, and C. HIV and tuberculosis testing were negative.
A computed tomographic (CT) study of the abdomen and pelvis revealed moderate ascites, liver congestion, and renal congestion. Bland thrombus was noted in the inferior vena cava (IVC) extending to the level of the renal veins. Evaluating more cephalad, the CT study showed bland thrombus filling the right atrium extending through the length of the superior vena cava (SVC), with the posterior aspect of the heart nearly encased by an irregular curvilinear mass. The mass was seen to extend along the left ventricular wall, along the posterior interventricular septum, and into the right atrium. This mass appeared to involve the medial diaphragmatic crus as well as adjacent mediastinal lymph nodes. The enhancing heterogeneous mass along the border of the left heart measured 7.0 × 3.0 cm (Fig. 1). Two 5-mm pulmonary nodules were noted to be suspicious for malignancy. A transthoracic echocardiogram showed a large, calcified, circular mass in the right atrium with an associated thickened pericardium (Fig. 2).Fig. 1 Abdomen/pelvis CT coronal reformat demonstrating thrombus extending from the right atrium (long red arrow) inferiorly to the level of the infra-renal inferior vena cava (short red arrow). Dense accumulation of intravenous contrast within the right atrium.
Fig 1Fig. 2 Abdomen/pelvis CT with contrast showing right atrial sarcoma extending into inferior vena cava (red arrow).
Fig. 2
Subsequently, a CT-guided core biopsy was performed. Microscopic histopathology revealed the presence of medium-sized hypochromatic spindled nuclei without prominent nucleoli and moderate eosinophilic cytoplasm with indistinct cell borders and immunostaining positive for vimentin, supporting the diagnosis of an undifferentiated pleomorphic sarcoma (Fig. 3).Fig. 3 Abdomen/pelvis CT coronal MIPS reformat demonstrating thrombus at the origin of the left renal vein (red arrow), contiguous with the IVC thrombosis.
Fig. 3
The patient arrived with a working diagnosis of congestive heart failure of uncertain etiology, presumed to be a sign of ischemia. However, given his negative cardiac history, unremarkable electrocardiogram and negative troponin I, imaging of the abdomen was ordered to determine the source and quantity of ascites. CT of the abdomen/pelvis showed moderate ascites, bilateral pleural effusions, and extensive clot formation in the IVC. The superior planes imaged included the heart, showing the massive extent of the clot throughout the length of the vena cava from the heart to the kidneys. Further inspection of the images revealed that mass as described as well as possible metastatic lesions in the lungs. A cardiac tumor, likely malignant, was diagnosed.
Transthoracic echocardiogram confirmed the presence of a right atrial mass of undetermined potential along with a constrictive epicardial mass as described. Percutaneous biopsy of the mass confirmed the core biopsy's aforementioned pathology.
Initial management included gentle diuresis and intravenous anticoagulation. Given the extensive nature of the clot, he was not deemed a candidate for thrombectomy. Thoracentesis and paracentesis combined with diuresis brought significant relief of symptoms. The patient developed esophageal varices along with portal hypertensive gastropathy, requiring several banding procedures for bleeding. The clot did extend into the renal veins, leading to acute kidney injury.
Discussions were held between hematology, oncology, hepatology, and cardiothoracic surgery. Given the extensive nature of both the tumor and the clot, he was not felt to be an operative candidate. The patient was not amenable initially to palliative care, hoping for a cure.
Due to his extensive mass and clot burden, he was unable to be offered an interventional procedure including resection and transitioned to compassionate use of pembrolizumab. He was readmitted 1.5 months later for hematemesis, melena, and anasarca along with have portal hypertension complications including bleeding 3+ esophageal varices requiring band ligation x4 and portal hypertensive gastropathy. Repeat TTE and CT showed the right atrial mass now extending external to the right heart chambers with a moderate pericardial effusion. He was medically stabilized with IV diuresis, paracentesis, and thoracentesis, and discharged with the plan to follow-up with GI for repeat upper endoscopy in 4-6 weeks. He was readmitted less than a month later for a hypervolemic exacerbation. Since the patient was unable to tolerate further immunotherapy, the multidisciplinary team and patient decided to focus on symptom management and strengthening at home. He expired 4 months after initial presentation during his fourth admission due to an esophageal variceal hemorrhage. A postmortem autopsy was not performed.
Discussion
Rapid onset of right-sided ventricular failure prompts the search for common cardiac etiologies including left-sided heart failure, mitral valve dysfunction, pulmonary hypertension, pulmonary emboli, myocarditis, pericardial fibrosis, or tricuspid valve dysfunction due to endocarditis or rheumatic myocarditis [1,2]. Despite a past medical history that was negative for the above conditions, this patient developed right-sided heart failure with rapid progression of expected stigmata including lower extremity edema, ascites, scrotal edema, liver engorgement, and portal hypertension with esophageal varices. While his initial presentation involved signs and symptoms below the diaphragm, further evaluation revealed that the source of his disease was a right atrial malignancy.
Primary cardiac malignancies are uncommon. Cardiac tumors have been noted in between 0.001% and 0.3% in autopsy series [3], [4], [5]. About 75% of cardiac tumors are benign [6]. Of all cardiac malignancies, about 75% are sarcomas [7,8]. Patients tend to be middle-age (unlike the current case) and present with advanced disease [9,10]. Undifferentiated pleomorphic sarcomas are a rare subtype of cardiac sarcomas, representing one-third of all primary cardiac sarcomas [4,11]. While cardiac malignancies may affect any structure from the endothelium to the pericardium [12], most undifferentiated pleomorphic sarcomas develop in the left atrium.
Because of the distensibility of the atria, atrial tumors can become quite extensive and bulky before producing symptoms. The onset of symptoms is often insidious, and diagnostic imaging including transthoracic echocardiogram and computed tomography demonstrate an intracardiac mass that is typically located in the left atrium in 81% of undifferentiated pleomorphic sarcomas [12]. The current patient presented with a tumor that essentially filled the right atrium, and arguably the majority of his symptoms were related more to the subsequent development of an extensive bland clot extending from the heart to the kidneys. Diagnosis using ultrasound, contrast CT, and/or MRI is followed by biopsy confirmation [13,14].
Cardiac sarcomas are typically aggressive tumors [4,15]. Complete surgical resection combined with adjuvant chemotherapy and/or radiation is recommended for resectable disease, although there is a high risk of rapid recurrence [16,17]. While it is often technically difficult, R0 resection has shown significantly better outcomes than R1 resection. Therapeutic success is often challenging and unfeasible due to the highly aggressive and invasive nature of the sarcoma, with positive surgical margins being an independent predictor for poor survival [18,19]. More recent surgical approaches have included autotransplantation wherein the heart is removed, the lesion is excised, the heart is reconstructed, then reimplanted [7,20]. Cardiac transplantation is an emerging option in select patients.
Unfortunately due to the lack of prevalence of the disease and therapeutic data, evidence-based recommendations on choice or timing of chemotherapy and radiation are challenging [21]. In a series by Abu Salah, adding neoadjuvant chemotherapy to radical surgery was found to improve outcomes in right heart sarcomas, with overall survival increasing from 9.5 to 20 months [22]. Overall prognosis for undifferentiated pleomorphic sarcomas remains very poor with a median survival of less than 1 year [11,19,23,24]. Immunotherapy and tyrosine kinase angiogenesis inhibitors have shown some benefit [25] while a phase 2 trial of the programmed cell death 1 inhibitor pembrolizumab showed limited efficacy [26] in the treatment of cardiac sarcomas (Fig. 4, Fig. 5).Fig. 4 TTE showing a large, calcified, circular mass in the right atrium (red arrow) with an associated thickened pericardium.
Fig. 4Fig. 5 High magnification microscopic histopathology with H&E staining revealed the presence of medium-sized hypochromatic spindled nuclei without prominent nucleoli and moderate eosinophilic cytoplasm with indistinct cell borders.
Fig. 5
Patient consent
Please check that all articles state that patient consent has been obtained. Please raise a query to the author if no such statement is present. | PEMBROLIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33552334 | 19,303,620 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cerebral artery occlusion'. | Iatrogenic intracranial vessel dissection during mechanical thrombectomy rescued by emergent stenting: 2 case reports.
Intracranial vessel dissection is a procedural complication associated with endovascular treatment. However, there have been few reports on its potential causes and management during mechanical thrombectomy. In approximately 250 cases of mechanical thrombectomy over the past 5 years at our institution, iatrogenic intracranial dissection occurred in 2 patients (0.8%). In this report, we described these 2 cases that were rescued through emergent stenting. Mechanical thrombectomy, using both a stent retriever and an aspiration catheter, was performed for acute middle cerebral artery M2 occlusion in Patient 1 (a 69-year-old man) and for distal M1 occlusion in Patient 2 (an 83-year-old woman). In both cases, recanalization was achieved with the procedure, but irregular stenosis developed at the initially nonoccluded, but mildly arteriosclerotic, M1, after recanalization. During the thrombectomy procedure, the aspiration catheter sifted up to the arteriosclerotic M1. In both cases, the lesions were considered vessel dissection, due to a shift of the aspiration catheter tip into the arteriosclerotic vessel wall. Repeated percutaneous angiography with antithrombotic therapy failed to improve the lesions and to maintain the antegrade blood flow. Finally, lesions in each patient were successfully rescued through the use of emergent stenting. A drug-eluting stent for coronary use was deployed in Patient 1, and an Enterprise stent was applied in Patient 2. Inadvertent shift of the aspiration catheter into arteriosclerotic vessels can cause a serious intracranial vessel dissection. When performing mechanical thrombectomy, intracranial stents need to be available as rescue treatment devices to manage refractory iatrogenic intracranial vessel dissection.
Introduction
Mechanical thrombectomy using a stent retriever (SR) has proven to be effective for patients with acute ischemic stroke secondary to large vessel occlusions [1]. In addition to the use of a single SR, various devices and techniques for mechanical thrombectomy have emerged and are now widely used to achieve good procedural results [2], [3], [4], [5], [6]. Furthermore, mechanical thrombectomy is now being used to target more peripheral arteries [7], [8], [9]. However, mechanical thrombectomy can sometimes be associated with several procedural complications, including vessel injury, distal embolism, puncture site problems, and postprocedural intracranial hemorrhage [10], [11], [12], [13], [14].
Vessel injury is the most directly related procedural complication, usually caused by clinician error while using endovascular devices and techniques. Vessel perforation is common and requires urgent management because it can lead to critical conditions [15,16]. Vessel perforation is usually noticed as an obvious protrusion of a device from the vascular structure, or is visualized as a contrast leak at the distal site of the manipulation. Improper mechanical thrombectomy procedures can also cause vessel dissection, another type of vessel injury [17], [18], [19]. Unlike vessel perforation, vessel dissection is not always apparent on subsequent angiography and can occur at any procedural site without the obvious protrusion of a device from a vascular structure. To prevent and manage vessel dissection during mechanical thrombectomy, clinicians need to be aware of procedures causing this complication and ways to avoid them as well as rescue them.
Two patients (0.8%), out of approximately 250 cases of mechanical thrombectomy over the past 5 years at our institution, were definitively diagnosed with iatrogenic intracranial dissection caused by the thrombectomy procedure [20], [21], [22], [23]. In this report, we provide the details of these 2 cases of refractory iatrogenic intracranial artery dissection that occurred during mechanical thrombectomy performed with the combined use of an SR and an aspiration catheter. Both occurred on a mildly arteriosclerotic vessel proximal to the occlusion, and each was rescued through emergent stenting.
Case descriptions
Case 1
A 69-year-old man with a history of hypertension and diabetes mellitus was hospitalized at our institute for myocardial infarction. He suddenly developed aphasia with a National Institutes of Health Stroke Scale score of 8. He had previously undergone percutaneous coronary intervention with drug-eluting stents (DES) and was taking 100 mg of aspirin and 3.75 mg of prasugrel daily. Magnetic resonance angiography (MRA) and diffusion-weighted imaging (DWI) showed occlusion of the M2 segment of the left middle cerebral artery (MCA) with only slight ischemic change (Fig. 1A, B). There was mild atherosclerotic stenosis at the mid-M1 segment of the MCA proximal to the occlusion (Fig. 1A). After initiating intravenous thrombolysis with alteplase, endovascular treatment was performed. Written informed consent was obtained from a member of the patient's family before the procedure.Fig. 1 Case 1. (A, B) Magnetic resonance angiography and diffusion-weighted imaging performed upon patient admission, showing occlusion of the M2 segment of the left middle cerebral artery with only slight ischemic change. Note the mild atherosclerotic stenosis at the mid-M1 proximal to the occlusion (arrow). (C, D) Magnetic resonance angiography and diffusion-weighted imaging performed the day after the procedure, showing successful recanalization with localized ischemic change.
Fig 1
The endovascular procedure was performed via femoral access under local anesthesia. Heparin was not administered initially because of the ongoing administration of alteplase. A 9-French balloon-guide catheter (BGC) was placed in the left cervical internal carotid artery (ICA). Initial angiography revealed persistent occlusion of the inferior M2 segment of the left MCA with mild atherosclerotic stenosis at the mid-M1 proximal to the occlusion (Fig. 2A, B). The occlusion was crossed with a Marksman microcatheter (Medtronic, Minneapolis, MN), and a microguidewire using a Penumbra 5MAX ACE 68 catheter (Penumbra Inc., Alameda, CA) as an intermediate support catheter.Fig. 2 Case 1. (A, B) Initial angiography showing occlusion of the inferior M2 of the left middle cerebral artery. Note the mild atherosclerotic stenosis of the mid-M1 proximal to the occlusion (arrow). (C, D) A microcatheter navigated into the distal portion of the thrombus, and a Trevo XP 3 mm × 20 mm stent retriever placed across the occluded lesion. We attempted to place the Penumbra catheter at the proximal M1 as an intermediate support catheter, but could not advance beyond the origin of the ophthalmic artery at that time. (E) Upon removal of the microcatheter, the Penumbra sifted up to the mid-M1, which was initially nonoccluded but mildly arteriosclerotic. (F) The stent retriever pulled back, and a small clot was retrieved. (G) Upon pulling back the Penumbra proximally, after being wedged at the mid-M1, angiography demonstrated recanalization. (H) Irregular stenosis noticed at mid-M1 which gradually progressed with decreasing peripheral blood flow. (I, J, K) Despite performing percutaneous transluminal angioplasty, the lesion is dilated and then restenosed repeatedly. (L, M, N) A drug-eluting stent placed at the lesion, and cone-beam computed tomography showing the lesion successfully recovered with sufficient stent-wall apposition. (O) Final angiography confirming complete recanalization.
Fig 2
We attempted to place the Penumbra at the proximal M1 but could not advance beyond the ophthalmic artery origin because of the ledge effect at that time. A Trevo XP 3 mm × 20 mm SR (Stryker Neurovascular, Kalamazoo, MI) was placed across the occluded lesion (Fig. 2C, D). When the microcatheter was removed to increase suction force from the Penumbra, the Penumbra unintentionally shifted up to the mid-M1 which was initially nonoccluded but mildly arteriosclerotic (Fig. 2E). The placed SR was pulled back through the Penumbra under continuous aspiration, and a small clot was retrieved (Fig. 2F). The Penumbra was pulled back to the C1 portion of the ICA from mid-M1, as it was wedged at the mid M1, and angiography showed the occlusion at M2 had been recanalized (Fig. 2G). The time from femoral puncture to recanalization was 35 minutes, and the time from stroke onset to recanalization was 205 minutes. However, irregular stenosis was noticed in the mid-M1, and it gradually progressed with decreasing peripheral blood flow (Fig. 2H). Based on the appearance of the irregular stenosis and the unintentional shift of the Penumbra, this lesion was considered a vessel dissection induced by the tip of the Penumbra at an initially atherosclerotic vessel. Intravenous alteplase infusion was not yet finished, but systemic heparinization was started.
Percutaneous transluminal angioplasty (PTA) was performed using a Gateway 2 mm × 9 mm balloon catheter (Stryker Neurovascular) several times over for an hour, and the stenotic lesion was dilated and then restenosed repeatedly (Fig. 2I, J, K). Because an intracranial stent was not readily available at the time of surgery, we employed a DES for coronary use that was regularly available for percutaneous coronary intervention at our institution. A Xience Sierra DES 2.25 mm × 15 mm (Abbott Vascular, Santa Clara, CA) was placed at the lesion, and the stenosis was successfully recovered with sufficient stent-wall apposition which was viewed with cone-beam computed tomography (Fig. 2L, M, N). Final angiography confirmed a score of 3 on thrombolysis in cerebral infarction recanalization (Fig. 2O).
MRA and DWI on the day after the procedure showed successful recanalization with localized ischemic change (Fig. 1C, D). Anticoagulant therapy for the prevention of cardiogenic embolism was started and continued in addition to dual antiplatelets. At the 3-month follow-up, the patient was almost independent with only mild sensory aphasia.
Case 2
An 83-year-old woman was admitted to our institute with left hemiparesis, a National Institutes of Health Stroke Scale score of 4, and an unknown time of symptom onset. She had a history of atrial fibrillation but was not taking anticoagulants. MRA and DWI showed occlusion of the M1 segment of the right MCA with subtle ischemic change (Fig. 3A, B). There was a mild atherosclerotic stenosis at the mid-M1 proximal to the occlusion (Fig. 3A). Intravenous thrombolysis was not initiated because of the time course. Written informed consent was obtained from a member of the patient's family before the procedure.Fig. 3 Case 2. (A, B) Magnetic resonance angiography and diffusion-weighted imaging performed upon patient admission showing occlusion of the M1 segment of the left middle cerebral artery with subtle ischemic change. Note the mild atherosclerotic stenosis at the mid-M1 proximal to the occlusion (arrow). (C, D) Magnetic resonance angiography and diffusion-weighted imaging performed the day after the procedure showing successful recanalization with small ischemic change.
Fig 3
The endovascular procedure was performed via femoral access under local anesthesia after systemic heparinization. A 9-French BGC was placed in the right cervical ICA. Initial angiography revealed occlusion of the M1 of the right MCA (Fig. 4A). One pass of the simple SR technique using a Trevo XP 4 mm × 20 mm (Stryker Neurovascular) failed to recanalize the occlusion (Fig. 4B, C). Subsequently, a Penumbra 5MAX ACE 60 catheter (Penumbra Inc.), a Trevo Pro18 microcatheter (Stryker Neurovascular), and a microguidewire were advanced as a unit, with the microcatheter traversing the occlusion. A Penumbra ACE 60 was used instead of an ACE 68 because previous angiography revealed mild stenosis at the mid-M1 (Fig. 4C). However, during this manipulation, the Penumbra shifted up to the occluded site through the mildly arteriosclerotic mid-M1 (Fig. 4D). A Trevo XP 4 mm × 20 mm (Stryker Neurovascular) was placed beyond the Penumbra without reposition of the Penumbra (Fig. 4E). The SR and the Penumbra were pulled back together through the BGC under continuous aspiration, and a hard clot was retrieved (Fig. 4F). Subsequent angiography demonstrated recanalization of the occlusion (Fig. 4G).Fig. 4 Case 2. (A) Initial angiography showing occlusion of the M1 of the right middle cerebral artery. (B, C) One pass of a simple stent retriever technique using a Trevo XP 4 mm × 20 mm failed to recanalize the occlusion. Note the mild atherosclerotic stenosis of the mid-M1 proximal to the occlusion (arrow). (D) During the second pass with a combined technique using a Penumbra 5MAX ACE 60 catheter, the Penumbra shifted to the occluded site through the mid-M1, which was initially non-occluded but mildly arteriosclerotic. (E) A Trevo XP 4 mm × 20 mm stent retriever placed beyond the Penumbra without repositioning the Penumbra. (F) The placed stent retriever and the Penumbra pulled together, and a hard clot was retrieved. (G) Angiography demonstrating recanalization. (H) Irregular stenosis noticed at mid-M1 which gradually progressed with decreasing peripheral blood flow. (I, J, K) Despite performing percutaneous transluminal angioplasty, the lesion is dilated and then restenosed repeatedly. (L, M, N) An Enterprise stent placed at the lesion, and the lesion successfully recovered with sufficient stent-wall apposition, as viewed on cone-beam computed tomography. (O) Final angiography confirming successful recanalization.
Fig 4
The time from femoral puncture to recanalization was 38 minutes. However, irregular stenosis developed at the mid-M1 which gradually progressed, eliminating peripheral blood flow (Fig. 4H). Based on the irregular stenosis and the preceding maneuver, this lesion was considered a vessel dissection induced by the tip of the Penumbra catheter at an initially atherosclerotic vessel. Over the course of an hour, PTA was conducted several times, using a Gateway 2.5 mm × 9 mm (Stryker Neurovascular). Dosing with dual antiplatelet drugs (300 mg of aspirin and 300 mg of clopidogrel) also failed to improve the lesion or maintain the blood flow (Fig. 4I, J, K). Therefore, an Enterprise stent 4 mm × 23 mm (Cordis, Miami Lakes, FL) was placed at the lesion, and the stenosis was successfully recovered with sufficient stent-wall apposition (Fig. 4L, M, N). Final angiography confirmed a score of 2b on thrombolysis in cerebral infarction recanalization (Fig. 4O).
MRA and DWI on the day after the procedure showed successful recanalization with small ischemic change (Fig. 3C, D). Oral anticoagulant therapy was started and continued in addition to dual antiplatelets. At the 3-month follow-up, the patient was independent with no neurological symptoms.
Discussion
We report 2 cases of iatrogenic intracranial artery dissection during mechanical thrombectomy that were rescued through emergent stenting. In each case, an inadvertent shift of the aspiration catheter into mildly arteriosclerotic vessels during the procedure was the suggested cause of vessel dissection. When performing mechanical thrombectomy, it is necessary to manipulate the aspiration catheter to avoid such movement near arteriosclerotic vessels. Stenting may be necessary in cases of dissection where blood flow to the periphery is not maintained.
Iatrogenic intracranial vessel dissection is not seen frequently, but it is one of the procedural complications associated with endovascular procedures for intracranial lesions. During mechanical thrombectomy, intracranial vessel dissection can also occur and might be more likely because mechanical thrombectomy is the procedure used for occluded vessels with emergent setting. It has been reported that iatrogenic vessel dissection occurs in 0.6%-3.9% of mechanical thrombectomy cases [11], [12], [13]. Among these cases, extracranial dissection was more common, whereas intracranial vessel dissection was precisely described in only a small number [11,17]. Among approximately 250 cases of mechanical thrombectomy at our institute over the past 5 years, only these 2 patients were definitively diagnosed with iatrogenic intracranial dissection (0.8%) [20], [21], [22], [23]. However, there is a current concern that instances of intracranial dissection may increase because more peripheral lesions are being treated with a variety of interventions other than the simple SR technique. Therefore, it is necessary to describe the procedural causes of iatrogenic intracranial vessel dissection, their implications, and strategies for managing them during mechanical thrombectomy.
Our findings from these 2 cases suggest that an inadvertent shift of the aspiration catheter into the arteriosclerotic vessels caused intracranial vessel dissection during mechanical thrombectomy. In both cases, dissection occurred at the initially nonoccluded but mildly arteriosclerotic M1, where a large-bore aspiration catheter shifted up into the distal vessel through the atherosclerotic lesion. Among the few previous reports of intracranial vessel dissection during mechanical thrombectomy, the aspiration catheter was reported as the estimated cause of dissection [17]. Various large-bore aspiration catheters for mechanical thrombectomy have been developed and are now widely used with contact aspiration or an SR and aspiration catheter combined. It has been reported that in older patients, it is prudent to use an appropriate inner catheter with the large-bore aspiration catheters in order to minimize the lip as it crosses the origin of the ophthalmic artery, while taking into account the amount of force applied to the aspiration catheter to reach the M1 segment [24]. Inadvertent shift of the aspiration catheter into arteriosclerotic vessels, even if the arteriosclerotic change is mild, should be avoided during mechanical thrombectomy. Although other mechanical thrombectomy procedures, including the simple SR technique, might cause vessel dissection, clinicians should manipulate the aspiration catheter to prevent shifting to distal vessels with arteriosclerotic changes, as shown in our 2 cases. Especially for relatively peripheral vessels, it is necessary to plan exactly what caliber of aspiration catheter to use and where to use it.
Currently there is no published evidence regarding the management of iatrogenic vessel dissection, especially in intracranial arteries. Generally, PTA or stenting may be considered if blood flow is strongly impaired [12]. In our 2 cases, repeated PTA with antithrombotic therapy failed to improve the lesion and to maintain the blood flow distally. The dissected lesions were rescued through emergent stenting, and the postoperative course in each case was uneventful. A DES for coronary use was employed in the Case 1 case because an intracranial stent was not available for emergency use at the time. However, the Enterprise stent, which had become available for emergency use at our institution, was applied in the Case 2. DES is not generally indicated for intracranial use, but there are some reports of its off-label use for intracranial arteries [25,26]. One of the problems with DES implantation is in-stent thrombosis, which usually requires long-term antiplatelet therapy to prevent [27]. The efficacy and safety of intracranial implantation of DES should be discussed after long-term follow-up. When performing mechanical thrombectomy, intracranial stents should be made available as a rescue treatment device, in order to manage refractory iatrogenic intracranial vessel dissection.
Conclusions
In this report, we describe 2 cases of iatrogenic intracranial artery dissection during mechanical thrombectomy that were rescued through emergent stenting. Our 2 cases suggest that an inadvertent shift of the aspiration catheter into arteriosclerotic vessels, even if the arteriosclerotic change is mild, is a probable cause of iatrogenic intracranial vessel dissection. When performing mechanical thrombectomy using an aspiration catheter, it is necessary to plan the exact placement and caliber of the aspiration catheter to prevent this complication. Stenting may be necessary in cases of dissection where blood flow to the periphery is not maintained, despite PTA with antithrombotic therapy.
Informed consent
Informed consent was obtained from each patient for inclusion of their information in publication of the case report and accompanying images.
Acknowledgments: A part of this research was supported by the Japanese Society for the Promotion of Science Grants-in-Aid for Scientific Research (JSPS KAKENHI Grant Number JP20K17968).
Competing Interests: None. | ASPIRIN, PRASUGREL HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33552335 | 19,226,765 | 2021-04 |
What was the dosage of drug 'ASPIRIN'? | Iatrogenic intracranial vessel dissection during mechanical thrombectomy rescued by emergent stenting: 2 case reports.
Intracranial vessel dissection is a procedural complication associated with endovascular treatment. However, there have been few reports on its potential causes and management during mechanical thrombectomy. In approximately 250 cases of mechanical thrombectomy over the past 5 years at our institution, iatrogenic intracranial dissection occurred in 2 patients (0.8%). In this report, we described these 2 cases that were rescued through emergent stenting. Mechanical thrombectomy, using both a stent retriever and an aspiration catheter, was performed for acute middle cerebral artery M2 occlusion in Patient 1 (a 69-year-old man) and for distal M1 occlusion in Patient 2 (an 83-year-old woman). In both cases, recanalization was achieved with the procedure, but irregular stenosis developed at the initially nonoccluded, but mildly arteriosclerotic, M1, after recanalization. During the thrombectomy procedure, the aspiration catheter sifted up to the arteriosclerotic M1. In both cases, the lesions were considered vessel dissection, due to a shift of the aspiration catheter tip into the arteriosclerotic vessel wall. Repeated percutaneous angiography with antithrombotic therapy failed to improve the lesions and to maintain the antegrade blood flow. Finally, lesions in each patient were successfully rescued through the use of emergent stenting. A drug-eluting stent for coronary use was deployed in Patient 1, and an Enterprise stent was applied in Patient 2. Inadvertent shift of the aspiration catheter into arteriosclerotic vessels can cause a serious intracranial vessel dissection. When performing mechanical thrombectomy, intracranial stents need to be available as rescue treatment devices to manage refractory iatrogenic intracranial vessel dissection.
Introduction
Mechanical thrombectomy using a stent retriever (SR) has proven to be effective for patients with acute ischemic stroke secondary to large vessel occlusions [1]. In addition to the use of a single SR, various devices and techniques for mechanical thrombectomy have emerged and are now widely used to achieve good procedural results [2], [3], [4], [5], [6]. Furthermore, mechanical thrombectomy is now being used to target more peripheral arteries [7], [8], [9]. However, mechanical thrombectomy can sometimes be associated with several procedural complications, including vessel injury, distal embolism, puncture site problems, and postprocedural intracranial hemorrhage [10], [11], [12], [13], [14].
Vessel injury is the most directly related procedural complication, usually caused by clinician error while using endovascular devices and techniques. Vessel perforation is common and requires urgent management because it can lead to critical conditions [15,16]. Vessel perforation is usually noticed as an obvious protrusion of a device from the vascular structure, or is visualized as a contrast leak at the distal site of the manipulation. Improper mechanical thrombectomy procedures can also cause vessel dissection, another type of vessel injury [17], [18], [19]. Unlike vessel perforation, vessel dissection is not always apparent on subsequent angiography and can occur at any procedural site without the obvious protrusion of a device from a vascular structure. To prevent and manage vessel dissection during mechanical thrombectomy, clinicians need to be aware of procedures causing this complication and ways to avoid them as well as rescue them.
Two patients (0.8%), out of approximately 250 cases of mechanical thrombectomy over the past 5 years at our institution, were definitively diagnosed with iatrogenic intracranial dissection caused by the thrombectomy procedure [20], [21], [22], [23]. In this report, we provide the details of these 2 cases of refractory iatrogenic intracranial artery dissection that occurred during mechanical thrombectomy performed with the combined use of an SR and an aspiration catheter. Both occurred on a mildly arteriosclerotic vessel proximal to the occlusion, and each was rescued through emergent stenting.
Case descriptions
Case 1
A 69-year-old man with a history of hypertension and diabetes mellitus was hospitalized at our institute for myocardial infarction. He suddenly developed aphasia with a National Institutes of Health Stroke Scale score of 8. He had previously undergone percutaneous coronary intervention with drug-eluting stents (DES) and was taking 100 mg of aspirin and 3.75 mg of prasugrel daily. Magnetic resonance angiography (MRA) and diffusion-weighted imaging (DWI) showed occlusion of the M2 segment of the left middle cerebral artery (MCA) with only slight ischemic change (Fig. 1A, B). There was mild atherosclerotic stenosis at the mid-M1 segment of the MCA proximal to the occlusion (Fig. 1A). After initiating intravenous thrombolysis with alteplase, endovascular treatment was performed. Written informed consent was obtained from a member of the patient's family before the procedure.Fig. 1 Case 1. (A, B) Magnetic resonance angiography and diffusion-weighted imaging performed upon patient admission, showing occlusion of the M2 segment of the left middle cerebral artery with only slight ischemic change. Note the mild atherosclerotic stenosis at the mid-M1 proximal to the occlusion (arrow). (C, D) Magnetic resonance angiography and diffusion-weighted imaging performed the day after the procedure, showing successful recanalization with localized ischemic change.
Fig 1
The endovascular procedure was performed via femoral access under local anesthesia. Heparin was not administered initially because of the ongoing administration of alteplase. A 9-French balloon-guide catheter (BGC) was placed in the left cervical internal carotid artery (ICA). Initial angiography revealed persistent occlusion of the inferior M2 segment of the left MCA with mild atherosclerotic stenosis at the mid-M1 proximal to the occlusion (Fig. 2A, B). The occlusion was crossed with a Marksman microcatheter (Medtronic, Minneapolis, MN), and a microguidewire using a Penumbra 5MAX ACE 68 catheter (Penumbra Inc., Alameda, CA) as an intermediate support catheter.Fig. 2 Case 1. (A, B) Initial angiography showing occlusion of the inferior M2 of the left middle cerebral artery. Note the mild atherosclerotic stenosis of the mid-M1 proximal to the occlusion (arrow). (C, D) A microcatheter navigated into the distal portion of the thrombus, and a Trevo XP 3 mm × 20 mm stent retriever placed across the occluded lesion. We attempted to place the Penumbra catheter at the proximal M1 as an intermediate support catheter, but could not advance beyond the origin of the ophthalmic artery at that time. (E) Upon removal of the microcatheter, the Penumbra sifted up to the mid-M1, which was initially nonoccluded but mildly arteriosclerotic. (F) The stent retriever pulled back, and a small clot was retrieved. (G) Upon pulling back the Penumbra proximally, after being wedged at the mid-M1, angiography demonstrated recanalization. (H) Irregular stenosis noticed at mid-M1 which gradually progressed with decreasing peripheral blood flow. (I, J, K) Despite performing percutaneous transluminal angioplasty, the lesion is dilated and then restenosed repeatedly. (L, M, N) A drug-eluting stent placed at the lesion, and cone-beam computed tomography showing the lesion successfully recovered with sufficient stent-wall apposition. (O) Final angiography confirming complete recanalization.
Fig 2
We attempted to place the Penumbra at the proximal M1 but could not advance beyond the ophthalmic artery origin because of the ledge effect at that time. A Trevo XP 3 mm × 20 mm SR (Stryker Neurovascular, Kalamazoo, MI) was placed across the occluded lesion (Fig. 2C, D). When the microcatheter was removed to increase suction force from the Penumbra, the Penumbra unintentionally shifted up to the mid-M1 which was initially nonoccluded but mildly arteriosclerotic (Fig. 2E). The placed SR was pulled back through the Penumbra under continuous aspiration, and a small clot was retrieved (Fig. 2F). The Penumbra was pulled back to the C1 portion of the ICA from mid-M1, as it was wedged at the mid M1, and angiography showed the occlusion at M2 had been recanalized (Fig. 2G). The time from femoral puncture to recanalization was 35 minutes, and the time from stroke onset to recanalization was 205 minutes. However, irregular stenosis was noticed in the mid-M1, and it gradually progressed with decreasing peripheral blood flow (Fig. 2H). Based on the appearance of the irregular stenosis and the unintentional shift of the Penumbra, this lesion was considered a vessel dissection induced by the tip of the Penumbra at an initially atherosclerotic vessel. Intravenous alteplase infusion was not yet finished, but systemic heparinization was started.
Percutaneous transluminal angioplasty (PTA) was performed using a Gateway 2 mm × 9 mm balloon catheter (Stryker Neurovascular) several times over for an hour, and the stenotic lesion was dilated and then restenosed repeatedly (Fig. 2I, J, K). Because an intracranial stent was not readily available at the time of surgery, we employed a DES for coronary use that was regularly available for percutaneous coronary intervention at our institution. A Xience Sierra DES 2.25 mm × 15 mm (Abbott Vascular, Santa Clara, CA) was placed at the lesion, and the stenosis was successfully recovered with sufficient stent-wall apposition which was viewed with cone-beam computed tomography (Fig. 2L, M, N). Final angiography confirmed a score of 3 on thrombolysis in cerebral infarction recanalization (Fig. 2O).
MRA and DWI on the day after the procedure showed successful recanalization with localized ischemic change (Fig. 1C, D). Anticoagulant therapy for the prevention of cardiogenic embolism was started and continued in addition to dual antiplatelets. At the 3-month follow-up, the patient was almost independent with only mild sensory aphasia.
Case 2
An 83-year-old woman was admitted to our institute with left hemiparesis, a National Institutes of Health Stroke Scale score of 4, and an unknown time of symptom onset. She had a history of atrial fibrillation but was not taking anticoagulants. MRA and DWI showed occlusion of the M1 segment of the right MCA with subtle ischemic change (Fig. 3A, B). There was a mild atherosclerotic stenosis at the mid-M1 proximal to the occlusion (Fig. 3A). Intravenous thrombolysis was not initiated because of the time course. Written informed consent was obtained from a member of the patient's family before the procedure.Fig. 3 Case 2. (A, B) Magnetic resonance angiography and diffusion-weighted imaging performed upon patient admission showing occlusion of the M1 segment of the left middle cerebral artery with subtle ischemic change. Note the mild atherosclerotic stenosis at the mid-M1 proximal to the occlusion (arrow). (C, D) Magnetic resonance angiography and diffusion-weighted imaging performed the day after the procedure showing successful recanalization with small ischemic change.
Fig 3
The endovascular procedure was performed via femoral access under local anesthesia after systemic heparinization. A 9-French BGC was placed in the right cervical ICA. Initial angiography revealed occlusion of the M1 of the right MCA (Fig. 4A). One pass of the simple SR technique using a Trevo XP 4 mm × 20 mm (Stryker Neurovascular) failed to recanalize the occlusion (Fig. 4B, C). Subsequently, a Penumbra 5MAX ACE 60 catheter (Penumbra Inc.), a Trevo Pro18 microcatheter (Stryker Neurovascular), and a microguidewire were advanced as a unit, with the microcatheter traversing the occlusion. A Penumbra ACE 60 was used instead of an ACE 68 because previous angiography revealed mild stenosis at the mid-M1 (Fig. 4C). However, during this manipulation, the Penumbra shifted up to the occluded site through the mildly arteriosclerotic mid-M1 (Fig. 4D). A Trevo XP 4 mm × 20 mm (Stryker Neurovascular) was placed beyond the Penumbra without reposition of the Penumbra (Fig. 4E). The SR and the Penumbra were pulled back together through the BGC under continuous aspiration, and a hard clot was retrieved (Fig. 4F). Subsequent angiography demonstrated recanalization of the occlusion (Fig. 4G).Fig. 4 Case 2. (A) Initial angiography showing occlusion of the M1 of the right middle cerebral artery. (B, C) One pass of a simple stent retriever technique using a Trevo XP 4 mm × 20 mm failed to recanalize the occlusion. Note the mild atherosclerotic stenosis of the mid-M1 proximal to the occlusion (arrow). (D) During the second pass with a combined technique using a Penumbra 5MAX ACE 60 catheter, the Penumbra shifted to the occluded site through the mid-M1, which was initially non-occluded but mildly arteriosclerotic. (E) A Trevo XP 4 mm × 20 mm stent retriever placed beyond the Penumbra without repositioning the Penumbra. (F) The placed stent retriever and the Penumbra pulled together, and a hard clot was retrieved. (G) Angiography demonstrating recanalization. (H) Irregular stenosis noticed at mid-M1 which gradually progressed with decreasing peripheral blood flow. (I, J, K) Despite performing percutaneous transluminal angioplasty, the lesion is dilated and then restenosed repeatedly. (L, M, N) An Enterprise stent placed at the lesion, and the lesion successfully recovered with sufficient stent-wall apposition, as viewed on cone-beam computed tomography. (O) Final angiography confirming successful recanalization.
Fig 4
The time from femoral puncture to recanalization was 38 minutes. However, irregular stenosis developed at the mid-M1 which gradually progressed, eliminating peripheral blood flow (Fig. 4H). Based on the irregular stenosis and the preceding maneuver, this lesion was considered a vessel dissection induced by the tip of the Penumbra catheter at an initially atherosclerotic vessel. Over the course of an hour, PTA was conducted several times, using a Gateway 2.5 mm × 9 mm (Stryker Neurovascular). Dosing with dual antiplatelet drugs (300 mg of aspirin and 300 mg of clopidogrel) also failed to improve the lesion or maintain the blood flow (Fig. 4I, J, K). Therefore, an Enterprise stent 4 mm × 23 mm (Cordis, Miami Lakes, FL) was placed at the lesion, and the stenosis was successfully recovered with sufficient stent-wall apposition (Fig. 4L, M, N). Final angiography confirmed a score of 2b on thrombolysis in cerebral infarction recanalization (Fig. 4O).
MRA and DWI on the day after the procedure showed successful recanalization with small ischemic change (Fig. 3C, D). Oral anticoagulant therapy was started and continued in addition to dual antiplatelets. At the 3-month follow-up, the patient was independent with no neurological symptoms.
Discussion
We report 2 cases of iatrogenic intracranial artery dissection during mechanical thrombectomy that were rescued through emergent stenting. In each case, an inadvertent shift of the aspiration catheter into mildly arteriosclerotic vessels during the procedure was the suggested cause of vessel dissection. When performing mechanical thrombectomy, it is necessary to manipulate the aspiration catheter to avoid such movement near arteriosclerotic vessels. Stenting may be necessary in cases of dissection where blood flow to the periphery is not maintained.
Iatrogenic intracranial vessel dissection is not seen frequently, but it is one of the procedural complications associated with endovascular procedures for intracranial lesions. During mechanical thrombectomy, intracranial vessel dissection can also occur and might be more likely because mechanical thrombectomy is the procedure used for occluded vessels with emergent setting. It has been reported that iatrogenic vessel dissection occurs in 0.6%-3.9% of mechanical thrombectomy cases [11], [12], [13]. Among these cases, extracranial dissection was more common, whereas intracranial vessel dissection was precisely described in only a small number [11,17]. Among approximately 250 cases of mechanical thrombectomy at our institute over the past 5 years, only these 2 patients were definitively diagnosed with iatrogenic intracranial dissection (0.8%) [20], [21], [22], [23]. However, there is a current concern that instances of intracranial dissection may increase because more peripheral lesions are being treated with a variety of interventions other than the simple SR technique. Therefore, it is necessary to describe the procedural causes of iatrogenic intracranial vessel dissection, their implications, and strategies for managing them during mechanical thrombectomy.
Our findings from these 2 cases suggest that an inadvertent shift of the aspiration catheter into the arteriosclerotic vessels caused intracranial vessel dissection during mechanical thrombectomy. In both cases, dissection occurred at the initially nonoccluded but mildly arteriosclerotic M1, where a large-bore aspiration catheter shifted up into the distal vessel through the atherosclerotic lesion. Among the few previous reports of intracranial vessel dissection during mechanical thrombectomy, the aspiration catheter was reported as the estimated cause of dissection [17]. Various large-bore aspiration catheters for mechanical thrombectomy have been developed and are now widely used with contact aspiration or an SR and aspiration catheter combined. It has been reported that in older patients, it is prudent to use an appropriate inner catheter with the large-bore aspiration catheters in order to minimize the lip as it crosses the origin of the ophthalmic artery, while taking into account the amount of force applied to the aspiration catheter to reach the M1 segment [24]. Inadvertent shift of the aspiration catheter into arteriosclerotic vessels, even if the arteriosclerotic change is mild, should be avoided during mechanical thrombectomy. Although other mechanical thrombectomy procedures, including the simple SR technique, might cause vessel dissection, clinicians should manipulate the aspiration catheter to prevent shifting to distal vessels with arteriosclerotic changes, as shown in our 2 cases. Especially for relatively peripheral vessels, it is necessary to plan exactly what caliber of aspiration catheter to use and where to use it.
Currently there is no published evidence regarding the management of iatrogenic vessel dissection, especially in intracranial arteries. Generally, PTA or stenting may be considered if blood flow is strongly impaired [12]. In our 2 cases, repeated PTA with antithrombotic therapy failed to improve the lesion and to maintain the blood flow distally. The dissected lesions were rescued through emergent stenting, and the postoperative course in each case was uneventful. A DES for coronary use was employed in the Case 1 case because an intracranial stent was not available for emergency use at the time. However, the Enterprise stent, which had become available for emergency use at our institution, was applied in the Case 2. DES is not generally indicated for intracranial use, but there are some reports of its off-label use for intracranial arteries [25,26]. One of the problems with DES implantation is in-stent thrombosis, which usually requires long-term antiplatelet therapy to prevent [27]. The efficacy and safety of intracranial implantation of DES should be discussed after long-term follow-up. When performing mechanical thrombectomy, intracranial stents should be made available as a rescue treatment device, in order to manage refractory iatrogenic intracranial vessel dissection.
Conclusions
In this report, we describe 2 cases of iatrogenic intracranial artery dissection during mechanical thrombectomy that were rescued through emergent stenting. Our 2 cases suggest that an inadvertent shift of the aspiration catheter into arteriosclerotic vessels, even if the arteriosclerotic change is mild, is a probable cause of iatrogenic intracranial vessel dissection. When performing mechanical thrombectomy using an aspiration catheter, it is necessary to plan the exact placement and caliber of the aspiration catheter to prevent this complication. Stenting may be necessary in cases of dissection where blood flow to the periphery is not maintained, despite PTA with antithrombotic therapy.
Informed consent
Informed consent was obtained from each patient for inclusion of their information in publication of the case report and accompanying images.
Acknowledgments: A part of this research was supported by the Japanese Society for the Promotion of Science Grants-in-Aid for Scientific Research (JSPS KAKENHI Grant Number JP20K17968).
Competing Interests: None. | 100MG/DAY | DrugDosageText | CC BY-NC-ND | 33552335 | 19,226,765 | 2021-04 |
What was the outcome of reaction 'Cerebral artery occlusion'? | Iatrogenic intracranial vessel dissection during mechanical thrombectomy rescued by emergent stenting: 2 case reports.
Intracranial vessel dissection is a procedural complication associated with endovascular treatment. However, there have been few reports on its potential causes and management during mechanical thrombectomy. In approximately 250 cases of mechanical thrombectomy over the past 5 years at our institution, iatrogenic intracranial dissection occurred in 2 patients (0.8%). In this report, we described these 2 cases that were rescued through emergent stenting. Mechanical thrombectomy, using both a stent retriever and an aspiration catheter, was performed for acute middle cerebral artery M2 occlusion in Patient 1 (a 69-year-old man) and for distal M1 occlusion in Patient 2 (an 83-year-old woman). In both cases, recanalization was achieved with the procedure, but irregular stenosis developed at the initially nonoccluded, but mildly arteriosclerotic, M1, after recanalization. During the thrombectomy procedure, the aspiration catheter sifted up to the arteriosclerotic M1. In both cases, the lesions were considered vessel dissection, due to a shift of the aspiration catheter tip into the arteriosclerotic vessel wall. Repeated percutaneous angiography with antithrombotic therapy failed to improve the lesions and to maintain the antegrade blood flow. Finally, lesions in each patient were successfully rescued through the use of emergent stenting. A drug-eluting stent for coronary use was deployed in Patient 1, and an Enterprise stent was applied in Patient 2. Inadvertent shift of the aspiration catheter into arteriosclerotic vessels can cause a serious intracranial vessel dissection. When performing mechanical thrombectomy, intracranial stents need to be available as rescue treatment devices to manage refractory iatrogenic intracranial vessel dissection.
Introduction
Mechanical thrombectomy using a stent retriever (SR) has proven to be effective for patients with acute ischemic stroke secondary to large vessel occlusions [1]. In addition to the use of a single SR, various devices and techniques for mechanical thrombectomy have emerged and are now widely used to achieve good procedural results [2], [3], [4], [5], [6]. Furthermore, mechanical thrombectomy is now being used to target more peripheral arteries [7], [8], [9]. However, mechanical thrombectomy can sometimes be associated with several procedural complications, including vessel injury, distal embolism, puncture site problems, and postprocedural intracranial hemorrhage [10], [11], [12], [13], [14].
Vessel injury is the most directly related procedural complication, usually caused by clinician error while using endovascular devices and techniques. Vessel perforation is common and requires urgent management because it can lead to critical conditions [15,16]. Vessel perforation is usually noticed as an obvious protrusion of a device from the vascular structure, or is visualized as a contrast leak at the distal site of the manipulation. Improper mechanical thrombectomy procedures can also cause vessel dissection, another type of vessel injury [17], [18], [19]. Unlike vessel perforation, vessel dissection is not always apparent on subsequent angiography and can occur at any procedural site without the obvious protrusion of a device from a vascular structure. To prevent and manage vessel dissection during mechanical thrombectomy, clinicians need to be aware of procedures causing this complication and ways to avoid them as well as rescue them.
Two patients (0.8%), out of approximately 250 cases of mechanical thrombectomy over the past 5 years at our institution, were definitively diagnosed with iatrogenic intracranial dissection caused by the thrombectomy procedure [20], [21], [22], [23]. In this report, we provide the details of these 2 cases of refractory iatrogenic intracranial artery dissection that occurred during mechanical thrombectomy performed with the combined use of an SR and an aspiration catheter. Both occurred on a mildly arteriosclerotic vessel proximal to the occlusion, and each was rescued through emergent stenting.
Case descriptions
Case 1
A 69-year-old man with a history of hypertension and diabetes mellitus was hospitalized at our institute for myocardial infarction. He suddenly developed aphasia with a National Institutes of Health Stroke Scale score of 8. He had previously undergone percutaneous coronary intervention with drug-eluting stents (DES) and was taking 100 mg of aspirin and 3.75 mg of prasugrel daily. Magnetic resonance angiography (MRA) and diffusion-weighted imaging (DWI) showed occlusion of the M2 segment of the left middle cerebral artery (MCA) with only slight ischemic change (Fig. 1A, B). There was mild atherosclerotic stenosis at the mid-M1 segment of the MCA proximal to the occlusion (Fig. 1A). After initiating intravenous thrombolysis with alteplase, endovascular treatment was performed. Written informed consent was obtained from a member of the patient's family before the procedure.Fig. 1 Case 1. (A, B) Magnetic resonance angiography and diffusion-weighted imaging performed upon patient admission, showing occlusion of the M2 segment of the left middle cerebral artery with only slight ischemic change. Note the mild atherosclerotic stenosis at the mid-M1 proximal to the occlusion (arrow). (C, D) Magnetic resonance angiography and diffusion-weighted imaging performed the day after the procedure, showing successful recanalization with localized ischemic change.
Fig 1
The endovascular procedure was performed via femoral access under local anesthesia. Heparin was not administered initially because of the ongoing administration of alteplase. A 9-French balloon-guide catheter (BGC) was placed in the left cervical internal carotid artery (ICA). Initial angiography revealed persistent occlusion of the inferior M2 segment of the left MCA with mild atherosclerotic stenosis at the mid-M1 proximal to the occlusion (Fig. 2A, B). The occlusion was crossed with a Marksman microcatheter (Medtronic, Minneapolis, MN), and a microguidewire using a Penumbra 5MAX ACE 68 catheter (Penumbra Inc., Alameda, CA) as an intermediate support catheter.Fig. 2 Case 1. (A, B) Initial angiography showing occlusion of the inferior M2 of the left middle cerebral artery. Note the mild atherosclerotic stenosis of the mid-M1 proximal to the occlusion (arrow). (C, D) A microcatheter navigated into the distal portion of the thrombus, and a Trevo XP 3 mm × 20 mm stent retriever placed across the occluded lesion. We attempted to place the Penumbra catheter at the proximal M1 as an intermediate support catheter, but could not advance beyond the origin of the ophthalmic artery at that time. (E) Upon removal of the microcatheter, the Penumbra sifted up to the mid-M1, which was initially nonoccluded but mildly arteriosclerotic. (F) The stent retriever pulled back, and a small clot was retrieved. (G) Upon pulling back the Penumbra proximally, after being wedged at the mid-M1, angiography demonstrated recanalization. (H) Irregular stenosis noticed at mid-M1 which gradually progressed with decreasing peripheral blood flow. (I, J, K) Despite performing percutaneous transluminal angioplasty, the lesion is dilated and then restenosed repeatedly. (L, M, N) A drug-eluting stent placed at the lesion, and cone-beam computed tomography showing the lesion successfully recovered with sufficient stent-wall apposition. (O) Final angiography confirming complete recanalization.
Fig 2
We attempted to place the Penumbra at the proximal M1 but could not advance beyond the ophthalmic artery origin because of the ledge effect at that time. A Trevo XP 3 mm × 20 mm SR (Stryker Neurovascular, Kalamazoo, MI) was placed across the occluded lesion (Fig. 2C, D). When the microcatheter was removed to increase suction force from the Penumbra, the Penumbra unintentionally shifted up to the mid-M1 which was initially nonoccluded but mildly arteriosclerotic (Fig. 2E). The placed SR was pulled back through the Penumbra under continuous aspiration, and a small clot was retrieved (Fig. 2F). The Penumbra was pulled back to the C1 portion of the ICA from mid-M1, as it was wedged at the mid M1, and angiography showed the occlusion at M2 had been recanalized (Fig. 2G). The time from femoral puncture to recanalization was 35 minutes, and the time from stroke onset to recanalization was 205 minutes. However, irregular stenosis was noticed in the mid-M1, and it gradually progressed with decreasing peripheral blood flow (Fig. 2H). Based on the appearance of the irregular stenosis and the unintentional shift of the Penumbra, this lesion was considered a vessel dissection induced by the tip of the Penumbra at an initially atherosclerotic vessel. Intravenous alteplase infusion was not yet finished, but systemic heparinization was started.
Percutaneous transluminal angioplasty (PTA) was performed using a Gateway 2 mm × 9 mm balloon catheter (Stryker Neurovascular) several times over for an hour, and the stenotic lesion was dilated and then restenosed repeatedly (Fig. 2I, J, K). Because an intracranial stent was not readily available at the time of surgery, we employed a DES for coronary use that was regularly available for percutaneous coronary intervention at our institution. A Xience Sierra DES 2.25 mm × 15 mm (Abbott Vascular, Santa Clara, CA) was placed at the lesion, and the stenosis was successfully recovered with sufficient stent-wall apposition which was viewed with cone-beam computed tomography (Fig. 2L, M, N). Final angiography confirmed a score of 3 on thrombolysis in cerebral infarction recanalization (Fig. 2O).
MRA and DWI on the day after the procedure showed successful recanalization with localized ischemic change (Fig. 1C, D). Anticoagulant therapy for the prevention of cardiogenic embolism was started and continued in addition to dual antiplatelets. At the 3-month follow-up, the patient was almost independent with only mild sensory aphasia.
Case 2
An 83-year-old woman was admitted to our institute with left hemiparesis, a National Institutes of Health Stroke Scale score of 4, and an unknown time of symptom onset. She had a history of atrial fibrillation but was not taking anticoagulants. MRA and DWI showed occlusion of the M1 segment of the right MCA with subtle ischemic change (Fig. 3A, B). There was a mild atherosclerotic stenosis at the mid-M1 proximal to the occlusion (Fig. 3A). Intravenous thrombolysis was not initiated because of the time course. Written informed consent was obtained from a member of the patient's family before the procedure.Fig. 3 Case 2. (A, B) Magnetic resonance angiography and diffusion-weighted imaging performed upon patient admission showing occlusion of the M1 segment of the left middle cerebral artery with subtle ischemic change. Note the mild atherosclerotic stenosis at the mid-M1 proximal to the occlusion (arrow). (C, D) Magnetic resonance angiography and diffusion-weighted imaging performed the day after the procedure showing successful recanalization with small ischemic change.
Fig 3
The endovascular procedure was performed via femoral access under local anesthesia after systemic heparinization. A 9-French BGC was placed in the right cervical ICA. Initial angiography revealed occlusion of the M1 of the right MCA (Fig. 4A). One pass of the simple SR technique using a Trevo XP 4 mm × 20 mm (Stryker Neurovascular) failed to recanalize the occlusion (Fig. 4B, C). Subsequently, a Penumbra 5MAX ACE 60 catheter (Penumbra Inc.), a Trevo Pro18 microcatheter (Stryker Neurovascular), and a microguidewire were advanced as a unit, with the microcatheter traversing the occlusion. A Penumbra ACE 60 was used instead of an ACE 68 because previous angiography revealed mild stenosis at the mid-M1 (Fig. 4C). However, during this manipulation, the Penumbra shifted up to the occluded site through the mildly arteriosclerotic mid-M1 (Fig. 4D). A Trevo XP 4 mm × 20 mm (Stryker Neurovascular) was placed beyond the Penumbra without reposition of the Penumbra (Fig. 4E). The SR and the Penumbra were pulled back together through the BGC under continuous aspiration, and a hard clot was retrieved (Fig. 4F). Subsequent angiography demonstrated recanalization of the occlusion (Fig. 4G).Fig. 4 Case 2. (A) Initial angiography showing occlusion of the M1 of the right middle cerebral artery. (B, C) One pass of a simple stent retriever technique using a Trevo XP 4 mm × 20 mm failed to recanalize the occlusion. Note the mild atherosclerotic stenosis of the mid-M1 proximal to the occlusion (arrow). (D) During the second pass with a combined technique using a Penumbra 5MAX ACE 60 catheter, the Penumbra shifted to the occluded site through the mid-M1, which was initially non-occluded but mildly arteriosclerotic. (E) A Trevo XP 4 mm × 20 mm stent retriever placed beyond the Penumbra without repositioning the Penumbra. (F) The placed stent retriever and the Penumbra pulled together, and a hard clot was retrieved. (G) Angiography demonstrating recanalization. (H) Irregular stenosis noticed at mid-M1 which gradually progressed with decreasing peripheral blood flow. (I, J, K) Despite performing percutaneous transluminal angioplasty, the lesion is dilated and then restenosed repeatedly. (L, M, N) An Enterprise stent placed at the lesion, and the lesion successfully recovered with sufficient stent-wall apposition, as viewed on cone-beam computed tomography. (O) Final angiography confirming successful recanalization.
Fig 4
The time from femoral puncture to recanalization was 38 minutes. However, irregular stenosis developed at the mid-M1 which gradually progressed, eliminating peripheral blood flow (Fig. 4H). Based on the irregular stenosis and the preceding maneuver, this lesion was considered a vessel dissection induced by the tip of the Penumbra catheter at an initially atherosclerotic vessel. Over the course of an hour, PTA was conducted several times, using a Gateway 2.5 mm × 9 mm (Stryker Neurovascular). Dosing with dual antiplatelet drugs (300 mg of aspirin and 300 mg of clopidogrel) also failed to improve the lesion or maintain the blood flow (Fig. 4I, J, K). Therefore, an Enterprise stent 4 mm × 23 mm (Cordis, Miami Lakes, FL) was placed at the lesion, and the stenosis was successfully recovered with sufficient stent-wall apposition (Fig. 4L, M, N). Final angiography confirmed a score of 2b on thrombolysis in cerebral infarction recanalization (Fig. 4O).
MRA and DWI on the day after the procedure showed successful recanalization with small ischemic change (Fig. 3C, D). Oral anticoagulant therapy was started and continued in addition to dual antiplatelets. At the 3-month follow-up, the patient was independent with no neurological symptoms.
Discussion
We report 2 cases of iatrogenic intracranial artery dissection during mechanical thrombectomy that were rescued through emergent stenting. In each case, an inadvertent shift of the aspiration catheter into mildly arteriosclerotic vessels during the procedure was the suggested cause of vessel dissection. When performing mechanical thrombectomy, it is necessary to manipulate the aspiration catheter to avoid such movement near arteriosclerotic vessels. Stenting may be necessary in cases of dissection where blood flow to the periphery is not maintained.
Iatrogenic intracranial vessel dissection is not seen frequently, but it is one of the procedural complications associated with endovascular procedures for intracranial lesions. During mechanical thrombectomy, intracranial vessel dissection can also occur and might be more likely because mechanical thrombectomy is the procedure used for occluded vessels with emergent setting. It has been reported that iatrogenic vessel dissection occurs in 0.6%-3.9% of mechanical thrombectomy cases [11], [12], [13]. Among these cases, extracranial dissection was more common, whereas intracranial vessel dissection was precisely described in only a small number [11,17]. Among approximately 250 cases of mechanical thrombectomy at our institute over the past 5 years, only these 2 patients were definitively diagnosed with iatrogenic intracranial dissection (0.8%) [20], [21], [22], [23]. However, there is a current concern that instances of intracranial dissection may increase because more peripheral lesions are being treated with a variety of interventions other than the simple SR technique. Therefore, it is necessary to describe the procedural causes of iatrogenic intracranial vessel dissection, their implications, and strategies for managing them during mechanical thrombectomy.
Our findings from these 2 cases suggest that an inadvertent shift of the aspiration catheter into the arteriosclerotic vessels caused intracranial vessel dissection during mechanical thrombectomy. In both cases, dissection occurred at the initially nonoccluded but mildly arteriosclerotic M1, where a large-bore aspiration catheter shifted up into the distal vessel through the atherosclerotic lesion. Among the few previous reports of intracranial vessel dissection during mechanical thrombectomy, the aspiration catheter was reported as the estimated cause of dissection [17]. Various large-bore aspiration catheters for mechanical thrombectomy have been developed and are now widely used with contact aspiration or an SR and aspiration catheter combined. It has been reported that in older patients, it is prudent to use an appropriate inner catheter with the large-bore aspiration catheters in order to minimize the lip as it crosses the origin of the ophthalmic artery, while taking into account the amount of force applied to the aspiration catheter to reach the M1 segment [24]. Inadvertent shift of the aspiration catheter into arteriosclerotic vessels, even if the arteriosclerotic change is mild, should be avoided during mechanical thrombectomy. Although other mechanical thrombectomy procedures, including the simple SR technique, might cause vessel dissection, clinicians should manipulate the aspiration catheter to prevent shifting to distal vessels with arteriosclerotic changes, as shown in our 2 cases. Especially for relatively peripheral vessels, it is necessary to plan exactly what caliber of aspiration catheter to use and where to use it.
Currently there is no published evidence regarding the management of iatrogenic vessel dissection, especially in intracranial arteries. Generally, PTA or stenting may be considered if blood flow is strongly impaired [12]. In our 2 cases, repeated PTA with antithrombotic therapy failed to improve the lesion and to maintain the blood flow distally. The dissected lesions were rescued through emergent stenting, and the postoperative course in each case was uneventful. A DES for coronary use was employed in the Case 1 case because an intracranial stent was not available for emergency use at the time. However, the Enterprise stent, which had become available for emergency use at our institution, was applied in the Case 2. DES is not generally indicated for intracranial use, but there are some reports of its off-label use for intracranial arteries [25,26]. One of the problems with DES implantation is in-stent thrombosis, which usually requires long-term antiplatelet therapy to prevent [27]. The efficacy and safety of intracranial implantation of DES should be discussed after long-term follow-up. When performing mechanical thrombectomy, intracranial stents should be made available as a rescue treatment device, in order to manage refractory iatrogenic intracranial vessel dissection.
Conclusions
In this report, we describe 2 cases of iatrogenic intracranial artery dissection during mechanical thrombectomy that were rescued through emergent stenting. Our 2 cases suggest that an inadvertent shift of the aspiration catheter into arteriosclerotic vessels, even if the arteriosclerotic change is mild, is a probable cause of iatrogenic intracranial vessel dissection. When performing mechanical thrombectomy using an aspiration catheter, it is necessary to plan the exact placement and caliber of the aspiration catheter to prevent this complication. Stenting may be necessary in cases of dissection where blood flow to the periphery is not maintained, despite PTA with antithrombotic therapy.
Informed consent
Informed consent was obtained from each patient for inclusion of their information in publication of the case report and accompanying images.
Acknowledgments: A part of this research was supported by the Japanese Society for the Promotion of Science Grants-in-Aid for Scientific Research (JSPS KAKENHI Grant Number JP20K17968).
Competing Interests: None. | Recovering | ReactionOutcome | CC BY-NC-ND | 33552335 | 19,226,765 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Mixed liver injury'. | A case of meropenem-induced liver injury and jaundice.
This report describes what we believe is the first reported case of clinically significant cholestasis and acute liver injury within three days of meropenem therapy. An 83-year-old Hispanic female was admitted for sepsis of unknown origin and was started on intravenous meropenem. Three days following initiation of the antibiotic, the patient developed mixed hepatocellular and cholestatic liver injury with jaundice and pruritus. Possible causes of cholestasis were excluded after extensive investigations. A drug-induced liver injury was suspected and meropenem was discontinued. Following discontinuation of meropenem, the patient demonstrated symptomatic and laboratory improvements, and her liver enzymes and bilirubin levels were normalized.
1. Introduction
Meropenem is a broad-spectrum antibiotic that has excellent activity against many gram-negative, gram-positive and anaerobic organisms. It is commonly used in the hospital setting for complicated infections. Mild, transient, asymptomatic aminotransferase elevations have been reported with meropenem use, but it rarely results in clinically apparent, symptomatic cholestasis [1–3].
2. Case report
An 83-year-old female with a medical history of hypertension and type II diabetes mellitus presented to the emergency department with a two-day history of dark color stools. Patient had no prior history of gastrointestinal (GI) bleed; she denied fever, abdominal pain, jaundice or weight loss. Her home medications include metformin and lisinopril. Patient was afebrile; initial vital signs were significant for sinus tachycardia and blood pressure was 150/72 mmHg. Physical examination revealed dark color stool on rectal exam. The rest of the physical examination was unremarkable. Initial laboratory studies were significant for a white blood cell count of 15.2 mm3, lactic acid 3.8 mmol/L, hemoglobin 7.3 g/dL and hematocrit 31%. Liver enzymes and bilirubin level were within normal limits. Urinalysis, chest radiograph and influenza viral testing were negative. Computed tomography (CT) scan of abdomen without contrast was unremarkable. The patient was admitted for acute anemia and sepsis of unknown origin. While a septic workup was undertaken, the patient received two units of packed red blood cell transfusion, intravenous (IV) fluid resuscitation and was started on broad spectrum antibiotic with IV meropenem 500 milligrams every eight hours. Post-transfusion hemoglobin was 9.4 g/dL and remained stable. No further episode of dark stool was reported. Fecal occult blood testing was negative. Blood cultures showed no growth after two days of incubation.
Three days following hospital admission, routine laboratory study showed a markedly elevated liver function test (LFT) with aspartate aminotransferase (AST) 230 U/L and alanine transaminase (ALT) 753 U/L, total bilirubin 8.3 mg/dL, direct bilirubin 6.7 mg/dL and serum alkaline phosphatase (ALP) 167 U/L. On physical examination, patient was noted to have mild jaundice. She denied any GI symptoms. Right upper quadrant ultrasound showed normal gallbladder and biliary ducts, no evidence of gallstones or biliary dilation. On the following day, repeat laboratory study showed worsening LFT with AST 370 U/L and ALT 1191 U/L, total bilirubin 12 mg/dl, direct bilirubin 10.89 mg/dl and serum ALP 192 U/L. Lactate dehydrogenase and serum inflammatory markers erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP) were within normal limits. Patient denied GI symptoms but reported to have generalized pruritus. On physical examination, vital signs were stable; conjunctival icterus and worsening jaundice were noted. Viral hepatitis serology, autoimmune markers including antinuclear antibodies, anti-smooth muscle antibodies and anti-mitochondrial antibodies were unremarkable. Further investigation with abdominal CT scan, magnetic resonance imaging (MRI) of abdomen and magnetic resonance cholangiopancreatography (MRCP) were unrevealing; there was no evidence of gallstones or choledocholithiasis, no intra- or extra-biliary ductal dilatation. Given recent dark colored stools, patient also underwent upper endoscopy and colonoscopy which revealed mild gastritis and a few small colonic polyps, respectively; no source of anemia was identified during the procedures. However, patient’s liver enzymes and bilirubin levels continued to rise with worsening jaundice and pruritus. A drug-induced liver injury (DILI) was suspected, her medication list was reviewed and meropenem was discontinued. Two days following discontinuation of meropenem, the patient demonstrated symptomatic improvements. Her liver enzymes, bilirubin and ALP levels improved steadily and returned to normal by Day 5 following meropenem discontinuation. Patient was discharged home and was instructed to follow up with gastroenterologist as outpatient.
3. Discussion
Meropenem is a beta-lactam antibiotic that belongs to the carbapenem class; it acts by binding to the penicillin-binding proteins and interferes with the structural integrity of bacterial cell wall. Meropenem has a broad spectrum of activity against many gram-negative and gram-positive organisms; it is administered intravenously with the recommended dosage of 0.5–1 gram every 8 hours. Meropenem is mainly cleared by renal excretion and is a generally well-tolerated antibiotic with most common adverse GI effects being nausea, vomiting and diarrhea [3]. Meropenem was reported to cause mild, asymptomatic, transient serum aminotransferase elevation when it is being used daily for more than 14 days and it rarely requires dose adjustments or discontinuation [4]. To our knowledge, clinically apparent, symptomatic cholestasis and liver injury within three days of meropenem therapy, as the patient in our case, has not been reported in the literature [1,3,4].
DILI is a diagnosis of exclusion. It is diagnosed when other potential causes of liver injury such as viral hepatitis, autoimmune disease, immunologic conditions, biliary obstruction and malignancy have been excluded and laboratory abnormality correlates with drug exposure and subsides after cessation of medication [2,5]. Beta-lactam antibiotics such as amoxicillin-clavulanate are well-recognized causes of cholestasis [6]; however, meropenem-induced jaundice and liver injury are very rarely reported. Review of literature shows there is one instance of meropenem induced vanishing bile duct syndrome after three weeks of therapy [1] and one reported case of DILI with asymptomatic liver enzyme elevation after meropenem use [4]. The patient in our case developed mixed hepatocellular and cholestatic liver injury with jaundice and pruritus within a few days of meropenem therapy; cessation of the antibiotic lead to laboratory and symptomatic improvements; after ruling out other potential causes, we believe this is a DILI caused by meropenem.
Early recognition of drug-induced jaundice and liver injury is important; it should be part of the differential diagnoses when managing a patient with unexplained jaundice and abnormal LFTs. Clinicians should be aware of such side effect of meropenem since it is a widespread used antibiotic in the hospital setting.
Authors’ contributions
S. Cheung performed chart review, literature review, and is the author of the manuscript and article guarantor.
J. Bulovic, A. Pillai, T. Manoj and K. Neeraj performed literature review and editing of the manuscript.
Disclosure statement
The authors report no conflict of interest.
Informed consent
Informed patient consent was obtained for this case report. | LISINOPRIL, MEROPENEM, METFORMIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33552438 | 20,027,626 | 2021-01-26 |
What was the administration route of drug 'MEROPENEM'? | A case of meropenem-induced liver injury and jaundice.
This report describes what we believe is the first reported case of clinically significant cholestasis and acute liver injury within three days of meropenem therapy. An 83-year-old Hispanic female was admitted for sepsis of unknown origin and was started on intravenous meropenem. Three days following initiation of the antibiotic, the patient developed mixed hepatocellular and cholestatic liver injury with jaundice and pruritus. Possible causes of cholestasis were excluded after extensive investigations. A drug-induced liver injury was suspected and meropenem was discontinued. Following discontinuation of meropenem, the patient demonstrated symptomatic and laboratory improvements, and her liver enzymes and bilirubin levels were normalized.
1. Introduction
Meropenem is a broad-spectrum antibiotic that has excellent activity against many gram-negative, gram-positive and anaerobic organisms. It is commonly used in the hospital setting for complicated infections. Mild, transient, asymptomatic aminotransferase elevations have been reported with meropenem use, but it rarely results in clinically apparent, symptomatic cholestasis [1–3].
2. Case report
An 83-year-old female with a medical history of hypertension and type II diabetes mellitus presented to the emergency department with a two-day history of dark color stools. Patient had no prior history of gastrointestinal (GI) bleed; she denied fever, abdominal pain, jaundice or weight loss. Her home medications include metformin and lisinopril. Patient was afebrile; initial vital signs were significant for sinus tachycardia and blood pressure was 150/72 mmHg. Physical examination revealed dark color stool on rectal exam. The rest of the physical examination was unremarkable. Initial laboratory studies were significant for a white blood cell count of 15.2 mm3, lactic acid 3.8 mmol/L, hemoglobin 7.3 g/dL and hematocrit 31%. Liver enzymes and bilirubin level were within normal limits. Urinalysis, chest radiograph and influenza viral testing were negative. Computed tomography (CT) scan of abdomen without contrast was unremarkable. The patient was admitted for acute anemia and sepsis of unknown origin. While a septic workup was undertaken, the patient received two units of packed red blood cell transfusion, intravenous (IV) fluid resuscitation and was started on broad spectrum antibiotic with IV meropenem 500 milligrams every eight hours. Post-transfusion hemoglobin was 9.4 g/dL and remained stable. No further episode of dark stool was reported. Fecal occult blood testing was negative. Blood cultures showed no growth after two days of incubation.
Three days following hospital admission, routine laboratory study showed a markedly elevated liver function test (LFT) with aspartate aminotransferase (AST) 230 U/L and alanine transaminase (ALT) 753 U/L, total bilirubin 8.3 mg/dL, direct bilirubin 6.7 mg/dL and serum alkaline phosphatase (ALP) 167 U/L. On physical examination, patient was noted to have mild jaundice. She denied any GI symptoms. Right upper quadrant ultrasound showed normal gallbladder and biliary ducts, no evidence of gallstones or biliary dilation. On the following day, repeat laboratory study showed worsening LFT with AST 370 U/L and ALT 1191 U/L, total bilirubin 12 mg/dl, direct bilirubin 10.89 mg/dl and serum ALP 192 U/L. Lactate dehydrogenase and serum inflammatory markers erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP) were within normal limits. Patient denied GI symptoms but reported to have generalized pruritus. On physical examination, vital signs were stable; conjunctival icterus and worsening jaundice were noted. Viral hepatitis serology, autoimmune markers including antinuclear antibodies, anti-smooth muscle antibodies and anti-mitochondrial antibodies were unremarkable. Further investigation with abdominal CT scan, magnetic resonance imaging (MRI) of abdomen and magnetic resonance cholangiopancreatography (MRCP) were unrevealing; there was no evidence of gallstones or choledocholithiasis, no intra- or extra-biliary ductal dilatation. Given recent dark colored stools, patient also underwent upper endoscopy and colonoscopy which revealed mild gastritis and a few small colonic polyps, respectively; no source of anemia was identified during the procedures. However, patient’s liver enzymes and bilirubin levels continued to rise with worsening jaundice and pruritus. A drug-induced liver injury (DILI) was suspected, her medication list was reviewed and meropenem was discontinued. Two days following discontinuation of meropenem, the patient demonstrated symptomatic improvements. Her liver enzymes, bilirubin and ALP levels improved steadily and returned to normal by Day 5 following meropenem discontinuation. Patient was discharged home and was instructed to follow up with gastroenterologist as outpatient.
3. Discussion
Meropenem is a beta-lactam antibiotic that belongs to the carbapenem class; it acts by binding to the penicillin-binding proteins and interferes with the structural integrity of bacterial cell wall. Meropenem has a broad spectrum of activity against many gram-negative and gram-positive organisms; it is administered intravenously with the recommended dosage of 0.5–1 gram every 8 hours. Meropenem is mainly cleared by renal excretion and is a generally well-tolerated antibiotic with most common adverse GI effects being nausea, vomiting and diarrhea [3]. Meropenem was reported to cause mild, asymptomatic, transient serum aminotransferase elevation when it is being used daily for more than 14 days and it rarely requires dose adjustments or discontinuation [4]. To our knowledge, clinically apparent, symptomatic cholestasis and liver injury within three days of meropenem therapy, as the patient in our case, has not been reported in the literature [1,3,4].
DILI is a diagnosis of exclusion. It is diagnosed when other potential causes of liver injury such as viral hepatitis, autoimmune disease, immunologic conditions, biliary obstruction and malignancy have been excluded and laboratory abnormality correlates with drug exposure and subsides after cessation of medication [2,5]. Beta-lactam antibiotics such as amoxicillin-clavulanate are well-recognized causes of cholestasis [6]; however, meropenem-induced jaundice and liver injury are very rarely reported. Review of literature shows there is one instance of meropenem induced vanishing bile duct syndrome after three weeks of therapy [1] and one reported case of DILI with asymptomatic liver enzyme elevation after meropenem use [4]. The patient in our case developed mixed hepatocellular and cholestatic liver injury with jaundice and pruritus within a few days of meropenem therapy; cessation of the antibiotic lead to laboratory and symptomatic improvements; after ruling out other potential causes, we believe this is a DILI caused by meropenem.
Early recognition of drug-induced jaundice and liver injury is important; it should be part of the differential diagnoses when managing a patient with unexplained jaundice and abnormal LFTs. Clinicians should be aware of such side effect of meropenem since it is a widespread used antibiotic in the hospital setting.
Authors’ contributions
S. Cheung performed chart review, literature review, and is the author of the manuscript and article guarantor.
J. Bulovic, A. Pillai, T. Manoj and K. Neeraj performed literature review and editing of the manuscript.
Disclosure statement
The authors report no conflict of interest.
Informed consent
Informed patient consent was obtained for this case report. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33552438 | 20,027,626 | 2021-01-26 |
What was the outcome of reaction 'Mixed liver injury'? | A case of meropenem-induced liver injury and jaundice.
This report describes what we believe is the first reported case of clinically significant cholestasis and acute liver injury within three days of meropenem therapy. An 83-year-old Hispanic female was admitted for sepsis of unknown origin and was started on intravenous meropenem. Three days following initiation of the antibiotic, the patient developed mixed hepatocellular and cholestatic liver injury with jaundice and pruritus. Possible causes of cholestasis were excluded after extensive investigations. A drug-induced liver injury was suspected and meropenem was discontinued. Following discontinuation of meropenem, the patient demonstrated symptomatic and laboratory improvements, and her liver enzymes and bilirubin levels were normalized.
1. Introduction
Meropenem is a broad-spectrum antibiotic that has excellent activity against many gram-negative, gram-positive and anaerobic organisms. It is commonly used in the hospital setting for complicated infections. Mild, transient, asymptomatic aminotransferase elevations have been reported with meropenem use, but it rarely results in clinically apparent, symptomatic cholestasis [1–3].
2. Case report
An 83-year-old female with a medical history of hypertension and type II diabetes mellitus presented to the emergency department with a two-day history of dark color stools. Patient had no prior history of gastrointestinal (GI) bleed; she denied fever, abdominal pain, jaundice or weight loss. Her home medications include metformin and lisinopril. Patient was afebrile; initial vital signs were significant for sinus tachycardia and blood pressure was 150/72 mmHg. Physical examination revealed dark color stool on rectal exam. The rest of the physical examination was unremarkable. Initial laboratory studies were significant for a white blood cell count of 15.2 mm3, lactic acid 3.8 mmol/L, hemoglobin 7.3 g/dL and hematocrit 31%. Liver enzymes and bilirubin level were within normal limits. Urinalysis, chest radiograph and influenza viral testing were negative. Computed tomography (CT) scan of abdomen without contrast was unremarkable. The patient was admitted for acute anemia and sepsis of unknown origin. While a septic workup was undertaken, the patient received two units of packed red blood cell transfusion, intravenous (IV) fluid resuscitation and was started on broad spectrum antibiotic with IV meropenem 500 milligrams every eight hours. Post-transfusion hemoglobin was 9.4 g/dL and remained stable. No further episode of dark stool was reported. Fecal occult blood testing was negative. Blood cultures showed no growth after two days of incubation.
Three days following hospital admission, routine laboratory study showed a markedly elevated liver function test (LFT) with aspartate aminotransferase (AST) 230 U/L and alanine transaminase (ALT) 753 U/L, total bilirubin 8.3 mg/dL, direct bilirubin 6.7 mg/dL and serum alkaline phosphatase (ALP) 167 U/L. On physical examination, patient was noted to have mild jaundice. She denied any GI symptoms. Right upper quadrant ultrasound showed normal gallbladder and biliary ducts, no evidence of gallstones or biliary dilation. On the following day, repeat laboratory study showed worsening LFT with AST 370 U/L and ALT 1191 U/L, total bilirubin 12 mg/dl, direct bilirubin 10.89 mg/dl and serum ALP 192 U/L. Lactate dehydrogenase and serum inflammatory markers erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP) were within normal limits. Patient denied GI symptoms but reported to have generalized pruritus. On physical examination, vital signs were stable; conjunctival icterus and worsening jaundice were noted. Viral hepatitis serology, autoimmune markers including antinuclear antibodies, anti-smooth muscle antibodies and anti-mitochondrial antibodies were unremarkable. Further investigation with abdominal CT scan, magnetic resonance imaging (MRI) of abdomen and magnetic resonance cholangiopancreatography (MRCP) were unrevealing; there was no evidence of gallstones or choledocholithiasis, no intra- or extra-biliary ductal dilatation. Given recent dark colored stools, patient also underwent upper endoscopy and colonoscopy which revealed mild gastritis and a few small colonic polyps, respectively; no source of anemia was identified during the procedures. However, patient’s liver enzymes and bilirubin levels continued to rise with worsening jaundice and pruritus. A drug-induced liver injury (DILI) was suspected, her medication list was reviewed and meropenem was discontinued. Two days following discontinuation of meropenem, the patient demonstrated symptomatic improvements. Her liver enzymes, bilirubin and ALP levels improved steadily and returned to normal by Day 5 following meropenem discontinuation. Patient was discharged home and was instructed to follow up with gastroenterologist as outpatient.
3. Discussion
Meropenem is a beta-lactam antibiotic that belongs to the carbapenem class; it acts by binding to the penicillin-binding proteins and interferes with the structural integrity of bacterial cell wall. Meropenem has a broad spectrum of activity against many gram-negative and gram-positive organisms; it is administered intravenously with the recommended dosage of 0.5–1 gram every 8 hours. Meropenem is mainly cleared by renal excretion and is a generally well-tolerated antibiotic with most common adverse GI effects being nausea, vomiting and diarrhea [3]. Meropenem was reported to cause mild, asymptomatic, transient serum aminotransferase elevation when it is being used daily for more than 14 days and it rarely requires dose adjustments or discontinuation [4]. To our knowledge, clinically apparent, symptomatic cholestasis and liver injury within three days of meropenem therapy, as the patient in our case, has not been reported in the literature [1,3,4].
DILI is a diagnosis of exclusion. It is diagnosed when other potential causes of liver injury such as viral hepatitis, autoimmune disease, immunologic conditions, biliary obstruction and malignancy have been excluded and laboratory abnormality correlates with drug exposure and subsides after cessation of medication [2,5]. Beta-lactam antibiotics such as amoxicillin-clavulanate are well-recognized causes of cholestasis [6]; however, meropenem-induced jaundice and liver injury are very rarely reported. Review of literature shows there is one instance of meropenem induced vanishing bile duct syndrome after three weeks of therapy [1] and one reported case of DILI with asymptomatic liver enzyme elevation after meropenem use [4]. The patient in our case developed mixed hepatocellular and cholestatic liver injury with jaundice and pruritus within a few days of meropenem therapy; cessation of the antibiotic lead to laboratory and symptomatic improvements; after ruling out other potential causes, we believe this is a DILI caused by meropenem.
Early recognition of drug-induced jaundice and liver injury is important; it should be part of the differential diagnoses when managing a patient with unexplained jaundice and abnormal LFTs. Clinicians should be aware of such side effect of meropenem since it is a widespread used antibiotic in the hospital setting.
Authors’ contributions
S. Cheung performed chart review, literature review, and is the author of the manuscript and article guarantor.
J. Bulovic, A. Pillai, T. Manoj and K. Neeraj performed literature review and editing of the manuscript.
Disclosure statement
The authors report no conflict of interest.
Informed consent
Informed patient consent was obtained for this case report. | Recovering | ReactionOutcome | CC BY-NC | 33552438 | 20,027,626 | 2021-01-26 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'No adverse event'. | The ugly duckling of aphasia: cerebral venous sinus thrombosis as a mimic of TIA and stroke.
Cerebral venous sinus thrombosis may present with transient aphasia and focal seizure-likeactivity mimicking a TIA or stroke. In this case, the patient's presentation was further complicated by non-diagnostic CT findings, which can be common in up to 27% of cases [1]. An 86-year-old right-handed male with a history of colon adenocarcinoma status post resection and recent surgery for right sphenoid wing meningioma presented to the ED with transient episodes of fluent aphasia lasting approximately 10 minutes and one episode of involuntary right-hand clenching, both of which resolved spontaneously and were concerning for possible TIA. Non-contrast head CT, CTA head and neck, and CT perfusion studies showed non-opacification of the left transverse and sigmoid sinuses, but no perfusion defects. Subsequent MRI brain with gadolinium revealed a new left transverse sinus thrombus. EEG was without epileptiform features. For the 13-day remainder of his hospitalization the patient received low molecular weight heparin for anticoagulation, and he experienced no recurrence of his symptoms. He was discharged on apixiban and levetiracetam to follow-up for possible tumor recurrence. Cerebral venous sinus thrombosis can present with stroke-like symptoms, and CT perfusion studies can be normal. CT venography, MRI with gadolinium, and MR venography are sensitive imaging modalities for diagnosing dural sinus thrombosis and should be considered, especially for patients with hypercoagulable risk factors, MR venography being the most sensitive, preferred modality [2]. Additionally, it is important to recall the laterality of focal symptoms, as a history of cerebrovascular disease can be a confounding factor in diagnosis.
Cerebral venous sinus thrombosis may present with transient aphasia and focal seizure-like activity mimicking a TIA or stroke. In this case, the patient’s presentation was further complicated by non-diagnostic CT findings, which can be common in up to 27% of cases [1].
An 86-year-old right-handed male with a history of colon adenocarcinoma status post resection and recent surgery for right sphenoid wing meningioma presented to the ED with transient episodes of fluent aphasia lasting approximately 10 minutes and one episode of involuntary right-hand clenching, both of which resolved spontaneously and were concerning for possible TIA. Non-contrast head CT, CTA head and neck, and CT perfusion studies showed non-opacification of the left transverse and sigmoid sinuses, but no perfusion defects. Subsequent MRI brain with gadolinium revealed a new left transverse sinus thrombus. EEG was without epileptiform features. For the 13-day remainder of his hospitalization the patient received low molecular weight heparin for anticoagulation, and he experienced no recurrence of his symptoms. He was discharged on apixiban and levetiracetam to follow-up for possible tumor recurrence.
Cerebral venous sinus thrombosis can present with stroke-like symptoms, and CT perfusion studies can be normal. CT venography, MRI with gadolinium, and MR venography are sensitive imaging modalities for diagnosing dural sinus thrombosis and should be considered, especially for patients with hypercoagulable risk factors, MR venography being the most sensitive, preferred modality [2]. Additionally, it is important to recall the laterality of focal symptoms, as a history of cerebrovascular disease can be a confounding factor in diagnosis.
Disclosure statement
No authors involved in the production of this manuscript have any commercial associations that might create or pose a conflict of interest with information presented herein. Such associations include consultancies, stock ownership, or other equity interests, patent licensing arrangements, and payments for conducting or publicizing a study described in the manuscript. | APIXABAN, LEVETIRACETAM | DrugsGivenReaction | CC BY-NC | 33552442 | 20,499,793 | 2021-01-26 |
What was the dosage of drug 'APIXABAN'? | The ugly duckling of aphasia: cerebral venous sinus thrombosis as a mimic of TIA and stroke.
Cerebral venous sinus thrombosis may present with transient aphasia and focal seizure-likeactivity mimicking a TIA or stroke. In this case, the patient's presentation was further complicated by non-diagnostic CT findings, which can be common in up to 27% of cases [1]. An 86-year-old right-handed male with a history of colon adenocarcinoma status post resection and recent surgery for right sphenoid wing meningioma presented to the ED with transient episodes of fluent aphasia lasting approximately 10 minutes and one episode of involuntary right-hand clenching, both of which resolved spontaneously and were concerning for possible TIA. Non-contrast head CT, CTA head and neck, and CT perfusion studies showed non-opacification of the left transverse and sigmoid sinuses, but no perfusion defects. Subsequent MRI brain with gadolinium revealed a new left transverse sinus thrombus. EEG was without epileptiform features. For the 13-day remainder of his hospitalization the patient received low molecular weight heparin for anticoagulation, and he experienced no recurrence of his symptoms. He was discharged on apixiban and levetiracetam to follow-up for possible tumor recurrence. Cerebral venous sinus thrombosis can present with stroke-like symptoms, and CT perfusion studies can be normal. CT venography, MRI with gadolinium, and MR venography are sensitive imaging modalities for diagnosing dural sinus thrombosis and should be considered, especially for patients with hypercoagulable risk factors, MR venography being the most sensitive, preferred modality [2]. Additionally, it is important to recall the laterality of focal symptoms, as a history of cerebrovascular disease can be a confounding factor in diagnosis.
Cerebral venous sinus thrombosis may present with transient aphasia and focal seizure-like activity mimicking a TIA or stroke. In this case, the patient’s presentation was further complicated by non-diagnostic CT findings, which can be common in up to 27% of cases [1].
An 86-year-old right-handed male with a history of colon adenocarcinoma status post resection and recent surgery for right sphenoid wing meningioma presented to the ED with transient episodes of fluent aphasia lasting approximately 10 minutes and one episode of involuntary right-hand clenching, both of which resolved spontaneously and were concerning for possible TIA. Non-contrast head CT, CTA head and neck, and CT perfusion studies showed non-opacification of the left transverse and sigmoid sinuses, but no perfusion defects. Subsequent MRI brain with gadolinium revealed a new left transverse sinus thrombus. EEG was without epileptiform features. For the 13-day remainder of his hospitalization the patient received low molecular weight heparin for anticoagulation, and he experienced no recurrence of his symptoms. He was discharged on apixiban and levetiracetam to follow-up for possible tumor recurrence.
Cerebral venous sinus thrombosis can present with stroke-like symptoms, and CT perfusion studies can be normal. CT venography, MRI with gadolinium, and MR venography are sensitive imaging modalities for diagnosing dural sinus thrombosis and should be considered, especially for patients with hypercoagulable risk factors, MR venography being the most sensitive, preferred modality [2]. Additionally, it is important to recall the laterality of focal symptoms, as a history of cerebrovascular disease can be a confounding factor in diagnosis.
Disclosure statement
No authors involved in the production of this manuscript have any commercial associations that might create or pose a conflict of interest with information presented herein. Such associations include consultancies, stock ownership, or other equity interests, patent licensing arrangements, and payments for conducting or publicizing a study described in the manuscript. | UNKNON DOSE | DrugDosageText | CC BY-NC | 33552442 | 20,499,793 | 2021-01-26 |
What was the dosage of drug 'LEVETIRACETAM'? | The ugly duckling of aphasia: cerebral venous sinus thrombosis as a mimic of TIA and stroke.
Cerebral venous sinus thrombosis may present with transient aphasia and focal seizure-likeactivity mimicking a TIA or stroke. In this case, the patient's presentation was further complicated by non-diagnostic CT findings, which can be common in up to 27% of cases [1]. An 86-year-old right-handed male with a history of colon adenocarcinoma status post resection and recent surgery for right sphenoid wing meningioma presented to the ED with transient episodes of fluent aphasia lasting approximately 10 minutes and one episode of involuntary right-hand clenching, both of which resolved spontaneously and were concerning for possible TIA. Non-contrast head CT, CTA head and neck, and CT perfusion studies showed non-opacification of the left transverse and sigmoid sinuses, but no perfusion defects. Subsequent MRI brain with gadolinium revealed a new left transverse sinus thrombus. EEG was without epileptiform features. For the 13-day remainder of his hospitalization the patient received low molecular weight heparin for anticoagulation, and he experienced no recurrence of his symptoms. He was discharged on apixiban and levetiracetam to follow-up for possible tumor recurrence. Cerebral venous sinus thrombosis can present with stroke-like symptoms, and CT perfusion studies can be normal. CT venography, MRI with gadolinium, and MR venography are sensitive imaging modalities for diagnosing dural sinus thrombosis and should be considered, especially for patients with hypercoagulable risk factors, MR venography being the most sensitive, preferred modality [2]. Additionally, it is important to recall the laterality of focal symptoms, as a history of cerebrovascular disease can be a confounding factor in diagnosis.
Cerebral venous sinus thrombosis may present with transient aphasia and focal seizure-like activity mimicking a TIA or stroke. In this case, the patient’s presentation was further complicated by non-diagnostic CT findings, which can be common in up to 27% of cases [1].
An 86-year-old right-handed male with a history of colon adenocarcinoma status post resection and recent surgery for right sphenoid wing meningioma presented to the ED with transient episodes of fluent aphasia lasting approximately 10 minutes and one episode of involuntary right-hand clenching, both of which resolved spontaneously and were concerning for possible TIA. Non-contrast head CT, CTA head and neck, and CT perfusion studies showed non-opacification of the left transverse and sigmoid sinuses, but no perfusion defects. Subsequent MRI brain with gadolinium revealed a new left transverse sinus thrombus. EEG was without epileptiform features. For the 13-day remainder of his hospitalization the patient received low molecular weight heparin for anticoagulation, and he experienced no recurrence of his symptoms. He was discharged on apixiban and levetiracetam to follow-up for possible tumor recurrence.
Cerebral venous sinus thrombosis can present with stroke-like symptoms, and CT perfusion studies can be normal. CT venography, MRI with gadolinium, and MR venography are sensitive imaging modalities for diagnosing dural sinus thrombosis and should be considered, especially for patients with hypercoagulable risk factors, MR venography being the most sensitive, preferred modality [2]. Additionally, it is important to recall the laterality of focal symptoms, as a history of cerebrovascular disease can be a confounding factor in diagnosis.
Disclosure statement
No authors involved in the production of this manuscript have any commercial associations that might create or pose a conflict of interest with information presented herein. Such associations include consultancies, stock ownership, or other equity interests, patent licensing arrangements, and payments for conducting or publicizing a study described in the manuscript. | UNKNOWN DOSE | DrugDosageText | CC BY-NC | 33552442 | 20,499,793 | 2021-01-26 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Acute respiratory distress syndrome caused by varicella pneumonia in immunocompetent adult: Clinical case.
Varicella zona infection is a rare condition in immunocompetent adults. It can lead to severe and lethal complications including Varicella pneumonia that can rapidly progress to acute respiratory distress syndrome a rare and life-threatening situation.
A 63 years old man was admitted to the intensive care unit for pneumonia with generalized papulovesicular lesions. After investigations, the diagnosis of Varicella pneumonia complicated with acute respiratory distress syndrome was maintained and the patient was put on mechanical ventilation, and despite proper management (antiviral treatment; protective ventilation and prone position) the patient died 48 hours after his admission.
Despite its rarity, Varicella pneumonia can be a life-threatening situation in immunocompetent adults. The diagnosis must be evoked when the patient presented with respiratory manifestations with dermatologic lesions.
1 Introduction
Varicella is a highly contagious disease caused by Varicella-Zoster Virus, it's a common childhood self-limited disease but it can be a life-threatening situation in immunocompromised patients [[1], [2], [3]]. And despite its rarity, Varicella zona infection can lead to severe lethal complications in immunocompetent persons including varicella pneumonia that can rapidly progress to an acute respiratory distress syndrome despite conventional support [[4], [5], [6]].
In this paper; we will report the clinical case of a 63 years old man, with no medical history, admitted to the critical care unit for acute respiratory distress syndrome due to Varicella pneumonia. We will discuss the respiratory manifestations of Varicella-Zoster virus, the diagnosis and the treatment.
2 Clinical case
A 63-year-old man with a history of smoking 23 packets/years weaned for 10 years, with no other medical history was admitted to the emergency room for dyspnea, 5 days after a diffuse rash that started in his scalp.
The physical examination on his admission was as follow: fever at 38.5 °C, polypnea at 30 cycles/minute, pulse oxymetry at 65% under high concentration mask at 15 L/min, bilateral rhonchi, perioral and extremists cyanosis with signs of respiratory exhaustion: paradoxical respiration, high blood pressure at 180/110 mmHg, heart rate at 110 beats/min and generalized papulovesicular lesions with certain lesions with a necrotic center (Fig. 1).Fig. 1 Image of the patient showing generalized papulo-vesicular lesions with certain lesions with a necrotic center.
Fig. 1
High flow nasal cannula treatment was initiated with the flow of 80l/min and the inspiratory fraction of oxygen at 100% with no improvement, the patient was intubated.
The arterial blood gas after intubation was as followed: pH 7.23, PaO2 42 with FiO2 of 100% and PaO2/FiO2 of 42, PaCO2 65, HCO3- 14 and lactates at 4.05.
The complete blood count: hyperleukocytosis at 11,460/μm, lymphopenia at 450/mm3, thrombocytopenia at 110,000 μm, CRP at 113 mg/l, procalcitonin at 0.82, hepatic cytolysis with ASAT and ALAT 64 and 45 higher than limit respectively, the elevation of lactate dehydrogenase (LDH) at 1289 IU/l, hypoalbuminemia at 27 g/l, urinary antigen test for streptococcus pneumoniae and legionella pneumonia were negative, human immunodeficiency virus HIV testing was negative, RT-PCR (reverse transcriptase-polymerase chain reaction) for Covid-19 and H1N1 were negative, and Varicella zona virus serology was positive.
The chest X-ray showed the presence of bilateral and diffuse alveolar interstitial opacities in the two pulmonary fields (Fig. 2).Fig. 2 Chest X-ray showed the presence of bilateral and diffuse alveolar interstitial opacities in the two pulmonary fields.
Fig. 2
The diagnosis of acute respiratory distress syndrome caused by Varicella pneumonia was maintained by association of respiratory manifestations, dermatological lesions and positive serology for Varicella Zona Virus.
Initial treatment with acyclovir (10 mg/kg every 8 h) was initiated.
The evolution was fatal, despite prone position, curare perfusion and optimal sedation, the patient died after 48 hours of his admission.
3 Discussion
Varicella is a highly contagious disease caused by the Varicella-Zoster Virus with a worldwide distribution, it is a member of the « Herpesviridae » family of DNA virus which can cause lytic and latent infections [1,7,8]. It is acquired by inhalation of infected saliva droplets or rarely a direct contact with skin lesions [7].
It occurs in all countries with mild self-limiting symptoms lasting a few days and providing lifetime immunity but it can cause serious complications among high-risk populations with lethality of 7000 deaths/year [7,9].
Clinical signs of varicella are usually mild including intense prurit, blasters on palms and genitals; small painful and itchy ulcers on the oral cavity appearing 21 days after exposure to the virus [7].
The varicella reinfection is rare, causing serious painful illness in immunocompromised individuals with high a mortality rate [7,10,11].
Varicella pneumonia is the most common complication of adult Varicella with an incidence of 1/400 with risk factors such as smoking, immunosuppression and preexistent lung disease with a mortality rate of 10%–30% overall and up to 50% in those on mechanical ventilation [12,13].
Respiratory symptoms of Varicella pneumonia began 1–7 days after installation of the rash, they are usually mild with few respiratory symptoms such as dry cough, hemoptysis, thoracic pain, dyspnea, fever, and even acute respiratory distress [14,15].
Varicella induced acute respiratory distress syndrome is very rare but a life-threatening situation [16,17].
Radiologic images find ill-defined confluent nodules in 2 pulmonary fields, ground-glass opacities surrounding the nodules or diffuse, hilar lymphadenopathy, and pleural fluid [18,19].
Diagnosis is based on clinical findings, but laboratory tests are still essential in cases of atypical cases or disseminated infection, the virus is searched by molecular tests on skin lesion fluid, blood and respiratory samples and serologic diagnosis is useful to identify unprotected individuals and distinguish primary infection from reactivation [20].
Treatment of pulmonary chickenpox consists of antiviral drugs; acyclovir 10mg/kg/8 hours for a period of 7–10 days [7].
Purified immunoglobulins with anti-VZV antibodies can be administered intramuscularly 96 hours to 10 days after rash apparition [20].
4 Conclusion
Despite its rarity, varicella pneumonia can be a life-threatening situation in immunocompetent adults, with the possibility to develop an acute respiratory distress syndrome.
The diagnosis should be evoked in patients with respiratory distress with dermatologic lesions to start early management and avoid serious complications including death.
The work has been reported in line with the CARE 2018 criteria [21].
Ethical approval
The paper reflects the authors' own research and analysis in a truthful a complete manner.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
• Dr. AABDI MOHAMMED: Writing - original draft, Conceptualization, Methodology, Software, Validation, Formal analysis, Visualization.
• DR. MIMOUNI HAMZA: Resources, Data curation, Software. final approval of the version to be submitted
• Dr. LAZREG MOUSSA: Writing - review & editing, Formal analysis, Visualization. final approval of the version to be submitted
• Pr. BKIYAR HOUSSAM: Writing - review & editing, Visualization. final approval of the version to be submitted
• Pr. HOUSNI: Project administration, Visualization, Writing - review & editing, Resources, Conceptualization, Methodology, Validation. final approval of the version to be submitted
Consent
We have obtained the consent from the patient's wife for publication.
Guarantor
AABDI Mohammed MIMOUNI Hamza
Declaration of competing interest
The authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements). Or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. | ACYCLOVIR | DrugsGivenReaction | CC BY | 33552499 | 18,968,775 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Treatment failure'. | Acute respiratory distress syndrome caused by varicella pneumonia in immunocompetent adult: Clinical case.
Varicella zona infection is a rare condition in immunocompetent adults. It can lead to severe and lethal complications including Varicella pneumonia that can rapidly progress to acute respiratory distress syndrome a rare and life-threatening situation.
A 63 years old man was admitted to the intensive care unit for pneumonia with generalized papulovesicular lesions. After investigations, the diagnosis of Varicella pneumonia complicated with acute respiratory distress syndrome was maintained and the patient was put on mechanical ventilation, and despite proper management (antiviral treatment; protective ventilation and prone position) the patient died 48 hours after his admission.
Despite its rarity, Varicella pneumonia can be a life-threatening situation in immunocompetent adults. The diagnosis must be evoked when the patient presented with respiratory manifestations with dermatologic lesions.
1 Introduction
Varicella is a highly contagious disease caused by Varicella-Zoster Virus, it's a common childhood self-limited disease but it can be a life-threatening situation in immunocompromised patients [[1], [2], [3]]. And despite its rarity, Varicella zona infection can lead to severe lethal complications in immunocompetent persons including varicella pneumonia that can rapidly progress to an acute respiratory distress syndrome despite conventional support [[4], [5], [6]].
In this paper; we will report the clinical case of a 63 years old man, with no medical history, admitted to the critical care unit for acute respiratory distress syndrome due to Varicella pneumonia. We will discuss the respiratory manifestations of Varicella-Zoster virus, the diagnosis and the treatment.
2 Clinical case
A 63-year-old man with a history of smoking 23 packets/years weaned for 10 years, with no other medical history was admitted to the emergency room for dyspnea, 5 days after a diffuse rash that started in his scalp.
The physical examination on his admission was as follow: fever at 38.5 °C, polypnea at 30 cycles/minute, pulse oxymetry at 65% under high concentration mask at 15 L/min, bilateral rhonchi, perioral and extremists cyanosis with signs of respiratory exhaustion: paradoxical respiration, high blood pressure at 180/110 mmHg, heart rate at 110 beats/min and generalized papulovesicular lesions with certain lesions with a necrotic center (Fig. 1).Fig. 1 Image of the patient showing generalized papulo-vesicular lesions with certain lesions with a necrotic center.
Fig. 1
High flow nasal cannula treatment was initiated with the flow of 80l/min and the inspiratory fraction of oxygen at 100% with no improvement, the patient was intubated.
The arterial blood gas after intubation was as followed: pH 7.23, PaO2 42 with FiO2 of 100% and PaO2/FiO2 of 42, PaCO2 65, HCO3- 14 and lactates at 4.05.
The complete blood count: hyperleukocytosis at 11,460/μm, lymphopenia at 450/mm3, thrombocytopenia at 110,000 μm, CRP at 113 mg/l, procalcitonin at 0.82, hepatic cytolysis with ASAT and ALAT 64 and 45 higher than limit respectively, the elevation of lactate dehydrogenase (LDH) at 1289 IU/l, hypoalbuminemia at 27 g/l, urinary antigen test for streptococcus pneumoniae and legionella pneumonia were negative, human immunodeficiency virus HIV testing was negative, RT-PCR (reverse transcriptase-polymerase chain reaction) for Covid-19 and H1N1 were negative, and Varicella zona virus serology was positive.
The chest X-ray showed the presence of bilateral and diffuse alveolar interstitial opacities in the two pulmonary fields (Fig. 2).Fig. 2 Chest X-ray showed the presence of bilateral and diffuse alveolar interstitial opacities in the two pulmonary fields.
Fig. 2
The diagnosis of acute respiratory distress syndrome caused by Varicella pneumonia was maintained by association of respiratory manifestations, dermatological lesions and positive serology for Varicella Zona Virus.
Initial treatment with acyclovir (10 mg/kg every 8 h) was initiated.
The evolution was fatal, despite prone position, curare perfusion and optimal sedation, the patient died after 48 hours of his admission.
3 Discussion
Varicella is a highly contagious disease caused by the Varicella-Zoster Virus with a worldwide distribution, it is a member of the « Herpesviridae » family of DNA virus which can cause lytic and latent infections [1,7,8]. It is acquired by inhalation of infected saliva droplets or rarely a direct contact with skin lesions [7].
It occurs in all countries with mild self-limiting symptoms lasting a few days and providing lifetime immunity but it can cause serious complications among high-risk populations with lethality of 7000 deaths/year [7,9].
Clinical signs of varicella are usually mild including intense prurit, blasters on palms and genitals; small painful and itchy ulcers on the oral cavity appearing 21 days after exposure to the virus [7].
The varicella reinfection is rare, causing serious painful illness in immunocompromised individuals with high a mortality rate [7,10,11].
Varicella pneumonia is the most common complication of adult Varicella with an incidence of 1/400 with risk factors such as smoking, immunosuppression and preexistent lung disease with a mortality rate of 10%–30% overall and up to 50% in those on mechanical ventilation [12,13].
Respiratory symptoms of Varicella pneumonia began 1–7 days after installation of the rash, they are usually mild with few respiratory symptoms such as dry cough, hemoptysis, thoracic pain, dyspnea, fever, and even acute respiratory distress [14,15].
Varicella induced acute respiratory distress syndrome is very rare but a life-threatening situation [16,17].
Radiologic images find ill-defined confluent nodules in 2 pulmonary fields, ground-glass opacities surrounding the nodules or diffuse, hilar lymphadenopathy, and pleural fluid [18,19].
Diagnosis is based on clinical findings, but laboratory tests are still essential in cases of atypical cases or disseminated infection, the virus is searched by molecular tests on skin lesion fluid, blood and respiratory samples and serologic diagnosis is useful to identify unprotected individuals and distinguish primary infection from reactivation [20].
Treatment of pulmonary chickenpox consists of antiviral drugs; acyclovir 10mg/kg/8 hours for a period of 7–10 days [7].
Purified immunoglobulins with anti-VZV antibodies can be administered intramuscularly 96 hours to 10 days after rash apparition [20].
4 Conclusion
Despite its rarity, varicella pneumonia can be a life-threatening situation in immunocompetent adults, with the possibility to develop an acute respiratory distress syndrome.
The diagnosis should be evoked in patients with respiratory distress with dermatologic lesions to start early management and avoid serious complications including death.
The work has been reported in line with the CARE 2018 criteria [21].
Ethical approval
The paper reflects the authors' own research and analysis in a truthful a complete manner.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
• Dr. AABDI MOHAMMED: Writing - original draft, Conceptualization, Methodology, Software, Validation, Formal analysis, Visualization.
• DR. MIMOUNI HAMZA: Resources, Data curation, Software. final approval of the version to be submitted
• Dr. LAZREG MOUSSA: Writing - review & editing, Formal analysis, Visualization. final approval of the version to be submitted
• Pr. BKIYAR HOUSSAM: Writing - review & editing, Visualization. final approval of the version to be submitted
• Pr. HOUSNI: Project administration, Visualization, Writing - review & editing, Resources, Conceptualization, Methodology, Validation. final approval of the version to be submitted
Consent
We have obtained the consent from the patient's wife for publication.
Guarantor
AABDI Mohammed MIMOUNI Hamza
Declaration of competing interest
The authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements). Or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. | ACYCLOVIR SODIUM | DrugsGivenReaction | CC BY | 33552499 | 18,957,681 | 2021-02 |
What was the dosage of drug 'ACYCLOVIR'? | Acute respiratory distress syndrome caused by varicella pneumonia in immunocompetent adult: Clinical case.
Varicella zona infection is a rare condition in immunocompetent adults. It can lead to severe and lethal complications including Varicella pneumonia that can rapidly progress to acute respiratory distress syndrome a rare and life-threatening situation.
A 63 years old man was admitted to the intensive care unit for pneumonia with generalized papulovesicular lesions. After investigations, the diagnosis of Varicella pneumonia complicated with acute respiratory distress syndrome was maintained and the patient was put on mechanical ventilation, and despite proper management (antiviral treatment; protective ventilation and prone position) the patient died 48 hours after his admission.
Despite its rarity, Varicella pneumonia can be a life-threatening situation in immunocompetent adults. The diagnosis must be evoked when the patient presented with respiratory manifestations with dermatologic lesions.
1 Introduction
Varicella is a highly contagious disease caused by Varicella-Zoster Virus, it's a common childhood self-limited disease but it can be a life-threatening situation in immunocompromised patients [[1], [2], [3]]. And despite its rarity, Varicella zona infection can lead to severe lethal complications in immunocompetent persons including varicella pneumonia that can rapidly progress to an acute respiratory distress syndrome despite conventional support [[4], [5], [6]].
In this paper; we will report the clinical case of a 63 years old man, with no medical history, admitted to the critical care unit for acute respiratory distress syndrome due to Varicella pneumonia. We will discuss the respiratory manifestations of Varicella-Zoster virus, the diagnosis and the treatment.
2 Clinical case
A 63-year-old man with a history of smoking 23 packets/years weaned for 10 years, with no other medical history was admitted to the emergency room for dyspnea, 5 days after a diffuse rash that started in his scalp.
The physical examination on his admission was as follow: fever at 38.5 °C, polypnea at 30 cycles/minute, pulse oxymetry at 65% under high concentration mask at 15 L/min, bilateral rhonchi, perioral and extremists cyanosis with signs of respiratory exhaustion: paradoxical respiration, high blood pressure at 180/110 mmHg, heart rate at 110 beats/min and generalized papulovesicular lesions with certain lesions with a necrotic center (Fig. 1).Fig. 1 Image of the patient showing generalized papulo-vesicular lesions with certain lesions with a necrotic center.
Fig. 1
High flow nasal cannula treatment was initiated with the flow of 80l/min and the inspiratory fraction of oxygen at 100% with no improvement, the patient was intubated.
The arterial blood gas after intubation was as followed: pH 7.23, PaO2 42 with FiO2 of 100% and PaO2/FiO2 of 42, PaCO2 65, HCO3- 14 and lactates at 4.05.
The complete blood count: hyperleukocytosis at 11,460/μm, lymphopenia at 450/mm3, thrombocytopenia at 110,000 μm, CRP at 113 mg/l, procalcitonin at 0.82, hepatic cytolysis with ASAT and ALAT 64 and 45 higher than limit respectively, the elevation of lactate dehydrogenase (LDH) at 1289 IU/l, hypoalbuminemia at 27 g/l, urinary antigen test for streptococcus pneumoniae and legionella pneumonia were negative, human immunodeficiency virus HIV testing was negative, RT-PCR (reverse transcriptase-polymerase chain reaction) for Covid-19 and H1N1 were negative, and Varicella zona virus serology was positive.
The chest X-ray showed the presence of bilateral and diffuse alveolar interstitial opacities in the two pulmonary fields (Fig. 2).Fig. 2 Chest X-ray showed the presence of bilateral and diffuse alveolar interstitial opacities in the two pulmonary fields.
Fig. 2
The diagnosis of acute respiratory distress syndrome caused by Varicella pneumonia was maintained by association of respiratory manifestations, dermatological lesions and positive serology for Varicella Zona Virus.
Initial treatment with acyclovir (10 mg/kg every 8 h) was initiated.
The evolution was fatal, despite prone position, curare perfusion and optimal sedation, the patient died after 48 hours of his admission.
3 Discussion
Varicella is a highly contagious disease caused by the Varicella-Zoster Virus with a worldwide distribution, it is a member of the « Herpesviridae » family of DNA virus which can cause lytic and latent infections [1,7,8]. It is acquired by inhalation of infected saliva droplets or rarely a direct contact with skin lesions [7].
It occurs in all countries with mild self-limiting symptoms lasting a few days and providing lifetime immunity but it can cause serious complications among high-risk populations with lethality of 7000 deaths/year [7,9].
Clinical signs of varicella are usually mild including intense prurit, blasters on palms and genitals; small painful and itchy ulcers on the oral cavity appearing 21 days after exposure to the virus [7].
The varicella reinfection is rare, causing serious painful illness in immunocompromised individuals with high a mortality rate [7,10,11].
Varicella pneumonia is the most common complication of adult Varicella with an incidence of 1/400 with risk factors such as smoking, immunosuppression and preexistent lung disease with a mortality rate of 10%–30% overall and up to 50% in those on mechanical ventilation [12,13].
Respiratory symptoms of Varicella pneumonia began 1–7 days after installation of the rash, they are usually mild with few respiratory symptoms such as dry cough, hemoptysis, thoracic pain, dyspnea, fever, and even acute respiratory distress [14,15].
Varicella induced acute respiratory distress syndrome is very rare but a life-threatening situation [16,17].
Radiologic images find ill-defined confluent nodules in 2 pulmonary fields, ground-glass opacities surrounding the nodules or diffuse, hilar lymphadenopathy, and pleural fluid [18,19].
Diagnosis is based on clinical findings, but laboratory tests are still essential in cases of atypical cases or disseminated infection, the virus is searched by molecular tests on skin lesion fluid, blood and respiratory samples and serologic diagnosis is useful to identify unprotected individuals and distinguish primary infection from reactivation [20].
Treatment of pulmonary chickenpox consists of antiviral drugs; acyclovir 10mg/kg/8 hours for a period of 7–10 days [7].
Purified immunoglobulins with anti-VZV antibodies can be administered intramuscularly 96 hours to 10 days after rash apparition [20].
4 Conclusion
Despite its rarity, varicella pneumonia can be a life-threatening situation in immunocompetent adults, with the possibility to develop an acute respiratory distress syndrome.
The diagnosis should be evoked in patients with respiratory distress with dermatologic lesions to start early management and avoid serious complications including death.
The work has been reported in line with the CARE 2018 criteria [21].
Ethical approval
The paper reflects the authors' own research and analysis in a truthful a complete manner.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
• Dr. AABDI MOHAMMED: Writing - original draft, Conceptualization, Methodology, Software, Validation, Formal analysis, Visualization.
• DR. MIMOUNI HAMZA: Resources, Data curation, Software. final approval of the version to be submitted
• Dr. LAZREG MOUSSA: Writing - review & editing, Formal analysis, Visualization. final approval of the version to be submitted
• Pr. BKIYAR HOUSSAM: Writing - review & editing, Visualization. final approval of the version to be submitted
• Pr. HOUSNI: Project administration, Visualization, Writing - review & editing, Resources, Conceptualization, Methodology, Validation. final approval of the version to be submitted
Consent
We have obtained the consent from the patient's wife for publication.
Guarantor
AABDI Mohammed MIMOUNI Hamza
Declaration of competing interest
The authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements). Or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. | 10 MILLIGRAM/KILOGRAM, Q8H | DrugDosageText | CC BY | 33552499 | 18,968,775 | 2021-02 |
What was the outcome of reaction 'Drug ineffective'? | Acute respiratory distress syndrome caused by varicella pneumonia in immunocompetent adult: Clinical case.
Varicella zona infection is a rare condition in immunocompetent adults. It can lead to severe and lethal complications including Varicella pneumonia that can rapidly progress to acute respiratory distress syndrome a rare and life-threatening situation.
A 63 years old man was admitted to the intensive care unit for pneumonia with generalized papulovesicular lesions. After investigations, the diagnosis of Varicella pneumonia complicated with acute respiratory distress syndrome was maintained and the patient was put on mechanical ventilation, and despite proper management (antiviral treatment; protective ventilation and prone position) the patient died 48 hours after his admission.
Despite its rarity, Varicella pneumonia can be a life-threatening situation in immunocompetent adults. The diagnosis must be evoked when the patient presented with respiratory manifestations with dermatologic lesions.
1 Introduction
Varicella is a highly contagious disease caused by Varicella-Zoster Virus, it's a common childhood self-limited disease but it can be a life-threatening situation in immunocompromised patients [[1], [2], [3]]. And despite its rarity, Varicella zona infection can lead to severe lethal complications in immunocompetent persons including varicella pneumonia that can rapidly progress to an acute respiratory distress syndrome despite conventional support [[4], [5], [6]].
In this paper; we will report the clinical case of a 63 years old man, with no medical history, admitted to the critical care unit for acute respiratory distress syndrome due to Varicella pneumonia. We will discuss the respiratory manifestations of Varicella-Zoster virus, the diagnosis and the treatment.
2 Clinical case
A 63-year-old man with a history of smoking 23 packets/years weaned for 10 years, with no other medical history was admitted to the emergency room for dyspnea, 5 days after a diffuse rash that started in his scalp.
The physical examination on his admission was as follow: fever at 38.5 °C, polypnea at 30 cycles/minute, pulse oxymetry at 65% under high concentration mask at 15 L/min, bilateral rhonchi, perioral and extremists cyanosis with signs of respiratory exhaustion: paradoxical respiration, high blood pressure at 180/110 mmHg, heart rate at 110 beats/min and generalized papulovesicular lesions with certain lesions with a necrotic center (Fig. 1).Fig. 1 Image of the patient showing generalized papulo-vesicular lesions with certain lesions with a necrotic center.
Fig. 1
High flow nasal cannula treatment was initiated with the flow of 80l/min and the inspiratory fraction of oxygen at 100% with no improvement, the patient was intubated.
The arterial blood gas after intubation was as followed: pH 7.23, PaO2 42 with FiO2 of 100% and PaO2/FiO2 of 42, PaCO2 65, HCO3- 14 and lactates at 4.05.
The complete blood count: hyperleukocytosis at 11,460/μm, lymphopenia at 450/mm3, thrombocytopenia at 110,000 μm, CRP at 113 mg/l, procalcitonin at 0.82, hepatic cytolysis with ASAT and ALAT 64 and 45 higher than limit respectively, the elevation of lactate dehydrogenase (LDH) at 1289 IU/l, hypoalbuminemia at 27 g/l, urinary antigen test for streptococcus pneumoniae and legionella pneumonia were negative, human immunodeficiency virus HIV testing was negative, RT-PCR (reverse transcriptase-polymerase chain reaction) for Covid-19 and H1N1 were negative, and Varicella zona virus serology was positive.
The chest X-ray showed the presence of bilateral and diffuse alveolar interstitial opacities in the two pulmonary fields (Fig. 2).Fig. 2 Chest X-ray showed the presence of bilateral and diffuse alveolar interstitial opacities in the two pulmonary fields.
Fig. 2
The diagnosis of acute respiratory distress syndrome caused by Varicella pneumonia was maintained by association of respiratory manifestations, dermatological lesions and positive serology for Varicella Zona Virus.
Initial treatment with acyclovir (10 mg/kg every 8 h) was initiated.
The evolution was fatal, despite prone position, curare perfusion and optimal sedation, the patient died after 48 hours of his admission.
3 Discussion
Varicella is a highly contagious disease caused by the Varicella-Zoster Virus with a worldwide distribution, it is a member of the « Herpesviridae » family of DNA virus which can cause lytic and latent infections [1,7,8]. It is acquired by inhalation of infected saliva droplets or rarely a direct contact with skin lesions [7].
It occurs in all countries with mild self-limiting symptoms lasting a few days and providing lifetime immunity but it can cause serious complications among high-risk populations with lethality of 7000 deaths/year [7,9].
Clinical signs of varicella are usually mild including intense prurit, blasters on palms and genitals; small painful and itchy ulcers on the oral cavity appearing 21 days after exposure to the virus [7].
The varicella reinfection is rare, causing serious painful illness in immunocompromised individuals with high a mortality rate [7,10,11].
Varicella pneumonia is the most common complication of adult Varicella with an incidence of 1/400 with risk factors such as smoking, immunosuppression and preexistent lung disease with a mortality rate of 10%–30% overall and up to 50% in those on mechanical ventilation [12,13].
Respiratory symptoms of Varicella pneumonia began 1–7 days after installation of the rash, they are usually mild with few respiratory symptoms such as dry cough, hemoptysis, thoracic pain, dyspnea, fever, and even acute respiratory distress [14,15].
Varicella induced acute respiratory distress syndrome is very rare but a life-threatening situation [16,17].
Radiologic images find ill-defined confluent nodules in 2 pulmonary fields, ground-glass opacities surrounding the nodules or diffuse, hilar lymphadenopathy, and pleural fluid [18,19].
Diagnosis is based on clinical findings, but laboratory tests are still essential in cases of atypical cases or disseminated infection, the virus is searched by molecular tests on skin lesion fluid, blood and respiratory samples and serologic diagnosis is useful to identify unprotected individuals and distinguish primary infection from reactivation [20].
Treatment of pulmonary chickenpox consists of antiviral drugs; acyclovir 10mg/kg/8 hours for a period of 7–10 days [7].
Purified immunoglobulins with anti-VZV antibodies can be administered intramuscularly 96 hours to 10 days after rash apparition [20].
4 Conclusion
Despite its rarity, varicella pneumonia can be a life-threatening situation in immunocompetent adults, with the possibility to develop an acute respiratory distress syndrome.
The diagnosis should be evoked in patients with respiratory distress with dermatologic lesions to start early management and avoid serious complications including death.
The work has been reported in line with the CARE 2018 criteria [21].
Ethical approval
The paper reflects the authors' own research and analysis in a truthful a complete manner.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
• Dr. AABDI MOHAMMED: Writing - original draft, Conceptualization, Methodology, Software, Validation, Formal analysis, Visualization.
• DR. MIMOUNI HAMZA: Resources, Data curation, Software. final approval of the version to be submitted
• Dr. LAZREG MOUSSA: Writing - review & editing, Formal analysis, Visualization. final approval of the version to be submitted
• Pr. BKIYAR HOUSSAM: Writing - review & editing, Visualization. final approval of the version to be submitted
• Pr. HOUSNI: Project administration, Visualization, Writing - review & editing, Resources, Conceptualization, Methodology, Validation. final approval of the version to be submitted
Consent
We have obtained the consent from the patient's wife for publication.
Guarantor
AABDI Mohammed MIMOUNI Hamza
Declaration of competing interest
The authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements). Or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. | Fatal | ReactionOutcome | CC BY | 33552499 | 18,968,775 | 2021-02 |
What was the outcome of reaction 'Treatment failure'? | Acute respiratory distress syndrome caused by varicella pneumonia in immunocompetent adult: Clinical case.
Varicella zona infection is a rare condition in immunocompetent adults. It can lead to severe and lethal complications including Varicella pneumonia that can rapidly progress to acute respiratory distress syndrome a rare and life-threatening situation.
A 63 years old man was admitted to the intensive care unit for pneumonia with generalized papulovesicular lesions. After investigations, the diagnosis of Varicella pneumonia complicated with acute respiratory distress syndrome was maintained and the patient was put on mechanical ventilation, and despite proper management (antiviral treatment; protective ventilation and prone position) the patient died 48 hours after his admission.
Despite its rarity, Varicella pneumonia can be a life-threatening situation in immunocompetent adults. The diagnosis must be evoked when the patient presented with respiratory manifestations with dermatologic lesions.
1 Introduction
Varicella is a highly contagious disease caused by Varicella-Zoster Virus, it's a common childhood self-limited disease but it can be a life-threatening situation in immunocompromised patients [[1], [2], [3]]. And despite its rarity, Varicella zona infection can lead to severe lethal complications in immunocompetent persons including varicella pneumonia that can rapidly progress to an acute respiratory distress syndrome despite conventional support [[4], [5], [6]].
In this paper; we will report the clinical case of a 63 years old man, with no medical history, admitted to the critical care unit for acute respiratory distress syndrome due to Varicella pneumonia. We will discuss the respiratory manifestations of Varicella-Zoster virus, the diagnosis and the treatment.
2 Clinical case
A 63-year-old man with a history of smoking 23 packets/years weaned for 10 years, with no other medical history was admitted to the emergency room for dyspnea, 5 days after a diffuse rash that started in his scalp.
The physical examination on his admission was as follow: fever at 38.5 °C, polypnea at 30 cycles/minute, pulse oxymetry at 65% under high concentration mask at 15 L/min, bilateral rhonchi, perioral and extremists cyanosis with signs of respiratory exhaustion: paradoxical respiration, high blood pressure at 180/110 mmHg, heart rate at 110 beats/min and generalized papulovesicular lesions with certain lesions with a necrotic center (Fig. 1).Fig. 1 Image of the patient showing generalized papulo-vesicular lesions with certain lesions with a necrotic center.
Fig. 1
High flow nasal cannula treatment was initiated with the flow of 80l/min and the inspiratory fraction of oxygen at 100% with no improvement, the patient was intubated.
The arterial blood gas after intubation was as followed: pH 7.23, PaO2 42 with FiO2 of 100% and PaO2/FiO2 of 42, PaCO2 65, HCO3- 14 and lactates at 4.05.
The complete blood count: hyperleukocytosis at 11,460/μm, lymphopenia at 450/mm3, thrombocytopenia at 110,000 μm, CRP at 113 mg/l, procalcitonin at 0.82, hepatic cytolysis with ASAT and ALAT 64 and 45 higher than limit respectively, the elevation of lactate dehydrogenase (LDH) at 1289 IU/l, hypoalbuminemia at 27 g/l, urinary antigen test for streptococcus pneumoniae and legionella pneumonia were negative, human immunodeficiency virus HIV testing was negative, RT-PCR (reverse transcriptase-polymerase chain reaction) for Covid-19 and H1N1 were negative, and Varicella zona virus serology was positive.
The chest X-ray showed the presence of bilateral and diffuse alveolar interstitial opacities in the two pulmonary fields (Fig. 2).Fig. 2 Chest X-ray showed the presence of bilateral and diffuse alveolar interstitial opacities in the two pulmonary fields.
Fig. 2
The diagnosis of acute respiratory distress syndrome caused by Varicella pneumonia was maintained by association of respiratory manifestations, dermatological lesions and positive serology for Varicella Zona Virus.
Initial treatment with acyclovir (10 mg/kg every 8 h) was initiated.
The evolution was fatal, despite prone position, curare perfusion and optimal sedation, the patient died after 48 hours of his admission.
3 Discussion
Varicella is a highly contagious disease caused by the Varicella-Zoster Virus with a worldwide distribution, it is a member of the « Herpesviridae » family of DNA virus which can cause lytic and latent infections [1,7,8]. It is acquired by inhalation of infected saliva droplets or rarely a direct contact with skin lesions [7].
It occurs in all countries with mild self-limiting symptoms lasting a few days and providing lifetime immunity but it can cause serious complications among high-risk populations with lethality of 7000 deaths/year [7,9].
Clinical signs of varicella are usually mild including intense prurit, blasters on palms and genitals; small painful and itchy ulcers on the oral cavity appearing 21 days after exposure to the virus [7].
The varicella reinfection is rare, causing serious painful illness in immunocompromised individuals with high a mortality rate [7,10,11].
Varicella pneumonia is the most common complication of adult Varicella with an incidence of 1/400 with risk factors such as smoking, immunosuppression and preexistent lung disease with a mortality rate of 10%–30% overall and up to 50% in those on mechanical ventilation [12,13].
Respiratory symptoms of Varicella pneumonia began 1–7 days after installation of the rash, they are usually mild with few respiratory symptoms such as dry cough, hemoptysis, thoracic pain, dyspnea, fever, and even acute respiratory distress [14,15].
Varicella induced acute respiratory distress syndrome is very rare but a life-threatening situation [16,17].
Radiologic images find ill-defined confluent nodules in 2 pulmonary fields, ground-glass opacities surrounding the nodules or diffuse, hilar lymphadenopathy, and pleural fluid [18,19].
Diagnosis is based on clinical findings, but laboratory tests are still essential in cases of atypical cases or disseminated infection, the virus is searched by molecular tests on skin lesion fluid, blood and respiratory samples and serologic diagnosis is useful to identify unprotected individuals and distinguish primary infection from reactivation [20].
Treatment of pulmonary chickenpox consists of antiviral drugs; acyclovir 10mg/kg/8 hours for a period of 7–10 days [7].
Purified immunoglobulins with anti-VZV antibodies can be administered intramuscularly 96 hours to 10 days after rash apparition [20].
4 Conclusion
Despite its rarity, varicella pneumonia can be a life-threatening situation in immunocompetent adults, with the possibility to develop an acute respiratory distress syndrome.
The diagnosis should be evoked in patients with respiratory distress with dermatologic lesions to start early management and avoid serious complications including death.
The work has been reported in line with the CARE 2018 criteria [21].
Ethical approval
The paper reflects the authors' own research and analysis in a truthful a complete manner.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
• Dr. AABDI MOHAMMED: Writing - original draft, Conceptualization, Methodology, Software, Validation, Formal analysis, Visualization.
• DR. MIMOUNI HAMZA: Resources, Data curation, Software. final approval of the version to be submitted
• Dr. LAZREG MOUSSA: Writing - review & editing, Formal analysis, Visualization. final approval of the version to be submitted
• Pr. BKIYAR HOUSSAM: Writing - review & editing, Visualization. final approval of the version to be submitted
• Pr. HOUSNI: Project administration, Visualization, Writing - review & editing, Resources, Conceptualization, Methodology, Validation. final approval of the version to be submitted
Consent
We have obtained the consent from the patient's wife for publication.
Guarantor
AABDI Mohammed MIMOUNI Hamza
Declaration of competing interest
The authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements). Or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. | Fatal | ReactionOutcome | CC BY | 33552499 | 18,957,681 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Breast cancer'. | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | CARBOCYSTEINE, CLOPIDOGREL BISULFATE, ELDECALCITOL, FAMOTIDINE, LIMAPROST, LOSARTAN POTASSIUM, LOXOPROFEN SODIUM, NINTEDANIB, PREGABALIN, REBAMIPIDE, SARPOGRELATE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33552523 | 18,850,965 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'. | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | CARBOCYSTEINE, CLOPIDOGREL BISULFATE, ELDECALCITOL, FAMOTIDINE, LIMAPROST, LOSARTAN POTASSIUM, LOXOPROFEN SODIUM, NINTEDANIB, PREGABALIN, REBAMIPIDE, SARPOGRELATE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33552523 | 18,850,965 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumothorax spontaneous'. | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | NINTEDANIB, TACROLIMUS | DrugsGivenReaction | CC BY | 33552523 | 18,897,192 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | CARBOCYSTEINE, CLOPIDOGREL BISULFATE, ELDECALCITOL, FAMOTIDINE, LIMAPROST, LOSARTAN POTASSIUM, LOXOPROFEN SODIUM, NINTEDANIB, PREGABALIN, REBAMIPIDE, SARPOGRELATE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33552523 | 18,850,965 | 2021-03 |
What was the administration route of drug 'ACETAMINOPHEN'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | Oral | DrugAdministrationRoute | CC BY | 33552523 | 18,808,925 | 2021-03 |
What was the administration route of drug 'CARBOCYSTEINE'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | Oral | DrugAdministrationRoute | CC BY | 33552523 | 18,850,965 | 2021-03 |
What was the administration route of drug 'CLOPIDOGREL BISULFATE'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | Oral | DrugAdministrationRoute | CC BY | 33552523 | 18,850,965 | 2021-03 |
What was the administration route of drug 'DEXTROMETHORPHAN HYDROBROMIDE'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | Oral | DrugAdministrationRoute | CC BY | 33552523 | 18,808,925 | 2021-03 |
What was the administration route of drug 'ELDECALCITOL'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | Oral | DrugAdministrationRoute | CC BY | 33552523 | 18,850,965 | 2021-03 |
What was the administration route of drug 'FAMOTIDINE'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | Oral | DrugAdministrationRoute | CC BY | 33552523 | 18,850,965 | 2021-03 |
What was the administration route of drug 'LANSOPRAZOLE'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | Oral | DrugAdministrationRoute | CC BY | 33552523 | 18,808,925 | 2021-03 |
What was the administration route of drug 'LIMAPROST'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | Oral | DrugAdministrationRoute | CC BY | 33552523 | 18,850,965 | 2021-03 |
What was the administration route of drug 'LOSARTAN POTASSIUM'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | Oral | DrugAdministrationRoute | CC BY | 33552523 | 18,850,965 | 2021-03 |
What was the administration route of drug 'LOXOPROFEN SODIUM'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | Oral | DrugAdministrationRoute | CC BY | 33552523 | 18,850,965 | 2021-03 |
What was the administration route of drug 'NINTEDANIB'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | Oral | DrugAdministrationRoute | CC BY | 33552523 | 18,850,965 | 2021-03 |
What was the administration route of drug 'PREGABALIN'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | Oral | DrugAdministrationRoute | CC BY | 33552523 | 18,850,965 | 2021-03 |
What was the administration route of drug 'REBAMIPIDE'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | Oral | DrugAdministrationRoute | CC BY | 33552523 | 18,850,965 | 2021-03 |
What was the administration route of drug 'SARPOGRELATE HYDROCHLORIDE'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | Oral | DrugAdministrationRoute | CC BY | 33552523 | 18,850,965 | 2021-03 |
What was the administration route of drug 'TACROLIMUS'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | Oral | DrugAdministrationRoute | CC BY | 33552523 | 18,808,925 | 2021-03 |
What was the dosage of drug 'ACETAMINOPHEN'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | 50 mg (milligrams). | DrugDosage | CC BY | 33552523 | 18,808,925 | 2021-03 |
What was the dosage of drug 'CARBOCYSTEINE'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | 500 mg (milligrams). | DrugDosage | CC BY | 33552523 | 18,850,965 | 2021-03 |
What was the dosage of drug 'CLOPIDOGREL BISULFATE'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | 75 mg (milligrams). | DrugDosage | CC BY | 33552523 | 18,850,965 | 2021-03 |
What was the dosage of drug 'DEXTROMETHORPHAN HYDROBROMIDE'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | 30 mg (milligrams). | DrugDosage | CC BY | 33552523 | 18,808,925 | 2021-03 |
What was the dosage of drug 'ELDECALCITOL'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | .75 µg (micrograms). | DrugDosage | CC BY | 33552523 | 18,850,965 | 2021-03 |
What was the dosage of drug 'FAMOTIDINE'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | 10 mg (milligrams). | DrugDosage | CC BY | 33552523 | 18,850,965 | 2021-03 |
What was the dosage of drug 'LANSOPRAZOLE'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | 15 mg (milligrams). | DrugDosage | CC BY | 33552523 | 18,808,925 | 2021-03 |
What was the dosage of drug 'LIMAPROST'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | 5 µg (micrograms). | DrugDosage | CC BY | 33552523 | 18,850,965 | 2021-03 |
What was the dosage of drug 'LOSARTAN POTASSIUM'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | 50 mg (milligrams). | DrugDosage | CC BY | 33552523 | 18,850,965 | 2021-03 |
What was the dosage of drug 'LOXOPROFEN SODIUM'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | 60 mg (milligrams). | DrugDosage | CC BY | 33552523 | 18,850,965 | 2021-03 |
What was the dosage of drug 'PREGABALIN'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | 25 mg (milligrams). | DrugDosage | CC BY | 33552523 | 18,850,965 | 2021-03 |
What was the dosage of drug 'REBAMIPIDE'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | 100 mg (milligrams). | DrugDosage | CC BY | 33552523 | 18,850,965 | 2021-03 |
What was the dosage of drug 'SARPOGRELATE HYDROCHLORIDE'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | 100 mg (milligrams). | DrugDosage | CC BY | 33552523 | 18,850,965 | 2021-03 |
What was the dosage of drug 'TACROLIMUS'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | 1.5 mg (milligrams). | DrugDosage | CC BY | 33552523 | 18,808,925 | 2021-03 |
What was the outcome of reaction 'Nausea'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | Recovering | ReactionOutcome | CC BY | 33552523 | 18,850,965 | 2021-03 |
What was the outcome of reaction 'Pneumothorax'? | Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.
Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.
Introduction
Systemic sclerosis (SSc) is a systemic connective tissue disease characterized by a combination of fibrosis of the skin and various organs, peripheral circulatory disturbances, and autoantibody production [1]. Functional disorders of the lungs, gastrointestinal tract, and heart may be present during the course of the disease. Interstitial lung disease (ILD) is the most common organ lesion associated with SSc, and it is also the most common cause of SSc‐related death, accounting for approximately 30% of deaths due to SSc [2, 3]. Pulmonary infection is the leading cause of death in patients with respiratory failure due to SSc‐ILD progression, followed by pneumothorax, lung cancer, and cardiopulmonary dysfunction with secondary pulmonary hypertension [4]. In the SENSCIS trial, nintedanib, an antifibrotic drug recently approved for the treatment of SSc‐ILD, significantly inhibited forced vital capacity (FVC) decline compared to placebo in patients with SSc‐ILD; measurements were obtained annually. A double‐blind clinical trial investigating the safety of nintedanib reported no pneumothorax in patients with SSc‐ILD [5]. However, patients in the SENSICS trial had a mean FVC of 2500 mL (73% of predicted), which indicates relatively good lung function. Nevertheless, the safety of nintedanib use in patients with impaired lung function is not clear. Here, we report on two patients with SSc‐ILD and impaired lung function, who developed refractory spontaneous pneumothorax during nintedanib therapy.
Case Report
Case 1
A 62‐year‐old woman was referred to our hospital for a follow‐up evaluation of ILD. She was diagnosed with SSc at the age of 50 years, and had been treated with the immunosuppressant tacrolimus since the time of diagnosis. High‐resolution chest computed tomography showed ILD in 36.6% of the lung fields; the method of measurement was defined in a previous study [6] (Fig. 1A). Pulmonary function tests revealed an FVC of 1050 mL (43.6% of predicted) and a diffusing capacity for carbon monoxide (DLCO) of 47.8%; she had an elevated Sialylated carbohydrate antigen Krebs von den Lungen‐6 (KL‐6) level of 673 U/mL. A year later, she was started on 150 mg of nintedanib twice daily, because her FVC had declined by 140 mL and was predicted to decline further over time. No gastrointestinal symptoms such as diarrhoea or nausea were observed after starting nintedanib. Fourteen weeks after nintedanib initiation, she visited the emergency room due to dyspnoea and was diagnosed with pneumothorax (Fig. 1B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. Thoracic drainage continued for three weeks, but the air leak persisted and the lung did not expand. Four weeks after admission, thoracoscopic bullectomy was performed despite the high surgical risk due to low lung function (Fig. 1C–E). After the operation, the air leak disappeared; the chest tube was removed two weeks after surgery.
Figure 1 (A) Chest computed tomography showing ground‐glass opacities and honeycombing distributed dorsally in the lungs bilaterally. (B) The left lung is highly collapsed, and the right lung is mildly collapsed. (C–E) Pathological findings. (C) Macroscopic image of surgical specimens. (D) A bulla, an emphysematous cyst localized in the lungs, and a bleb with emphysematous cyst changes in the pleura (upper fragmentation); haematoxylin and eosin staining, loupe view. (E) Lymphocytes and plasmacytoid infiltrates in the peribronchial area with possible chronic inflammation associated with collagen disease; haematoxylin and eosin staining 10×.
Case 2
An 81‐year‐old woman was referred to our hospital for the treatment of interstitial pneumonia. History‐taking revealed that she was diagnosed with SSc at the age of 70 years; although she had fingertip ulcerations, she was not being treated with steroids or immunosuppressants. ILD was observed in 20% of the lung fields (Fig. 2A). Pulmonary function tests revealed an FVC of 1220 mL (65.2% of predicted) and a DLCO of 84.4%; she had an elevated KL‐6 level of 613 U/mL. Her FVC had declined by 220 mL a year later, so it was expected to decline further in the future. Therefore, 150 mg of nintedanib twice daily was started. Two weeks after starting nintedanib, the dose was reduced to 100 mg twice daily due to nausea. She continued the medication at this reduced dosage without adverse effects; however, 16 weeks after the start of treatment, she was admitted to an emergency department for dyspnoea and diagnosed with pneumothorax (Fig. 2B). She was admitted to the hospital, nintedanib was stopped, and a chest tube was inserted. As surgical treatment was not considered possible, pleural attachments (autologous blood, 50% glucose, 300 mg of minocycline, and 5 Klinische Einheit (KE) of picibanil) were performed weekly. The chest tube was removed seven weeks after admission.
Figure 2 (A) Chest computed tomography showing subpleural interstitial shadows in the lungs. (B) A tube is inserted in the right thoracic cavity (red arrow), and mild subcutaneous emphysema is observed.
Discussion
We treated two patients with impaired lung function due to SSc‐ILD with nintedanib; both developed refractory spontaneous pneumothorax requiring prolonged drainage, pleurodesis, and surgery. It is necessary to consider that pneumothorax may occur during nintedanib treatment for low lung function in SSc‐ILD cases; if pneumothorax develops, it may be intractable.
In patients with severe lung dysfunction, the reversibility of ILD lesions is poor; in addition, the use of drugs with immunosuppressive effects may increase the risk of infection and death. Therapy with these drugs is therefore not recommended [4]. In elderly patients with severely deteriorated lung function (as in the present cases) who are unsuitable for lung transplantation, ILD progress is considered to be an extensive disease and the prognosis is poor [6]. Patients in the SENSCIS study, which showed that nintedanib reduced the annual FVC decline in patients with SSc‐ILD, had relatively good lung function [5]. There is currently no evidence that nintedanib, which has no immunosuppressive effect due to its mechanism of action, has any benefit in the treatment of patients with severe lung dysfunction. Therefore, it is necessary to evaluate the risks and benefits when administering nintedanib to patients with highly impaired lung function.
Pneumothorax was not reported with nintedanib use in the SENSCIS trial among patients with SSc‐ILD; it was also not reported in more than 5% of cases in the INPULSIS trial among patients with idiopathic pulmonary fibrosis (IPF) [5, 7]. In a post‐marketing survey in Japan, the frequency of pneumothorax in patients with IPF treated with nintedanib was also low at 0.33% [8]. However, both clinical trials were conducted in patients with relatively good lung function, with an average FVC of more than 70% of predicted. The two patients described here did not meet the exclusion criteria and one inclusion criteria (duration of less than seven years after onset of the first non‐Raynaud's symptom attributable to SSc) of the SENSCIS trial, but fulfilled all the other inclusion criteria (ILD ≥10%, %FVC ≥40%, and 30% ≤ %DLCO ≤ 89%). Patients with similar disease phenotypes were not included in the SENSCIS trial, and the safety profile of nintedanib is currently largely unknown in this population.
In IPF cases, spontaneous pneumothorax is a known and relatively frequent complication in IPF [9], and the risk of pneumothorax increases as the disease progresses [10]. Although spontaneous pneumothorax is a rare complication of SSc, it is also a likely cause of death in cases of advanced or severe ILD [4]. Nintedanib is a small‐molecule tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) receptor (VEGFR), platelet‐derived growth factor receptor‐alpha (PDGFRα), and fibroblast growth factor receptor (FGFR). Similarly, bevacizumab, which has an anti‐VEGF effect, has been shown to cause ischaemic changes and perforation of the lung tissue due to its anti‐VEGF action [11]. As the lungs of patients with progressed interstitial pneumonia have diminished elastic fibres and fragile lung tissue structure, the anti‐VEGF effect of nintedanib may have caused pneumothorax in the present patients who showed notable fibrosis. In addition, VEGFR, PDGFRα, and FGFR are involved in wound healing; therefore, delayed wound healing may occur in patients taking nintedanib. There were no reports on protracted wound healing in the nintedanib group of the SENSCIS study, and there was no difference in the occurrence of skin ulcers as an adverse event between the nintedanib and placebo groups (18.4% and 17.4%, respectively) [5]. However, a Japanese subgroup analysis of the SENSCIS revealed a trend towards increased prevalence of digital ulcers in the nintedanib than in the placebo group [12]. There may be racial differences in impaired wound healing with nintedanib.
The half‐life from the steady state of 300 mg of nintedanib twice daily is 27.5 h [13]; consequently, blood levels of nintedanib are expected to decline gradually after discontinuation. Therefore, the most likely reason for the refractory pneumothorax in these two cases was the inability of the lungs to reinflate sufficiently after thoracic drainage due to decreased lung compliance from interstitial pneumonia.
In summary, nintedanib treatment for SSc‐ILD, which is classified as an extensive disease, possibly increases the risk of refractory pneumothorax. However, this report only describes two patients, and this observation may have been a coincidence. Cumulative evidence from future cases is needed for evaluating the potential risk of this serious complication.
Disclosure Statement
Appropriate written informed consent was obtained for publication of this case report and accompanying images.
Author Contribution Statement
Conceptualization: Toshiyuki Sumi. Investigation: Toshiyuki Sumi, Hirofumi Uehara, Makoto Tada, Yoshiko Keira, Koki Kamada, Naoki Shijubou, Yuichi Yamada. Writing—original draft: Toshiyuki Sumi. Writing—review and editing: Hisashi Nakata, Yuji Mori, Hirofumi Chiba.
Acknowledgment
We would like to thank Editage for English language editing. | Recovered | ReactionOutcome | CC BY | 33552523 | 18,850,965 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective for unapproved indication'. | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis in Rheumatologic Disease.
Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections.
Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.
1. Background
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune overactivation that can lead to tissue destruction and organ failure. As a primary disorder, it is typically seen in pediatrics and has several associated genetic mutations [1]. In adults, it presents as a secondary phenomenon, seen in conjunction with infection, malignancy, immunodeficiency, or another immune dysregulating event. The diagnosis is established by meeting five of eight criteria, including fever greater than 38.5 degrees Celsius; splenomegaly; peripheral cytopenia (at least two of hemoglobin < 9 g/dL, platelets < 100, 000/microL, absolute neutrophil count < 1000/microL); hypertriglyceridemia (fasting > 265 mg/dL) or hypofibrinogenemia (<150 mg/dL); hemophagocytosis in the bone marrow, spleen, lymph node, or liver; decreased natural killer cell activity; ferritin > 500 ng/mL; and elevated soluble CD25 (IL-2 receptor α) two standard deviations above age-adjusted norms [2, 3]. Laboratory evaluation of soluble CD25 and natural killer cell activity require specialized testing and therefore do not result in real time. Without treatment, prognosis is limited to a few months, and the greatest barrier to survival is delay in diagnosis. Treatment entails identification and treatment of the underlying trigger. With proper treatment and identification of triggering event, survival increases to 54% at 6.2 years [4, 5]. Prognosis is worse with higher ferritin levels, underlying malignancy, older age, and low serum albumin levels [6, 7].
Although rheumatologic disease by itself can be a trigger for HLH, this is rare. Among adults on biological therapies for rheumatologic disease, infection is the most common trigger [8]. Histoplasmosis is a serious fungal infection that is endemic to the Ohio and Mississippi River valleys in the United States, as well as parts of Central and South America. The infective agent, Histoplasma capsulatum, is most likely to be found in soil containing bird or bat droppings. Inhalation of the spores allows them to transform into yeast and travel throughout the lymphatic and vascular system. Pulmonary histoplasmosis can cause pneumonia, mediastinal or hilar masses, pulmonary nodules, cavitary lung disease, and pericarditis. Risk factors for disseminated histoplasmosis include AIDS, immunodeficiency, immunosuppressive medications, and extremes of age. Untreated diffuse histoplasmosis is fatal within weeks, but proper antifungal treatment with amphotericin B or itraconazole increases survival rates dramatically [9].
Cases of HLH secondary to disseminated histoplasmosis are rare and extremely serious. Several case reports in the literature describe patients with AIDS [10–15], malignancy [16], or immunosuppression due to medications [17, 18]. Below we present two cases of patients with HLH secondary to disseminated histoplasmosis, both in the setting of recent immunosuppressive medication for underlying autoimmune disease.
2. Case Report #1
A 66-year-old woman presented to an emergency department near her home in Mexico with fever and abdominal pain of two weeks duration. She also described two months of increased fatigue and malaise, as well as increased swelling around her feet and ankles that had more recently developed. Although she was born in the United States in Oregon, she had been living in Mexico for several years. She denied travel to any other regions. A CT scan demonstrated appendicitis, and she was admitted to a hospital in Mexico for appendectomy. However, over the subsequent five days, she continued to have worsening fevers and abdominal pain. At this point, she flew to Mayo Clinic Arizona for further evaluation.
Her past medical history was significant for rheumatoid arthritis and chronic low back pain. Medications included gabapentin, daily prednisone (20 mg/day), spironolactone, and omeprazole. Following her appendix surgery, she had been placed on moxifloxacin for five days. She had been on methotrexate for several years, but this was discontinued a few months prior due to elevation of liver enzymes.
At the time of presentation, she appeared ill, and her vitals included fluid responsive hypotension, tachypnea with respiratory rate of 22, and mild hypoxia with oxygen saturation 88-95% on room air. Physical exam was significant for bibasilar crackles, abdominal distension, and diffuse tenderness to palpation without peritoneal signs, diffusely tender joints, and erythema over the left elbow and the right knee that was warm to touch. Initial laboratory evaluation demonstrated a hemoglobin of 12.5 g/dL (reference range 12.0–15.5 g/dL), platelet count of 8 × 10(9)/L (reference range 149–375 × 10(9)/L), and white blood cell count (WBC) 2.7 × 10(9)/L (reference range 3.4–10.6 × 10(9)/L) with neutrophilic predominance (absolute neutrophil count (ANC), 2.05 × 10(9)/L (reference range 1.40–6.60 × 10(9)/L)). Electrolyte panel showed hyponatremia 131 mmol/L (reference range 135–145 mmol/L) but was otherwise normal, including creatinine 0.9 mg/dL (reference range 0.6–1.1 mg/dL). LFTs were elevated with alkaline phosphatase 318 U/L (reference range 55–142 U/L), alanine aminotransferase (ALT) 145 U/L (reference range 7–45 U/L), and aspartate aminotransferase (AST) 252 U/L (reference range 9–43 U/L). Most notably, her ferritin was drastically elevated at 27,300 mcg/L (reference range 11–307 mcg/L). Additionally, triglycerides were elevated at 272 mg/dL (reference range < 150 mg/dL), and fibrinogen was reduced at 120 mg/dL (reference range 200–430 mg/dL). Chest X-ray showed trace bilateral pleural effusions and small calcified granulomata in the upper lungs bilaterally. Given her diffusely tender joints, X-ray of the hands were performed and revealed numerous subchondral cysts and erosion, as well as subluxation of the right index finger distal phalanx, with sparing of the metacarpophalangeal joints consistent with rheumatoid arthritis. Due to tachypnea, leukopenia, and hemodynamic instability, she was diagnosed with sepsis.
She initially received broad spectrum antibiotics and underwent paracentesis which was negative for peritonitis. Bacterial and fungal cultures of the ascitic fluid showed no growth. Her significantly elevated ferritin prompted a bone marrow biopsy (BMB), which showed features of hemophagocytic lymphohistiocytosis (Figure 1(a)). Given her findings of pancytopenia, elevated ferritin and triglycerides, reduced fibrinogen, and evidence of hemophagocytosis on BMB, she was treated with high-dose steroids and intravenous fluids. After initiation of steroids, her thrombocytopenia and joint pain improved. However, her WBC count continued to drop, and the patient continued to spike fevers; thus, antibiotics were adjusted to cover for neutropenic fever. Without an identified infectious source, a CT of the brain, chest, abdomen, and pelvis was performed which showed bilateral pulmonary infiltrates but was otherwise unremarkable. Liver biopsy was considered but was deemed unsafe due to coagulopathy. Her respiratory status declined eventually requiring high-flow oxygen due to acute respiratory distress syndrome (ARDS) (Figure 1(b)), and she was treated with aggressive diuresis. Initially, she had adequate response but ultimately developed oliguria and renal failure.
On hospital day four, the ferritin had improved to 609 mcg/L (reference range 11–307 mcg/L); however, LFTs continued to rise, and resultant coagulopathy required daily cryoprecipitate transfusion to maintain safe fibrinogen levels. Due to worsening clinical status with multiorgan failure including the liver, kidney, respiratory, and bone marrow, it was decided to add etoposide for more aggressive treatment of HLH. Despite these efforts, her ferritin rapidly climbed to over 80,000 mcg/L (reference range 11–307 mcg/L). Infectious workup to date was negative including blood bacterial and fungal cultures, ascites bacterial and fungal cultures, and blood tests for HIV, HHV-6, EBV DNA, hepatitis A and E IgM, parvovirus B19, adenovirus, and tuberculosis quantiferon.
Infectious etiology was identified when her urine histoplasmosis antigen returned positive above the upper detectable limit. The bone marrow biopsy was stained for histoplasmosis and confirmed disseminated infection (Figure 1(c)). Amphotericin therapy was initiated as the patient began CRRT for worsening kidney failure. Over the next eight days, however, she did not show any clinical improvement and was treated supportively for ICU delirium, respiratory failure, anuria requiring intermittent hemodialysis, worsening coagulopathy and rising ammonia, and malnutrition requiring tube feeds. On day twelve, voriconazole was added for additional antifungal coverage.
Unfortunately, despite these efforts, the patient's blood counts continued to decline, and she developed massive melena on hospital day 13 with a hemoglobin of 4 g/dL (reference range 12.0–15.5 g/dL), WBC 0.1/L (reference range 3.4–10.6 × 10(9)/L), ANC 0.11/L (reference range 1.40–6.60 × 10(9)/L), and platelets 41/L (reference range 149–375 × 10(9)/L). At this point, the patient and her power of attorney elected to withdraw aggressive treatments, and she was transferred to inpatient hospice.
3. Case Report #2
A 41-year-old woman residing in Arizona with a history of ulcerative colitis from who was on Remicade up until one month earlier was admitted three times over a course of a month with a variety of symptoms without identifying etiology. Initially, she had nonspecific fevers, headache, neck pain, fatigue, nausea, vomiting, and arthralgias. She was found to have an edematous gallbladder (Figure 2(a)) and mild splenomegaly, with a negative infectious workup. With symptomatic care, her fevers were controlled, and she was discharged with a diagnosis of presumed viral syndrome versus Remicade toxicity. However, symptoms worsened, and she represented with fever, sepsis, cholestatic jaundice, acute kidney injury, pancytopenia, and multiple metabolic abnormalities requiring admission to the intensive care unit. Initially, she underwent ERCP with sphincterotomy, and common bile duct stent was placed. On endoscopy, the duodenal mucosa was noted to be friable, biopsy revealed reactive gastropathy, and H. pylori testing was negative. She then underwent laparoscopic cholecystectomy for acalculous cholecystitis. Postoperatively, she developed bloody secretions from the endotracheal tube followed by ARDS; thus, she was unable to be extubated. She also had episodes of epistaxis and melena through this time. Her clinical status quickly deteriorated to multiorgan failure including renal failure requiring dialysis, cholestatic liver failure, respiratory failure requiring mechanical ventilation, and critical pancytopenia requiring high-volume transfusions including 17 units of packed red blood cells, 17 units of platelets, and 6 units of cryoprecipitate.
Workup through this point revealed a markedly elevated ferritin of 73,469 mcg/L (reference range 11–307 mcg/L), elevated lactate dehydrogenase of 2,375 U/L (reference range 122–222 U/L), hypofibrinogenemia of 135 mg/dL (reference range 200-430 mg/dL), and hypertriglyceridemia 2,259 mg/dL (reference range < 150 mg/dL), raising suspicion for HLH. Bone marrow biopsy confirmed the diagnosis (Figures 2(b)–2(d)), and she was initiated on high-dose steroids and etoposide. She developed a severe diffuse rash to etoposide necessitating its discontinuation. Investigation for an underlying trigger included bronchoalveolar lavage (BAL) culture which returned positive for Histoplasma capsulatum, in addition to positive histoplasma urinary antigen. During the same hospitalization, she additionally underwent cholecystectomy, and cultured gallbladder tissue ultimately grew H. capsulatum. Based on history, this was likely acquired in the setting of prior Remicade use while exploring bat caves in Cancun, Mexico, two weeks prior to admission. The patient was born and lived in Arizona until her presentation and denied travel to any endemic areas. Her Aspergillus antigen was also positive from BAL, but this was felt to be a false positive as Aspergillus antigen testing cross-reacts with Histoplasma.
For treatment of disseminated histoplasmosis, she received intravenous AmBisome starting on day 4 of hospitalization and later transitioned to oral itraconazole. With these treatments, she recovered well and was eventually transferred out of the intensive care unit on day 18. She required one dose of Neupogen for leukopenia, but her white blood cell count recovered thereafter, and platelet count returned to normal. Her ferritin had dramatically decreased to 1,568 mcg/L (reference range 11–307 mcg/L). Her kidney and liver function recovered to the point where she could be safely discharged to acute rehabilitation after an approximately four weeks stay in the hospital. She continued to improve during a two-week rehabilitation stay and was then discharged home with an oral steroid taper and oral itraconazole for one year following diagnosis.
4. Discussion
The diagnosis and treatment of acquired HLH in adults are serious and challenging, as the clinical presentation can be fairly nonspecific and diagnosis is based on a collection of both clinical and laboratory abnormalities. In pediatric patients with familial HLH, an elevated ferritin greater than 10,000 μg/L is highly sensitive and specific for diagnosis [19]. In adults, however, elevated ferritin has been linked to various conditions including malignancy, liver dysfunction, infection, anemia of chronic disease, or iron overload [20]. Markedly elevated ferritin, however, is thought to be more specific for adult onset stills disease, macrophage activation syndrome, and HLH. In a retrospective study [20] of patients with ferritin levels greater than 50,000 μg/L, 19% were found to have HLH. The most frequently seen diagnosis in these patients was renal failure (73%), liver injury (61%), infections (52%), and hematologic malignancies (36%). No ferritin cut off level was found to be specific for HLH in this study. Currently, ferritin > 500 μg/L is included in the diagnostic criteria for HLH, although many prefer to use >3000 μg/L. Given the lack of specific criteria for diagnosis of adult acquired HLH, a scoring system which includes the above mentioned diagnostic criteria for HLH was developed and has been shown to be 90% sensitive and 79% specific, although specificity decreases as patients become less stable [21]. Once the diagnosis is confirmed, treatment must be initiated immediately. Additionally, a search must be undertaken to find an underlying trigger for HLH; as without treating the source, there is little chance for clinical improvement.
Here, we present two cases of HLH secondary to disseminated histoplasmosis. Previously, published cases of histoplasmosis associated HLH were reported in HIV [22], hematologic malignancy [16], and transplant patients on immunosuppression [18, 22]. Disseminated histoplasmosis by itself is also quite serious but generally treatable with antifungal therapy. Current IDSA guidelines for moderate to severe disease include liposomal amphotericin B (3.0 mg/kg daily) for 1-2 weeks, followed with oral itraconazole for at least 12 months [9]. Patients who have both disseminated histoplasmosis and HLH portend a worse prognosis. In a retrospective review of eleven cases of histoplasmosis associated HLH, 45% died within 30 days, and 63% died within 90 days [22]. The main challenge of caring for patients with histoplasmosis associated HLH is management of the multiorgan failure that can result from this combination of diseases. Both HLH and histoplasmosis can cause hematologic abnormalities, namely, pancytopenia, and both patients presented here required large volume transfusions. In addition, both patients developed respiratory failure from ARDS, renal failure requiring renal replacement therapy, liver failure, and gastrointestinal bleeding. Disseminated histoplasmosis involving the gastrointestinal system can cause cholecystitis and appendicitis leading to surgery, as well as melena and gastritis, which were seen in these cases.
The main risk factors for disseminated histoplasmosis leading to HLH in these cases were immunosuppressive medication (methotrexate and infliximab) and environmental exposure (bird or bat droppings, especially in caves). Interestingly, in both cases, the offending medication had been discontinued due to laboratory abnormalities 1-2 months prior to any presenting symptoms. It is unclear whether this may have been a risk factor for disease. Nevertheless, with a presentation of diffuse infectious symptoms without an identified etiology in the context of recent immunosuppressive medication, an exhaustive history and laboratory inquiry should be pursued to avoid delayed diagnosis for serious conditions such as disseminated fungal infection and HLH.
Data Availability
No datasets were used.
Conflicts of Interest
No authors have conflict of interest to disclose.
Authors' Contributions
All authors included have made substantial contributions to conception, design, data acquisition, drafting, and/or revising of the manuscript. All authors have read and approved the submission of this manuscript.
Figure 1 (a) Bone marrow aspirate reveals evidence of hemophagocytosis. (b) Chest X-ray reveals evidence of bilateral infiltrates, and patient then diagnosed with ARDS. (c) Bone marrow core biopsy GMS stain reveals histoplasmosis.
Figure 2 (a) CT abdomen on admission reveals edematous gallbladder which was later found to have evidence of Histoplasma capsulatum. (b, c) Bone marrow aspirate reveals hemophagocytosis. (d) GMS stain of bone marrow core biopsy positive for histoplasmosis. | AMPHOTERICIN B, ETOPOSIDE, GABAPENTIN, METHOTREXATE, MOXIFLOXACIN, OMEPRAZOLE, PREDNISONE, SPIRONOLACTONE, VORICONAZOLE | DrugsGivenReaction | CC BY | 33552603 | 18,986,270 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis in Rheumatologic Disease.
Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections.
Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.
1. Background
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune overactivation that can lead to tissue destruction and organ failure. As a primary disorder, it is typically seen in pediatrics and has several associated genetic mutations [1]. In adults, it presents as a secondary phenomenon, seen in conjunction with infection, malignancy, immunodeficiency, or another immune dysregulating event. The diagnosis is established by meeting five of eight criteria, including fever greater than 38.5 degrees Celsius; splenomegaly; peripheral cytopenia (at least two of hemoglobin < 9 g/dL, platelets < 100, 000/microL, absolute neutrophil count < 1000/microL); hypertriglyceridemia (fasting > 265 mg/dL) or hypofibrinogenemia (<150 mg/dL); hemophagocytosis in the bone marrow, spleen, lymph node, or liver; decreased natural killer cell activity; ferritin > 500 ng/mL; and elevated soluble CD25 (IL-2 receptor α) two standard deviations above age-adjusted norms [2, 3]. Laboratory evaluation of soluble CD25 and natural killer cell activity require specialized testing and therefore do not result in real time. Without treatment, prognosis is limited to a few months, and the greatest barrier to survival is delay in diagnosis. Treatment entails identification and treatment of the underlying trigger. With proper treatment and identification of triggering event, survival increases to 54% at 6.2 years [4, 5]. Prognosis is worse with higher ferritin levels, underlying malignancy, older age, and low serum albumin levels [6, 7].
Although rheumatologic disease by itself can be a trigger for HLH, this is rare. Among adults on biological therapies for rheumatologic disease, infection is the most common trigger [8]. Histoplasmosis is a serious fungal infection that is endemic to the Ohio and Mississippi River valleys in the United States, as well as parts of Central and South America. The infective agent, Histoplasma capsulatum, is most likely to be found in soil containing bird or bat droppings. Inhalation of the spores allows them to transform into yeast and travel throughout the lymphatic and vascular system. Pulmonary histoplasmosis can cause pneumonia, mediastinal or hilar masses, pulmonary nodules, cavitary lung disease, and pericarditis. Risk factors for disseminated histoplasmosis include AIDS, immunodeficiency, immunosuppressive medications, and extremes of age. Untreated diffuse histoplasmosis is fatal within weeks, but proper antifungal treatment with amphotericin B or itraconazole increases survival rates dramatically [9].
Cases of HLH secondary to disseminated histoplasmosis are rare and extremely serious. Several case reports in the literature describe patients with AIDS [10–15], malignancy [16], or immunosuppression due to medications [17, 18]. Below we present two cases of patients with HLH secondary to disseminated histoplasmosis, both in the setting of recent immunosuppressive medication for underlying autoimmune disease.
2. Case Report #1
A 66-year-old woman presented to an emergency department near her home in Mexico with fever and abdominal pain of two weeks duration. She also described two months of increased fatigue and malaise, as well as increased swelling around her feet and ankles that had more recently developed. Although she was born in the United States in Oregon, she had been living in Mexico for several years. She denied travel to any other regions. A CT scan demonstrated appendicitis, and she was admitted to a hospital in Mexico for appendectomy. However, over the subsequent five days, she continued to have worsening fevers and abdominal pain. At this point, she flew to Mayo Clinic Arizona for further evaluation.
Her past medical history was significant for rheumatoid arthritis and chronic low back pain. Medications included gabapentin, daily prednisone (20 mg/day), spironolactone, and omeprazole. Following her appendix surgery, she had been placed on moxifloxacin for five days. She had been on methotrexate for several years, but this was discontinued a few months prior due to elevation of liver enzymes.
At the time of presentation, she appeared ill, and her vitals included fluid responsive hypotension, tachypnea with respiratory rate of 22, and mild hypoxia with oxygen saturation 88-95% on room air. Physical exam was significant for bibasilar crackles, abdominal distension, and diffuse tenderness to palpation without peritoneal signs, diffusely tender joints, and erythema over the left elbow and the right knee that was warm to touch. Initial laboratory evaluation demonstrated a hemoglobin of 12.5 g/dL (reference range 12.0–15.5 g/dL), platelet count of 8 × 10(9)/L (reference range 149–375 × 10(9)/L), and white blood cell count (WBC) 2.7 × 10(9)/L (reference range 3.4–10.6 × 10(9)/L) with neutrophilic predominance (absolute neutrophil count (ANC), 2.05 × 10(9)/L (reference range 1.40–6.60 × 10(9)/L)). Electrolyte panel showed hyponatremia 131 mmol/L (reference range 135–145 mmol/L) but was otherwise normal, including creatinine 0.9 mg/dL (reference range 0.6–1.1 mg/dL). LFTs were elevated with alkaline phosphatase 318 U/L (reference range 55–142 U/L), alanine aminotransferase (ALT) 145 U/L (reference range 7–45 U/L), and aspartate aminotransferase (AST) 252 U/L (reference range 9–43 U/L). Most notably, her ferritin was drastically elevated at 27,300 mcg/L (reference range 11–307 mcg/L). Additionally, triglycerides were elevated at 272 mg/dL (reference range < 150 mg/dL), and fibrinogen was reduced at 120 mg/dL (reference range 200–430 mg/dL). Chest X-ray showed trace bilateral pleural effusions and small calcified granulomata in the upper lungs bilaterally. Given her diffusely tender joints, X-ray of the hands were performed and revealed numerous subchondral cysts and erosion, as well as subluxation of the right index finger distal phalanx, with sparing of the metacarpophalangeal joints consistent with rheumatoid arthritis. Due to tachypnea, leukopenia, and hemodynamic instability, she was diagnosed with sepsis.
She initially received broad spectrum antibiotics and underwent paracentesis which was negative for peritonitis. Bacterial and fungal cultures of the ascitic fluid showed no growth. Her significantly elevated ferritin prompted a bone marrow biopsy (BMB), which showed features of hemophagocytic lymphohistiocytosis (Figure 1(a)). Given her findings of pancytopenia, elevated ferritin and triglycerides, reduced fibrinogen, and evidence of hemophagocytosis on BMB, she was treated with high-dose steroids and intravenous fluids. After initiation of steroids, her thrombocytopenia and joint pain improved. However, her WBC count continued to drop, and the patient continued to spike fevers; thus, antibiotics were adjusted to cover for neutropenic fever. Without an identified infectious source, a CT of the brain, chest, abdomen, and pelvis was performed which showed bilateral pulmonary infiltrates but was otherwise unremarkable. Liver biopsy was considered but was deemed unsafe due to coagulopathy. Her respiratory status declined eventually requiring high-flow oxygen due to acute respiratory distress syndrome (ARDS) (Figure 1(b)), and she was treated with aggressive diuresis. Initially, she had adequate response but ultimately developed oliguria and renal failure.
On hospital day four, the ferritin had improved to 609 mcg/L (reference range 11–307 mcg/L); however, LFTs continued to rise, and resultant coagulopathy required daily cryoprecipitate transfusion to maintain safe fibrinogen levels. Due to worsening clinical status with multiorgan failure including the liver, kidney, respiratory, and bone marrow, it was decided to add etoposide for more aggressive treatment of HLH. Despite these efforts, her ferritin rapidly climbed to over 80,000 mcg/L (reference range 11–307 mcg/L). Infectious workup to date was negative including blood bacterial and fungal cultures, ascites bacterial and fungal cultures, and blood tests for HIV, HHV-6, EBV DNA, hepatitis A and E IgM, parvovirus B19, adenovirus, and tuberculosis quantiferon.
Infectious etiology was identified when her urine histoplasmosis antigen returned positive above the upper detectable limit. The bone marrow biopsy was stained for histoplasmosis and confirmed disseminated infection (Figure 1(c)). Amphotericin therapy was initiated as the patient began CRRT for worsening kidney failure. Over the next eight days, however, she did not show any clinical improvement and was treated supportively for ICU delirium, respiratory failure, anuria requiring intermittent hemodialysis, worsening coagulopathy and rising ammonia, and malnutrition requiring tube feeds. On day twelve, voriconazole was added for additional antifungal coverage.
Unfortunately, despite these efforts, the patient's blood counts continued to decline, and she developed massive melena on hospital day 13 with a hemoglobin of 4 g/dL (reference range 12.0–15.5 g/dL), WBC 0.1/L (reference range 3.4–10.6 × 10(9)/L), ANC 0.11/L (reference range 1.40–6.60 × 10(9)/L), and platelets 41/L (reference range 149–375 × 10(9)/L). At this point, the patient and her power of attorney elected to withdraw aggressive treatments, and she was transferred to inpatient hospice.
3. Case Report #2
A 41-year-old woman residing in Arizona with a history of ulcerative colitis from who was on Remicade up until one month earlier was admitted three times over a course of a month with a variety of symptoms without identifying etiology. Initially, she had nonspecific fevers, headache, neck pain, fatigue, nausea, vomiting, and arthralgias. She was found to have an edematous gallbladder (Figure 2(a)) and mild splenomegaly, with a negative infectious workup. With symptomatic care, her fevers were controlled, and she was discharged with a diagnosis of presumed viral syndrome versus Remicade toxicity. However, symptoms worsened, and she represented with fever, sepsis, cholestatic jaundice, acute kidney injury, pancytopenia, and multiple metabolic abnormalities requiring admission to the intensive care unit. Initially, she underwent ERCP with sphincterotomy, and common bile duct stent was placed. On endoscopy, the duodenal mucosa was noted to be friable, biopsy revealed reactive gastropathy, and H. pylori testing was negative. She then underwent laparoscopic cholecystectomy for acalculous cholecystitis. Postoperatively, she developed bloody secretions from the endotracheal tube followed by ARDS; thus, she was unable to be extubated. She also had episodes of epistaxis and melena through this time. Her clinical status quickly deteriorated to multiorgan failure including renal failure requiring dialysis, cholestatic liver failure, respiratory failure requiring mechanical ventilation, and critical pancytopenia requiring high-volume transfusions including 17 units of packed red blood cells, 17 units of platelets, and 6 units of cryoprecipitate.
Workup through this point revealed a markedly elevated ferritin of 73,469 mcg/L (reference range 11–307 mcg/L), elevated lactate dehydrogenase of 2,375 U/L (reference range 122–222 U/L), hypofibrinogenemia of 135 mg/dL (reference range 200-430 mg/dL), and hypertriglyceridemia 2,259 mg/dL (reference range < 150 mg/dL), raising suspicion for HLH. Bone marrow biopsy confirmed the diagnosis (Figures 2(b)–2(d)), and she was initiated on high-dose steroids and etoposide. She developed a severe diffuse rash to etoposide necessitating its discontinuation. Investigation for an underlying trigger included bronchoalveolar lavage (BAL) culture which returned positive for Histoplasma capsulatum, in addition to positive histoplasma urinary antigen. During the same hospitalization, she additionally underwent cholecystectomy, and cultured gallbladder tissue ultimately grew H. capsulatum. Based on history, this was likely acquired in the setting of prior Remicade use while exploring bat caves in Cancun, Mexico, two weeks prior to admission. The patient was born and lived in Arizona until her presentation and denied travel to any endemic areas. Her Aspergillus antigen was also positive from BAL, but this was felt to be a false positive as Aspergillus antigen testing cross-reacts with Histoplasma.
For treatment of disseminated histoplasmosis, she received intravenous AmBisome starting on day 4 of hospitalization and later transitioned to oral itraconazole. With these treatments, she recovered well and was eventually transferred out of the intensive care unit on day 18. She required one dose of Neupogen for leukopenia, but her white blood cell count recovered thereafter, and platelet count returned to normal. Her ferritin had dramatically decreased to 1,568 mcg/L (reference range 11–307 mcg/L). Her kidney and liver function recovered to the point where she could be safely discharged to acute rehabilitation after an approximately four weeks stay in the hospital. She continued to improve during a two-week rehabilitation stay and was then discharged home with an oral steroid taper and oral itraconazole for one year following diagnosis.
4. Discussion
The diagnosis and treatment of acquired HLH in adults are serious and challenging, as the clinical presentation can be fairly nonspecific and diagnosis is based on a collection of both clinical and laboratory abnormalities. In pediatric patients with familial HLH, an elevated ferritin greater than 10,000 μg/L is highly sensitive and specific for diagnosis [19]. In adults, however, elevated ferritin has been linked to various conditions including malignancy, liver dysfunction, infection, anemia of chronic disease, or iron overload [20]. Markedly elevated ferritin, however, is thought to be more specific for adult onset stills disease, macrophage activation syndrome, and HLH. In a retrospective study [20] of patients with ferritin levels greater than 50,000 μg/L, 19% were found to have HLH. The most frequently seen diagnosis in these patients was renal failure (73%), liver injury (61%), infections (52%), and hematologic malignancies (36%). No ferritin cut off level was found to be specific for HLH in this study. Currently, ferritin > 500 μg/L is included in the diagnostic criteria for HLH, although many prefer to use >3000 μg/L. Given the lack of specific criteria for diagnosis of adult acquired HLH, a scoring system which includes the above mentioned diagnostic criteria for HLH was developed and has been shown to be 90% sensitive and 79% specific, although specificity decreases as patients become less stable [21]. Once the diagnosis is confirmed, treatment must be initiated immediately. Additionally, a search must be undertaken to find an underlying trigger for HLH; as without treating the source, there is little chance for clinical improvement.
Here, we present two cases of HLH secondary to disseminated histoplasmosis. Previously, published cases of histoplasmosis associated HLH were reported in HIV [22], hematologic malignancy [16], and transplant patients on immunosuppression [18, 22]. Disseminated histoplasmosis by itself is also quite serious but generally treatable with antifungal therapy. Current IDSA guidelines for moderate to severe disease include liposomal amphotericin B (3.0 mg/kg daily) for 1-2 weeks, followed with oral itraconazole for at least 12 months [9]. Patients who have both disseminated histoplasmosis and HLH portend a worse prognosis. In a retrospective review of eleven cases of histoplasmosis associated HLH, 45% died within 30 days, and 63% died within 90 days [22]. The main challenge of caring for patients with histoplasmosis associated HLH is management of the multiorgan failure that can result from this combination of diseases. Both HLH and histoplasmosis can cause hematologic abnormalities, namely, pancytopenia, and both patients presented here required large volume transfusions. In addition, both patients developed respiratory failure from ARDS, renal failure requiring renal replacement therapy, liver failure, and gastrointestinal bleeding. Disseminated histoplasmosis involving the gastrointestinal system can cause cholecystitis and appendicitis leading to surgery, as well as melena and gastritis, which were seen in these cases.
The main risk factors for disseminated histoplasmosis leading to HLH in these cases were immunosuppressive medication (methotrexate and infliximab) and environmental exposure (bird or bat droppings, especially in caves). Interestingly, in both cases, the offending medication had been discontinued due to laboratory abnormalities 1-2 months prior to any presenting symptoms. It is unclear whether this may have been a risk factor for disease. Nevertheless, with a presentation of diffuse infectious symptoms without an identified etiology in the context of recent immunosuppressive medication, an exhaustive history and laboratory inquiry should be pursued to avoid delayed diagnosis for serious conditions such as disseminated fungal infection and HLH.
Data Availability
No datasets were used.
Conflicts of Interest
No authors have conflict of interest to disclose.
Authors' Contributions
All authors included have made substantial contributions to conception, design, data acquisition, drafting, and/or revising of the manuscript. All authors have read and approved the submission of this manuscript.
Figure 1 (a) Bone marrow aspirate reveals evidence of hemophagocytosis. (b) Chest X-ray reveals evidence of bilateral infiltrates, and patient then diagnosed with ARDS. (c) Bone marrow core biopsy GMS stain reveals histoplasmosis.
Figure 2 (a) CT abdomen on admission reveals edematous gallbladder which was later found to have evidence of Histoplasma capsulatum. (b, c) Bone marrow aspirate reveals hemophagocytosis. (d) GMS stain of bone marrow core biopsy positive for histoplasmosis. | AMPHOTERICIN B, ETOPOSIDE, GABAPENTIN, METHOTREXATE, MOXIFLOXACIN, OMEPRAZOLE, PREDNISONE, SPIRONOLACTONE, VORICONAZOLE | DrugsGivenReaction | CC BY | 33552603 | 19,036,089 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemoglobin decreased'. | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis in Rheumatologic Disease.
Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections.
Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.
1. Background
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune overactivation that can lead to tissue destruction and organ failure. As a primary disorder, it is typically seen in pediatrics and has several associated genetic mutations [1]. In adults, it presents as a secondary phenomenon, seen in conjunction with infection, malignancy, immunodeficiency, or another immune dysregulating event. The diagnosis is established by meeting five of eight criteria, including fever greater than 38.5 degrees Celsius; splenomegaly; peripheral cytopenia (at least two of hemoglobin < 9 g/dL, platelets < 100, 000/microL, absolute neutrophil count < 1000/microL); hypertriglyceridemia (fasting > 265 mg/dL) or hypofibrinogenemia (<150 mg/dL); hemophagocytosis in the bone marrow, spleen, lymph node, or liver; decreased natural killer cell activity; ferritin > 500 ng/mL; and elevated soluble CD25 (IL-2 receptor α) two standard deviations above age-adjusted norms [2, 3]. Laboratory evaluation of soluble CD25 and natural killer cell activity require specialized testing and therefore do not result in real time. Without treatment, prognosis is limited to a few months, and the greatest barrier to survival is delay in diagnosis. Treatment entails identification and treatment of the underlying trigger. With proper treatment and identification of triggering event, survival increases to 54% at 6.2 years [4, 5]. Prognosis is worse with higher ferritin levels, underlying malignancy, older age, and low serum albumin levels [6, 7].
Although rheumatologic disease by itself can be a trigger for HLH, this is rare. Among adults on biological therapies for rheumatologic disease, infection is the most common trigger [8]. Histoplasmosis is a serious fungal infection that is endemic to the Ohio and Mississippi River valleys in the United States, as well as parts of Central and South America. The infective agent, Histoplasma capsulatum, is most likely to be found in soil containing bird or bat droppings. Inhalation of the spores allows them to transform into yeast and travel throughout the lymphatic and vascular system. Pulmonary histoplasmosis can cause pneumonia, mediastinal or hilar masses, pulmonary nodules, cavitary lung disease, and pericarditis. Risk factors for disseminated histoplasmosis include AIDS, immunodeficiency, immunosuppressive medications, and extremes of age. Untreated diffuse histoplasmosis is fatal within weeks, but proper antifungal treatment with amphotericin B or itraconazole increases survival rates dramatically [9].
Cases of HLH secondary to disseminated histoplasmosis are rare and extremely serious. Several case reports in the literature describe patients with AIDS [10–15], malignancy [16], or immunosuppression due to medications [17, 18]. Below we present two cases of patients with HLH secondary to disseminated histoplasmosis, both in the setting of recent immunosuppressive medication for underlying autoimmune disease.
2. Case Report #1
A 66-year-old woman presented to an emergency department near her home in Mexico with fever and abdominal pain of two weeks duration. She also described two months of increased fatigue and malaise, as well as increased swelling around her feet and ankles that had more recently developed. Although she was born in the United States in Oregon, she had been living in Mexico for several years. She denied travel to any other regions. A CT scan demonstrated appendicitis, and she was admitted to a hospital in Mexico for appendectomy. However, over the subsequent five days, she continued to have worsening fevers and abdominal pain. At this point, she flew to Mayo Clinic Arizona for further evaluation.
Her past medical history was significant for rheumatoid arthritis and chronic low back pain. Medications included gabapentin, daily prednisone (20 mg/day), spironolactone, and omeprazole. Following her appendix surgery, she had been placed on moxifloxacin for five days. She had been on methotrexate for several years, but this was discontinued a few months prior due to elevation of liver enzymes.
At the time of presentation, she appeared ill, and her vitals included fluid responsive hypotension, tachypnea with respiratory rate of 22, and mild hypoxia with oxygen saturation 88-95% on room air. Physical exam was significant for bibasilar crackles, abdominal distension, and diffuse tenderness to palpation without peritoneal signs, diffusely tender joints, and erythema over the left elbow and the right knee that was warm to touch. Initial laboratory evaluation demonstrated a hemoglobin of 12.5 g/dL (reference range 12.0–15.5 g/dL), platelet count of 8 × 10(9)/L (reference range 149–375 × 10(9)/L), and white blood cell count (WBC) 2.7 × 10(9)/L (reference range 3.4–10.6 × 10(9)/L) with neutrophilic predominance (absolute neutrophil count (ANC), 2.05 × 10(9)/L (reference range 1.40–6.60 × 10(9)/L)). Electrolyte panel showed hyponatremia 131 mmol/L (reference range 135–145 mmol/L) but was otherwise normal, including creatinine 0.9 mg/dL (reference range 0.6–1.1 mg/dL). LFTs were elevated with alkaline phosphatase 318 U/L (reference range 55–142 U/L), alanine aminotransferase (ALT) 145 U/L (reference range 7–45 U/L), and aspartate aminotransferase (AST) 252 U/L (reference range 9–43 U/L). Most notably, her ferritin was drastically elevated at 27,300 mcg/L (reference range 11–307 mcg/L). Additionally, triglycerides were elevated at 272 mg/dL (reference range < 150 mg/dL), and fibrinogen was reduced at 120 mg/dL (reference range 200–430 mg/dL). Chest X-ray showed trace bilateral pleural effusions and small calcified granulomata in the upper lungs bilaterally. Given her diffusely tender joints, X-ray of the hands were performed and revealed numerous subchondral cysts and erosion, as well as subluxation of the right index finger distal phalanx, with sparing of the metacarpophalangeal joints consistent with rheumatoid arthritis. Due to tachypnea, leukopenia, and hemodynamic instability, she was diagnosed with sepsis.
She initially received broad spectrum antibiotics and underwent paracentesis which was negative for peritonitis. Bacterial and fungal cultures of the ascitic fluid showed no growth. Her significantly elevated ferritin prompted a bone marrow biopsy (BMB), which showed features of hemophagocytic lymphohistiocytosis (Figure 1(a)). Given her findings of pancytopenia, elevated ferritin and triglycerides, reduced fibrinogen, and evidence of hemophagocytosis on BMB, she was treated with high-dose steroids and intravenous fluids. After initiation of steroids, her thrombocytopenia and joint pain improved. However, her WBC count continued to drop, and the patient continued to spike fevers; thus, antibiotics were adjusted to cover for neutropenic fever. Without an identified infectious source, a CT of the brain, chest, abdomen, and pelvis was performed which showed bilateral pulmonary infiltrates but was otherwise unremarkable. Liver biopsy was considered but was deemed unsafe due to coagulopathy. Her respiratory status declined eventually requiring high-flow oxygen due to acute respiratory distress syndrome (ARDS) (Figure 1(b)), and she was treated with aggressive diuresis. Initially, she had adequate response but ultimately developed oliguria and renal failure.
On hospital day four, the ferritin had improved to 609 mcg/L (reference range 11–307 mcg/L); however, LFTs continued to rise, and resultant coagulopathy required daily cryoprecipitate transfusion to maintain safe fibrinogen levels. Due to worsening clinical status with multiorgan failure including the liver, kidney, respiratory, and bone marrow, it was decided to add etoposide for more aggressive treatment of HLH. Despite these efforts, her ferritin rapidly climbed to over 80,000 mcg/L (reference range 11–307 mcg/L). Infectious workup to date was negative including blood bacterial and fungal cultures, ascites bacterial and fungal cultures, and blood tests for HIV, HHV-6, EBV DNA, hepatitis A and E IgM, parvovirus B19, adenovirus, and tuberculosis quantiferon.
Infectious etiology was identified when her urine histoplasmosis antigen returned positive above the upper detectable limit. The bone marrow biopsy was stained for histoplasmosis and confirmed disseminated infection (Figure 1(c)). Amphotericin therapy was initiated as the patient began CRRT for worsening kidney failure. Over the next eight days, however, she did not show any clinical improvement and was treated supportively for ICU delirium, respiratory failure, anuria requiring intermittent hemodialysis, worsening coagulopathy and rising ammonia, and malnutrition requiring tube feeds. On day twelve, voriconazole was added for additional antifungal coverage.
Unfortunately, despite these efforts, the patient's blood counts continued to decline, and she developed massive melena on hospital day 13 with a hemoglobin of 4 g/dL (reference range 12.0–15.5 g/dL), WBC 0.1/L (reference range 3.4–10.6 × 10(9)/L), ANC 0.11/L (reference range 1.40–6.60 × 10(9)/L), and platelets 41/L (reference range 149–375 × 10(9)/L). At this point, the patient and her power of attorney elected to withdraw aggressive treatments, and she was transferred to inpatient hospice.
3. Case Report #2
A 41-year-old woman residing in Arizona with a history of ulcerative colitis from who was on Remicade up until one month earlier was admitted three times over a course of a month with a variety of symptoms without identifying etiology. Initially, she had nonspecific fevers, headache, neck pain, fatigue, nausea, vomiting, and arthralgias. She was found to have an edematous gallbladder (Figure 2(a)) and mild splenomegaly, with a negative infectious workup. With symptomatic care, her fevers were controlled, and she was discharged with a diagnosis of presumed viral syndrome versus Remicade toxicity. However, symptoms worsened, and she represented with fever, sepsis, cholestatic jaundice, acute kidney injury, pancytopenia, and multiple metabolic abnormalities requiring admission to the intensive care unit. Initially, she underwent ERCP with sphincterotomy, and common bile duct stent was placed. On endoscopy, the duodenal mucosa was noted to be friable, biopsy revealed reactive gastropathy, and H. pylori testing was negative. She then underwent laparoscopic cholecystectomy for acalculous cholecystitis. Postoperatively, she developed bloody secretions from the endotracheal tube followed by ARDS; thus, she was unable to be extubated. She also had episodes of epistaxis and melena through this time. Her clinical status quickly deteriorated to multiorgan failure including renal failure requiring dialysis, cholestatic liver failure, respiratory failure requiring mechanical ventilation, and critical pancytopenia requiring high-volume transfusions including 17 units of packed red blood cells, 17 units of platelets, and 6 units of cryoprecipitate.
Workup through this point revealed a markedly elevated ferritin of 73,469 mcg/L (reference range 11–307 mcg/L), elevated lactate dehydrogenase of 2,375 U/L (reference range 122–222 U/L), hypofibrinogenemia of 135 mg/dL (reference range 200-430 mg/dL), and hypertriglyceridemia 2,259 mg/dL (reference range < 150 mg/dL), raising suspicion for HLH. Bone marrow biopsy confirmed the diagnosis (Figures 2(b)–2(d)), and she was initiated on high-dose steroids and etoposide. She developed a severe diffuse rash to etoposide necessitating its discontinuation. Investigation for an underlying trigger included bronchoalveolar lavage (BAL) culture which returned positive for Histoplasma capsulatum, in addition to positive histoplasma urinary antigen. During the same hospitalization, she additionally underwent cholecystectomy, and cultured gallbladder tissue ultimately grew H. capsulatum. Based on history, this was likely acquired in the setting of prior Remicade use while exploring bat caves in Cancun, Mexico, two weeks prior to admission. The patient was born and lived in Arizona until her presentation and denied travel to any endemic areas. Her Aspergillus antigen was also positive from BAL, but this was felt to be a false positive as Aspergillus antigen testing cross-reacts with Histoplasma.
For treatment of disseminated histoplasmosis, she received intravenous AmBisome starting on day 4 of hospitalization and later transitioned to oral itraconazole. With these treatments, she recovered well and was eventually transferred out of the intensive care unit on day 18. She required one dose of Neupogen for leukopenia, but her white blood cell count recovered thereafter, and platelet count returned to normal. Her ferritin had dramatically decreased to 1,568 mcg/L (reference range 11–307 mcg/L). Her kidney and liver function recovered to the point where she could be safely discharged to acute rehabilitation after an approximately four weeks stay in the hospital. She continued to improve during a two-week rehabilitation stay and was then discharged home with an oral steroid taper and oral itraconazole for one year following diagnosis.
4. Discussion
The diagnosis and treatment of acquired HLH in adults are serious and challenging, as the clinical presentation can be fairly nonspecific and diagnosis is based on a collection of both clinical and laboratory abnormalities. In pediatric patients with familial HLH, an elevated ferritin greater than 10,000 μg/L is highly sensitive and specific for diagnosis [19]. In adults, however, elevated ferritin has been linked to various conditions including malignancy, liver dysfunction, infection, anemia of chronic disease, or iron overload [20]. Markedly elevated ferritin, however, is thought to be more specific for adult onset stills disease, macrophage activation syndrome, and HLH. In a retrospective study [20] of patients with ferritin levels greater than 50,000 μg/L, 19% were found to have HLH. The most frequently seen diagnosis in these patients was renal failure (73%), liver injury (61%), infections (52%), and hematologic malignancies (36%). No ferritin cut off level was found to be specific for HLH in this study. Currently, ferritin > 500 μg/L is included in the diagnostic criteria for HLH, although many prefer to use >3000 μg/L. Given the lack of specific criteria for diagnosis of adult acquired HLH, a scoring system which includes the above mentioned diagnostic criteria for HLH was developed and has been shown to be 90% sensitive and 79% specific, although specificity decreases as patients become less stable [21]. Once the diagnosis is confirmed, treatment must be initiated immediately. Additionally, a search must be undertaken to find an underlying trigger for HLH; as without treating the source, there is little chance for clinical improvement.
Here, we present two cases of HLH secondary to disseminated histoplasmosis. Previously, published cases of histoplasmosis associated HLH were reported in HIV [22], hematologic malignancy [16], and transplant patients on immunosuppression [18, 22]. Disseminated histoplasmosis by itself is also quite serious but generally treatable with antifungal therapy. Current IDSA guidelines for moderate to severe disease include liposomal amphotericin B (3.0 mg/kg daily) for 1-2 weeks, followed with oral itraconazole for at least 12 months [9]. Patients who have both disseminated histoplasmosis and HLH portend a worse prognosis. In a retrospective review of eleven cases of histoplasmosis associated HLH, 45% died within 30 days, and 63% died within 90 days [22]. The main challenge of caring for patients with histoplasmosis associated HLH is management of the multiorgan failure that can result from this combination of diseases. Both HLH and histoplasmosis can cause hematologic abnormalities, namely, pancytopenia, and both patients presented here required large volume transfusions. In addition, both patients developed respiratory failure from ARDS, renal failure requiring renal replacement therapy, liver failure, and gastrointestinal bleeding. Disseminated histoplasmosis involving the gastrointestinal system can cause cholecystitis and appendicitis leading to surgery, as well as melena and gastritis, which were seen in these cases.
The main risk factors for disseminated histoplasmosis leading to HLH in these cases were immunosuppressive medication (methotrexate and infliximab) and environmental exposure (bird or bat droppings, especially in caves). Interestingly, in both cases, the offending medication had been discontinued due to laboratory abnormalities 1-2 months prior to any presenting symptoms. It is unclear whether this may have been a risk factor for disease. Nevertheless, with a presentation of diffuse infectious symptoms without an identified etiology in the context of recent immunosuppressive medication, an exhaustive history and laboratory inquiry should be pursued to avoid delayed diagnosis for serious conditions such as disseminated fungal infection and HLH.
Data Availability
No datasets were used.
Conflicts of Interest
No authors have conflict of interest to disclose.
Authors' Contributions
All authors included have made substantial contributions to conception, design, data acquisition, drafting, and/or revising of the manuscript. All authors have read and approved the submission of this manuscript.
Figure 1 (a) Bone marrow aspirate reveals evidence of hemophagocytosis. (b) Chest X-ray reveals evidence of bilateral infiltrates, and patient then diagnosed with ARDS. (c) Bone marrow core biopsy GMS stain reveals histoplasmosis.
Figure 2 (a) CT abdomen on admission reveals edematous gallbladder which was later found to have evidence of Histoplasma capsulatum. (b, c) Bone marrow aspirate reveals hemophagocytosis. (d) GMS stain of bone marrow core biopsy positive for histoplasmosis. | AMPHOTERICIN B, ETOPOSIDE, GABAPENTIN, METHOTREXATE, MOXIFLOXACIN, OMEPRAZOLE, PREDNISONE, SPIRONOLACTONE, VORICONAZOLE | DrugsGivenReaction | CC BY | 33552603 | 19,036,089 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Melaena'. | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis in Rheumatologic Disease.
Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections.
Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.
1. Background
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune overactivation that can lead to tissue destruction and organ failure. As a primary disorder, it is typically seen in pediatrics and has several associated genetic mutations [1]. In adults, it presents as a secondary phenomenon, seen in conjunction with infection, malignancy, immunodeficiency, or another immune dysregulating event. The diagnosis is established by meeting five of eight criteria, including fever greater than 38.5 degrees Celsius; splenomegaly; peripheral cytopenia (at least two of hemoglobin < 9 g/dL, platelets < 100, 000/microL, absolute neutrophil count < 1000/microL); hypertriglyceridemia (fasting > 265 mg/dL) or hypofibrinogenemia (<150 mg/dL); hemophagocytosis in the bone marrow, spleen, lymph node, or liver; decreased natural killer cell activity; ferritin > 500 ng/mL; and elevated soluble CD25 (IL-2 receptor α) two standard deviations above age-adjusted norms [2, 3]. Laboratory evaluation of soluble CD25 and natural killer cell activity require specialized testing and therefore do not result in real time. Without treatment, prognosis is limited to a few months, and the greatest barrier to survival is delay in diagnosis. Treatment entails identification and treatment of the underlying trigger. With proper treatment and identification of triggering event, survival increases to 54% at 6.2 years [4, 5]. Prognosis is worse with higher ferritin levels, underlying malignancy, older age, and low serum albumin levels [6, 7].
Although rheumatologic disease by itself can be a trigger for HLH, this is rare. Among adults on biological therapies for rheumatologic disease, infection is the most common trigger [8]. Histoplasmosis is a serious fungal infection that is endemic to the Ohio and Mississippi River valleys in the United States, as well as parts of Central and South America. The infective agent, Histoplasma capsulatum, is most likely to be found in soil containing bird or bat droppings. Inhalation of the spores allows them to transform into yeast and travel throughout the lymphatic and vascular system. Pulmonary histoplasmosis can cause pneumonia, mediastinal or hilar masses, pulmonary nodules, cavitary lung disease, and pericarditis. Risk factors for disseminated histoplasmosis include AIDS, immunodeficiency, immunosuppressive medications, and extremes of age. Untreated diffuse histoplasmosis is fatal within weeks, but proper antifungal treatment with amphotericin B or itraconazole increases survival rates dramatically [9].
Cases of HLH secondary to disseminated histoplasmosis are rare and extremely serious. Several case reports in the literature describe patients with AIDS [10–15], malignancy [16], or immunosuppression due to medications [17, 18]. Below we present two cases of patients with HLH secondary to disseminated histoplasmosis, both in the setting of recent immunosuppressive medication for underlying autoimmune disease.
2. Case Report #1
A 66-year-old woman presented to an emergency department near her home in Mexico with fever and abdominal pain of two weeks duration. She also described two months of increased fatigue and malaise, as well as increased swelling around her feet and ankles that had more recently developed. Although she was born in the United States in Oregon, she had been living in Mexico for several years. She denied travel to any other regions. A CT scan demonstrated appendicitis, and she was admitted to a hospital in Mexico for appendectomy. However, over the subsequent five days, she continued to have worsening fevers and abdominal pain. At this point, she flew to Mayo Clinic Arizona for further evaluation.
Her past medical history was significant for rheumatoid arthritis and chronic low back pain. Medications included gabapentin, daily prednisone (20 mg/day), spironolactone, and omeprazole. Following her appendix surgery, she had been placed on moxifloxacin for five days. She had been on methotrexate for several years, but this was discontinued a few months prior due to elevation of liver enzymes.
At the time of presentation, she appeared ill, and her vitals included fluid responsive hypotension, tachypnea with respiratory rate of 22, and mild hypoxia with oxygen saturation 88-95% on room air. Physical exam was significant for bibasilar crackles, abdominal distension, and diffuse tenderness to palpation without peritoneal signs, diffusely tender joints, and erythema over the left elbow and the right knee that was warm to touch. Initial laboratory evaluation demonstrated a hemoglobin of 12.5 g/dL (reference range 12.0–15.5 g/dL), platelet count of 8 × 10(9)/L (reference range 149–375 × 10(9)/L), and white blood cell count (WBC) 2.7 × 10(9)/L (reference range 3.4–10.6 × 10(9)/L) with neutrophilic predominance (absolute neutrophil count (ANC), 2.05 × 10(9)/L (reference range 1.40–6.60 × 10(9)/L)). Electrolyte panel showed hyponatremia 131 mmol/L (reference range 135–145 mmol/L) but was otherwise normal, including creatinine 0.9 mg/dL (reference range 0.6–1.1 mg/dL). LFTs were elevated with alkaline phosphatase 318 U/L (reference range 55–142 U/L), alanine aminotransferase (ALT) 145 U/L (reference range 7–45 U/L), and aspartate aminotransferase (AST) 252 U/L (reference range 9–43 U/L). Most notably, her ferritin was drastically elevated at 27,300 mcg/L (reference range 11–307 mcg/L). Additionally, triglycerides were elevated at 272 mg/dL (reference range < 150 mg/dL), and fibrinogen was reduced at 120 mg/dL (reference range 200–430 mg/dL). Chest X-ray showed trace bilateral pleural effusions and small calcified granulomata in the upper lungs bilaterally. Given her diffusely tender joints, X-ray of the hands were performed and revealed numerous subchondral cysts and erosion, as well as subluxation of the right index finger distal phalanx, with sparing of the metacarpophalangeal joints consistent with rheumatoid arthritis. Due to tachypnea, leukopenia, and hemodynamic instability, she was diagnosed with sepsis.
She initially received broad spectrum antibiotics and underwent paracentesis which was negative for peritonitis. Bacterial and fungal cultures of the ascitic fluid showed no growth. Her significantly elevated ferritin prompted a bone marrow biopsy (BMB), which showed features of hemophagocytic lymphohistiocytosis (Figure 1(a)). Given her findings of pancytopenia, elevated ferritin and triglycerides, reduced fibrinogen, and evidence of hemophagocytosis on BMB, she was treated with high-dose steroids and intravenous fluids. After initiation of steroids, her thrombocytopenia and joint pain improved. However, her WBC count continued to drop, and the patient continued to spike fevers; thus, antibiotics were adjusted to cover for neutropenic fever. Without an identified infectious source, a CT of the brain, chest, abdomen, and pelvis was performed which showed bilateral pulmonary infiltrates but was otherwise unremarkable. Liver biopsy was considered but was deemed unsafe due to coagulopathy. Her respiratory status declined eventually requiring high-flow oxygen due to acute respiratory distress syndrome (ARDS) (Figure 1(b)), and she was treated with aggressive diuresis. Initially, she had adequate response but ultimately developed oliguria and renal failure.
On hospital day four, the ferritin had improved to 609 mcg/L (reference range 11–307 mcg/L); however, LFTs continued to rise, and resultant coagulopathy required daily cryoprecipitate transfusion to maintain safe fibrinogen levels. Due to worsening clinical status with multiorgan failure including the liver, kidney, respiratory, and bone marrow, it was decided to add etoposide for more aggressive treatment of HLH. Despite these efforts, her ferritin rapidly climbed to over 80,000 mcg/L (reference range 11–307 mcg/L). Infectious workup to date was negative including blood bacterial and fungal cultures, ascites bacterial and fungal cultures, and blood tests for HIV, HHV-6, EBV DNA, hepatitis A and E IgM, parvovirus B19, adenovirus, and tuberculosis quantiferon.
Infectious etiology was identified when her urine histoplasmosis antigen returned positive above the upper detectable limit. The bone marrow biopsy was stained for histoplasmosis and confirmed disseminated infection (Figure 1(c)). Amphotericin therapy was initiated as the patient began CRRT for worsening kidney failure. Over the next eight days, however, she did not show any clinical improvement and was treated supportively for ICU delirium, respiratory failure, anuria requiring intermittent hemodialysis, worsening coagulopathy and rising ammonia, and malnutrition requiring tube feeds. On day twelve, voriconazole was added for additional antifungal coverage.
Unfortunately, despite these efforts, the patient's blood counts continued to decline, and she developed massive melena on hospital day 13 with a hemoglobin of 4 g/dL (reference range 12.0–15.5 g/dL), WBC 0.1/L (reference range 3.4–10.6 × 10(9)/L), ANC 0.11/L (reference range 1.40–6.60 × 10(9)/L), and platelets 41/L (reference range 149–375 × 10(9)/L). At this point, the patient and her power of attorney elected to withdraw aggressive treatments, and she was transferred to inpatient hospice.
3. Case Report #2
A 41-year-old woman residing in Arizona with a history of ulcerative colitis from who was on Remicade up until one month earlier was admitted three times over a course of a month with a variety of symptoms without identifying etiology. Initially, she had nonspecific fevers, headache, neck pain, fatigue, nausea, vomiting, and arthralgias. She was found to have an edematous gallbladder (Figure 2(a)) and mild splenomegaly, with a negative infectious workup. With symptomatic care, her fevers were controlled, and she was discharged with a diagnosis of presumed viral syndrome versus Remicade toxicity. However, symptoms worsened, and she represented with fever, sepsis, cholestatic jaundice, acute kidney injury, pancytopenia, and multiple metabolic abnormalities requiring admission to the intensive care unit. Initially, she underwent ERCP with sphincterotomy, and common bile duct stent was placed. On endoscopy, the duodenal mucosa was noted to be friable, biopsy revealed reactive gastropathy, and H. pylori testing was negative. She then underwent laparoscopic cholecystectomy for acalculous cholecystitis. Postoperatively, she developed bloody secretions from the endotracheal tube followed by ARDS; thus, she was unable to be extubated. She also had episodes of epistaxis and melena through this time. Her clinical status quickly deteriorated to multiorgan failure including renal failure requiring dialysis, cholestatic liver failure, respiratory failure requiring mechanical ventilation, and critical pancytopenia requiring high-volume transfusions including 17 units of packed red blood cells, 17 units of platelets, and 6 units of cryoprecipitate.
Workup through this point revealed a markedly elevated ferritin of 73,469 mcg/L (reference range 11–307 mcg/L), elevated lactate dehydrogenase of 2,375 U/L (reference range 122–222 U/L), hypofibrinogenemia of 135 mg/dL (reference range 200-430 mg/dL), and hypertriglyceridemia 2,259 mg/dL (reference range < 150 mg/dL), raising suspicion for HLH. Bone marrow biopsy confirmed the diagnosis (Figures 2(b)–2(d)), and she was initiated on high-dose steroids and etoposide. She developed a severe diffuse rash to etoposide necessitating its discontinuation. Investigation for an underlying trigger included bronchoalveolar lavage (BAL) culture which returned positive for Histoplasma capsulatum, in addition to positive histoplasma urinary antigen. During the same hospitalization, she additionally underwent cholecystectomy, and cultured gallbladder tissue ultimately grew H. capsulatum. Based on history, this was likely acquired in the setting of prior Remicade use while exploring bat caves in Cancun, Mexico, two weeks prior to admission. The patient was born and lived in Arizona until her presentation and denied travel to any endemic areas. Her Aspergillus antigen was also positive from BAL, but this was felt to be a false positive as Aspergillus antigen testing cross-reacts with Histoplasma.
For treatment of disseminated histoplasmosis, she received intravenous AmBisome starting on day 4 of hospitalization and later transitioned to oral itraconazole. With these treatments, she recovered well and was eventually transferred out of the intensive care unit on day 18. She required one dose of Neupogen for leukopenia, but her white blood cell count recovered thereafter, and platelet count returned to normal. Her ferritin had dramatically decreased to 1,568 mcg/L (reference range 11–307 mcg/L). Her kidney and liver function recovered to the point where she could be safely discharged to acute rehabilitation after an approximately four weeks stay in the hospital. She continued to improve during a two-week rehabilitation stay and was then discharged home with an oral steroid taper and oral itraconazole for one year following diagnosis.
4. Discussion
The diagnosis and treatment of acquired HLH in adults are serious and challenging, as the clinical presentation can be fairly nonspecific and diagnosis is based on a collection of both clinical and laboratory abnormalities. In pediatric patients with familial HLH, an elevated ferritin greater than 10,000 μg/L is highly sensitive and specific for diagnosis [19]. In adults, however, elevated ferritin has been linked to various conditions including malignancy, liver dysfunction, infection, anemia of chronic disease, or iron overload [20]. Markedly elevated ferritin, however, is thought to be more specific for adult onset stills disease, macrophage activation syndrome, and HLH. In a retrospective study [20] of patients with ferritin levels greater than 50,000 μg/L, 19% were found to have HLH. The most frequently seen diagnosis in these patients was renal failure (73%), liver injury (61%), infections (52%), and hematologic malignancies (36%). No ferritin cut off level was found to be specific for HLH in this study. Currently, ferritin > 500 μg/L is included in the diagnostic criteria for HLH, although many prefer to use >3000 μg/L. Given the lack of specific criteria for diagnosis of adult acquired HLH, a scoring system which includes the above mentioned diagnostic criteria for HLH was developed and has been shown to be 90% sensitive and 79% specific, although specificity decreases as patients become less stable [21]. Once the diagnosis is confirmed, treatment must be initiated immediately. Additionally, a search must be undertaken to find an underlying trigger for HLH; as without treating the source, there is little chance for clinical improvement.
Here, we present two cases of HLH secondary to disseminated histoplasmosis. Previously, published cases of histoplasmosis associated HLH were reported in HIV [22], hematologic malignancy [16], and transplant patients on immunosuppression [18, 22]. Disseminated histoplasmosis by itself is also quite serious but generally treatable with antifungal therapy. Current IDSA guidelines for moderate to severe disease include liposomal amphotericin B (3.0 mg/kg daily) for 1-2 weeks, followed with oral itraconazole for at least 12 months [9]. Patients who have both disseminated histoplasmosis and HLH portend a worse prognosis. In a retrospective review of eleven cases of histoplasmosis associated HLH, 45% died within 30 days, and 63% died within 90 days [22]. The main challenge of caring for patients with histoplasmosis associated HLH is management of the multiorgan failure that can result from this combination of diseases. Both HLH and histoplasmosis can cause hematologic abnormalities, namely, pancytopenia, and both patients presented here required large volume transfusions. In addition, both patients developed respiratory failure from ARDS, renal failure requiring renal replacement therapy, liver failure, and gastrointestinal bleeding. Disseminated histoplasmosis involving the gastrointestinal system can cause cholecystitis and appendicitis leading to surgery, as well as melena and gastritis, which were seen in these cases.
The main risk factors for disseminated histoplasmosis leading to HLH in these cases were immunosuppressive medication (methotrexate and infliximab) and environmental exposure (bird or bat droppings, especially in caves). Interestingly, in both cases, the offending medication had been discontinued due to laboratory abnormalities 1-2 months prior to any presenting symptoms. It is unclear whether this may have been a risk factor for disease. Nevertheless, with a presentation of diffuse infectious symptoms without an identified etiology in the context of recent immunosuppressive medication, an exhaustive history and laboratory inquiry should be pursued to avoid delayed diagnosis for serious conditions such as disseminated fungal infection and HLH.
Data Availability
No datasets were used.
Conflicts of Interest
No authors have conflict of interest to disclose.
Authors' Contributions
All authors included have made substantial contributions to conception, design, data acquisition, drafting, and/or revising of the manuscript. All authors have read and approved the submission of this manuscript.
Figure 1 (a) Bone marrow aspirate reveals evidence of hemophagocytosis. (b) Chest X-ray reveals evidence of bilateral infiltrates, and patient then diagnosed with ARDS. (c) Bone marrow core biopsy GMS stain reveals histoplasmosis.
Figure 2 (a) CT abdomen on admission reveals edematous gallbladder which was later found to have evidence of Histoplasma capsulatum. (b, c) Bone marrow aspirate reveals hemophagocytosis. (d) GMS stain of bone marrow core biopsy positive for histoplasmosis. | AMPHOTERICIN B, ETOPOSIDE, GABAPENTIN, METHOTREXATE, MOXIFLOXACIN, OMEPRAZOLE, PREDNISONE, SPIRONOLACTONE, VORICONAZOLE | DrugsGivenReaction | CC BY | 33552603 | 19,036,089 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rash'. | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis in Rheumatologic Disease.
Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections.
Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.
1. Background
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune overactivation that can lead to tissue destruction and organ failure. As a primary disorder, it is typically seen in pediatrics and has several associated genetic mutations [1]. In adults, it presents as a secondary phenomenon, seen in conjunction with infection, malignancy, immunodeficiency, or another immune dysregulating event. The diagnosis is established by meeting five of eight criteria, including fever greater than 38.5 degrees Celsius; splenomegaly; peripheral cytopenia (at least two of hemoglobin < 9 g/dL, platelets < 100, 000/microL, absolute neutrophil count < 1000/microL); hypertriglyceridemia (fasting > 265 mg/dL) or hypofibrinogenemia (<150 mg/dL); hemophagocytosis in the bone marrow, spleen, lymph node, or liver; decreased natural killer cell activity; ferritin > 500 ng/mL; and elevated soluble CD25 (IL-2 receptor α) two standard deviations above age-adjusted norms [2, 3]. Laboratory evaluation of soluble CD25 and natural killer cell activity require specialized testing and therefore do not result in real time. Without treatment, prognosis is limited to a few months, and the greatest barrier to survival is delay in diagnosis. Treatment entails identification and treatment of the underlying trigger. With proper treatment and identification of triggering event, survival increases to 54% at 6.2 years [4, 5]. Prognosis is worse with higher ferritin levels, underlying malignancy, older age, and low serum albumin levels [6, 7].
Although rheumatologic disease by itself can be a trigger for HLH, this is rare. Among adults on biological therapies for rheumatologic disease, infection is the most common trigger [8]. Histoplasmosis is a serious fungal infection that is endemic to the Ohio and Mississippi River valleys in the United States, as well as parts of Central and South America. The infective agent, Histoplasma capsulatum, is most likely to be found in soil containing bird or bat droppings. Inhalation of the spores allows them to transform into yeast and travel throughout the lymphatic and vascular system. Pulmonary histoplasmosis can cause pneumonia, mediastinal or hilar masses, pulmonary nodules, cavitary lung disease, and pericarditis. Risk factors for disseminated histoplasmosis include AIDS, immunodeficiency, immunosuppressive medications, and extremes of age. Untreated diffuse histoplasmosis is fatal within weeks, but proper antifungal treatment with amphotericin B or itraconazole increases survival rates dramatically [9].
Cases of HLH secondary to disseminated histoplasmosis are rare and extremely serious. Several case reports in the literature describe patients with AIDS [10–15], malignancy [16], or immunosuppression due to medications [17, 18]. Below we present two cases of patients with HLH secondary to disseminated histoplasmosis, both in the setting of recent immunosuppressive medication for underlying autoimmune disease.
2. Case Report #1
A 66-year-old woman presented to an emergency department near her home in Mexico with fever and abdominal pain of two weeks duration. She also described two months of increased fatigue and malaise, as well as increased swelling around her feet and ankles that had more recently developed. Although she was born in the United States in Oregon, she had been living in Mexico for several years. She denied travel to any other regions. A CT scan demonstrated appendicitis, and she was admitted to a hospital in Mexico for appendectomy. However, over the subsequent five days, she continued to have worsening fevers and abdominal pain. At this point, she flew to Mayo Clinic Arizona for further evaluation.
Her past medical history was significant for rheumatoid arthritis and chronic low back pain. Medications included gabapentin, daily prednisone (20 mg/day), spironolactone, and omeprazole. Following her appendix surgery, she had been placed on moxifloxacin for five days. She had been on methotrexate for several years, but this was discontinued a few months prior due to elevation of liver enzymes.
At the time of presentation, she appeared ill, and her vitals included fluid responsive hypotension, tachypnea with respiratory rate of 22, and mild hypoxia with oxygen saturation 88-95% on room air. Physical exam was significant for bibasilar crackles, abdominal distension, and diffuse tenderness to palpation without peritoneal signs, diffusely tender joints, and erythema over the left elbow and the right knee that was warm to touch. Initial laboratory evaluation demonstrated a hemoglobin of 12.5 g/dL (reference range 12.0–15.5 g/dL), platelet count of 8 × 10(9)/L (reference range 149–375 × 10(9)/L), and white blood cell count (WBC) 2.7 × 10(9)/L (reference range 3.4–10.6 × 10(9)/L) with neutrophilic predominance (absolute neutrophil count (ANC), 2.05 × 10(9)/L (reference range 1.40–6.60 × 10(9)/L)). Electrolyte panel showed hyponatremia 131 mmol/L (reference range 135–145 mmol/L) but was otherwise normal, including creatinine 0.9 mg/dL (reference range 0.6–1.1 mg/dL). LFTs were elevated with alkaline phosphatase 318 U/L (reference range 55–142 U/L), alanine aminotransferase (ALT) 145 U/L (reference range 7–45 U/L), and aspartate aminotransferase (AST) 252 U/L (reference range 9–43 U/L). Most notably, her ferritin was drastically elevated at 27,300 mcg/L (reference range 11–307 mcg/L). Additionally, triglycerides were elevated at 272 mg/dL (reference range < 150 mg/dL), and fibrinogen was reduced at 120 mg/dL (reference range 200–430 mg/dL). Chest X-ray showed trace bilateral pleural effusions and small calcified granulomata in the upper lungs bilaterally. Given her diffusely tender joints, X-ray of the hands were performed and revealed numerous subchondral cysts and erosion, as well as subluxation of the right index finger distal phalanx, with sparing of the metacarpophalangeal joints consistent with rheumatoid arthritis. Due to tachypnea, leukopenia, and hemodynamic instability, she was diagnosed with sepsis.
She initially received broad spectrum antibiotics and underwent paracentesis which was negative for peritonitis. Bacterial and fungal cultures of the ascitic fluid showed no growth. Her significantly elevated ferritin prompted a bone marrow biopsy (BMB), which showed features of hemophagocytic lymphohistiocytosis (Figure 1(a)). Given her findings of pancytopenia, elevated ferritin and triglycerides, reduced fibrinogen, and evidence of hemophagocytosis on BMB, she was treated with high-dose steroids and intravenous fluids. After initiation of steroids, her thrombocytopenia and joint pain improved. However, her WBC count continued to drop, and the patient continued to spike fevers; thus, antibiotics were adjusted to cover for neutropenic fever. Without an identified infectious source, a CT of the brain, chest, abdomen, and pelvis was performed which showed bilateral pulmonary infiltrates but was otherwise unremarkable. Liver biopsy was considered but was deemed unsafe due to coagulopathy. Her respiratory status declined eventually requiring high-flow oxygen due to acute respiratory distress syndrome (ARDS) (Figure 1(b)), and she was treated with aggressive diuresis. Initially, she had adequate response but ultimately developed oliguria and renal failure.
On hospital day four, the ferritin had improved to 609 mcg/L (reference range 11–307 mcg/L); however, LFTs continued to rise, and resultant coagulopathy required daily cryoprecipitate transfusion to maintain safe fibrinogen levels. Due to worsening clinical status with multiorgan failure including the liver, kidney, respiratory, and bone marrow, it was decided to add etoposide for more aggressive treatment of HLH. Despite these efforts, her ferritin rapidly climbed to over 80,000 mcg/L (reference range 11–307 mcg/L). Infectious workup to date was negative including blood bacterial and fungal cultures, ascites bacterial and fungal cultures, and blood tests for HIV, HHV-6, EBV DNA, hepatitis A and E IgM, parvovirus B19, adenovirus, and tuberculosis quantiferon.
Infectious etiology was identified when her urine histoplasmosis antigen returned positive above the upper detectable limit. The bone marrow biopsy was stained for histoplasmosis and confirmed disseminated infection (Figure 1(c)). Amphotericin therapy was initiated as the patient began CRRT for worsening kidney failure. Over the next eight days, however, she did not show any clinical improvement and was treated supportively for ICU delirium, respiratory failure, anuria requiring intermittent hemodialysis, worsening coagulopathy and rising ammonia, and malnutrition requiring tube feeds. On day twelve, voriconazole was added for additional antifungal coverage.
Unfortunately, despite these efforts, the patient's blood counts continued to decline, and she developed massive melena on hospital day 13 with a hemoglobin of 4 g/dL (reference range 12.0–15.5 g/dL), WBC 0.1/L (reference range 3.4–10.6 × 10(9)/L), ANC 0.11/L (reference range 1.40–6.60 × 10(9)/L), and platelets 41/L (reference range 149–375 × 10(9)/L). At this point, the patient and her power of attorney elected to withdraw aggressive treatments, and she was transferred to inpatient hospice.
3. Case Report #2
A 41-year-old woman residing in Arizona with a history of ulcerative colitis from who was on Remicade up until one month earlier was admitted three times over a course of a month with a variety of symptoms without identifying etiology. Initially, she had nonspecific fevers, headache, neck pain, fatigue, nausea, vomiting, and arthralgias. She was found to have an edematous gallbladder (Figure 2(a)) and mild splenomegaly, with a negative infectious workup. With symptomatic care, her fevers were controlled, and she was discharged with a diagnosis of presumed viral syndrome versus Remicade toxicity. However, symptoms worsened, and she represented with fever, sepsis, cholestatic jaundice, acute kidney injury, pancytopenia, and multiple metabolic abnormalities requiring admission to the intensive care unit. Initially, she underwent ERCP with sphincterotomy, and common bile duct stent was placed. On endoscopy, the duodenal mucosa was noted to be friable, biopsy revealed reactive gastropathy, and H. pylori testing was negative. She then underwent laparoscopic cholecystectomy for acalculous cholecystitis. Postoperatively, she developed bloody secretions from the endotracheal tube followed by ARDS; thus, she was unable to be extubated. She also had episodes of epistaxis and melena through this time. Her clinical status quickly deteriorated to multiorgan failure including renal failure requiring dialysis, cholestatic liver failure, respiratory failure requiring mechanical ventilation, and critical pancytopenia requiring high-volume transfusions including 17 units of packed red blood cells, 17 units of platelets, and 6 units of cryoprecipitate.
Workup through this point revealed a markedly elevated ferritin of 73,469 mcg/L (reference range 11–307 mcg/L), elevated lactate dehydrogenase of 2,375 U/L (reference range 122–222 U/L), hypofibrinogenemia of 135 mg/dL (reference range 200-430 mg/dL), and hypertriglyceridemia 2,259 mg/dL (reference range < 150 mg/dL), raising suspicion for HLH. Bone marrow biopsy confirmed the diagnosis (Figures 2(b)–2(d)), and she was initiated on high-dose steroids and etoposide. She developed a severe diffuse rash to etoposide necessitating its discontinuation. Investigation for an underlying trigger included bronchoalveolar lavage (BAL) culture which returned positive for Histoplasma capsulatum, in addition to positive histoplasma urinary antigen. During the same hospitalization, she additionally underwent cholecystectomy, and cultured gallbladder tissue ultimately grew H. capsulatum. Based on history, this was likely acquired in the setting of prior Remicade use while exploring bat caves in Cancun, Mexico, two weeks prior to admission. The patient was born and lived in Arizona until her presentation and denied travel to any endemic areas. Her Aspergillus antigen was also positive from BAL, but this was felt to be a false positive as Aspergillus antigen testing cross-reacts with Histoplasma.
For treatment of disseminated histoplasmosis, she received intravenous AmBisome starting on day 4 of hospitalization and later transitioned to oral itraconazole. With these treatments, she recovered well and was eventually transferred out of the intensive care unit on day 18. She required one dose of Neupogen for leukopenia, but her white blood cell count recovered thereafter, and platelet count returned to normal. Her ferritin had dramatically decreased to 1,568 mcg/L (reference range 11–307 mcg/L). Her kidney and liver function recovered to the point where she could be safely discharged to acute rehabilitation after an approximately four weeks stay in the hospital. She continued to improve during a two-week rehabilitation stay and was then discharged home with an oral steroid taper and oral itraconazole for one year following diagnosis.
4. Discussion
The diagnosis and treatment of acquired HLH in adults are serious and challenging, as the clinical presentation can be fairly nonspecific and diagnosis is based on a collection of both clinical and laboratory abnormalities. In pediatric patients with familial HLH, an elevated ferritin greater than 10,000 μg/L is highly sensitive and specific for diagnosis [19]. In adults, however, elevated ferritin has been linked to various conditions including malignancy, liver dysfunction, infection, anemia of chronic disease, or iron overload [20]. Markedly elevated ferritin, however, is thought to be more specific for adult onset stills disease, macrophage activation syndrome, and HLH. In a retrospective study [20] of patients with ferritin levels greater than 50,000 μg/L, 19% were found to have HLH. The most frequently seen diagnosis in these patients was renal failure (73%), liver injury (61%), infections (52%), and hematologic malignancies (36%). No ferritin cut off level was found to be specific for HLH in this study. Currently, ferritin > 500 μg/L is included in the diagnostic criteria for HLH, although many prefer to use >3000 μg/L. Given the lack of specific criteria for diagnosis of adult acquired HLH, a scoring system which includes the above mentioned diagnostic criteria for HLH was developed and has been shown to be 90% sensitive and 79% specific, although specificity decreases as patients become less stable [21]. Once the diagnosis is confirmed, treatment must be initiated immediately. Additionally, a search must be undertaken to find an underlying trigger for HLH; as without treating the source, there is little chance for clinical improvement.
Here, we present two cases of HLH secondary to disseminated histoplasmosis. Previously, published cases of histoplasmosis associated HLH were reported in HIV [22], hematologic malignancy [16], and transplant patients on immunosuppression [18, 22]. Disseminated histoplasmosis by itself is also quite serious but generally treatable with antifungal therapy. Current IDSA guidelines for moderate to severe disease include liposomal amphotericin B (3.0 mg/kg daily) for 1-2 weeks, followed with oral itraconazole for at least 12 months [9]. Patients who have both disseminated histoplasmosis and HLH portend a worse prognosis. In a retrospective review of eleven cases of histoplasmosis associated HLH, 45% died within 30 days, and 63% died within 90 days [22]. The main challenge of caring for patients with histoplasmosis associated HLH is management of the multiorgan failure that can result from this combination of diseases. Both HLH and histoplasmosis can cause hematologic abnormalities, namely, pancytopenia, and both patients presented here required large volume transfusions. In addition, both patients developed respiratory failure from ARDS, renal failure requiring renal replacement therapy, liver failure, and gastrointestinal bleeding. Disseminated histoplasmosis involving the gastrointestinal system can cause cholecystitis and appendicitis leading to surgery, as well as melena and gastritis, which were seen in these cases.
The main risk factors for disseminated histoplasmosis leading to HLH in these cases were immunosuppressive medication (methotrexate and infliximab) and environmental exposure (bird or bat droppings, especially in caves). Interestingly, in both cases, the offending medication had been discontinued due to laboratory abnormalities 1-2 months prior to any presenting symptoms. It is unclear whether this may have been a risk factor for disease. Nevertheless, with a presentation of diffuse infectious symptoms without an identified etiology in the context of recent immunosuppressive medication, an exhaustive history and laboratory inquiry should be pursued to avoid delayed diagnosis for serious conditions such as disseminated fungal infection and HLH.
Data Availability
No datasets were used.
Conflicts of Interest
No authors have conflict of interest to disclose.
Authors' Contributions
All authors included have made substantial contributions to conception, design, data acquisition, drafting, and/or revising of the manuscript. All authors have read and approved the submission of this manuscript.
Figure 1 (a) Bone marrow aspirate reveals evidence of hemophagocytosis. (b) Chest X-ray reveals evidence of bilateral infiltrates, and patient then diagnosed with ARDS. (c) Bone marrow core biopsy GMS stain reveals histoplasmosis.
Figure 2 (a) CT abdomen on admission reveals edematous gallbladder which was later found to have evidence of Histoplasma capsulatum. (b, c) Bone marrow aspirate reveals hemophagocytosis. (d) GMS stain of bone marrow core biopsy positive for histoplasmosis. | ETOPOSIDE | DrugsGivenReaction | CC BY | 33552603 | 18,986,284 | 2021 |
What was the administration route of drug 'INFLIXIMAB'? | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis in Rheumatologic Disease.
Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections.
Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.
1. Background
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune overactivation that can lead to tissue destruction and organ failure. As a primary disorder, it is typically seen in pediatrics and has several associated genetic mutations [1]. In adults, it presents as a secondary phenomenon, seen in conjunction with infection, malignancy, immunodeficiency, or another immune dysregulating event. The diagnosis is established by meeting five of eight criteria, including fever greater than 38.5 degrees Celsius; splenomegaly; peripheral cytopenia (at least two of hemoglobin < 9 g/dL, platelets < 100, 000/microL, absolute neutrophil count < 1000/microL); hypertriglyceridemia (fasting > 265 mg/dL) or hypofibrinogenemia (<150 mg/dL); hemophagocytosis in the bone marrow, spleen, lymph node, or liver; decreased natural killer cell activity; ferritin > 500 ng/mL; and elevated soluble CD25 (IL-2 receptor α) two standard deviations above age-adjusted norms [2, 3]. Laboratory evaluation of soluble CD25 and natural killer cell activity require specialized testing and therefore do not result in real time. Without treatment, prognosis is limited to a few months, and the greatest barrier to survival is delay in diagnosis. Treatment entails identification and treatment of the underlying trigger. With proper treatment and identification of triggering event, survival increases to 54% at 6.2 years [4, 5]. Prognosis is worse with higher ferritin levels, underlying malignancy, older age, and low serum albumin levels [6, 7].
Although rheumatologic disease by itself can be a trigger for HLH, this is rare. Among adults on biological therapies for rheumatologic disease, infection is the most common trigger [8]. Histoplasmosis is a serious fungal infection that is endemic to the Ohio and Mississippi River valleys in the United States, as well as parts of Central and South America. The infective agent, Histoplasma capsulatum, is most likely to be found in soil containing bird or bat droppings. Inhalation of the spores allows them to transform into yeast and travel throughout the lymphatic and vascular system. Pulmonary histoplasmosis can cause pneumonia, mediastinal or hilar masses, pulmonary nodules, cavitary lung disease, and pericarditis. Risk factors for disseminated histoplasmosis include AIDS, immunodeficiency, immunosuppressive medications, and extremes of age. Untreated diffuse histoplasmosis is fatal within weeks, but proper antifungal treatment with amphotericin B or itraconazole increases survival rates dramatically [9].
Cases of HLH secondary to disseminated histoplasmosis are rare and extremely serious. Several case reports in the literature describe patients with AIDS [10–15], malignancy [16], or immunosuppression due to medications [17, 18]. Below we present two cases of patients with HLH secondary to disseminated histoplasmosis, both in the setting of recent immunosuppressive medication for underlying autoimmune disease.
2. Case Report #1
A 66-year-old woman presented to an emergency department near her home in Mexico with fever and abdominal pain of two weeks duration. She also described two months of increased fatigue and malaise, as well as increased swelling around her feet and ankles that had more recently developed. Although she was born in the United States in Oregon, she had been living in Mexico for several years. She denied travel to any other regions. A CT scan demonstrated appendicitis, and she was admitted to a hospital in Mexico for appendectomy. However, over the subsequent five days, she continued to have worsening fevers and abdominal pain. At this point, she flew to Mayo Clinic Arizona for further evaluation.
Her past medical history was significant for rheumatoid arthritis and chronic low back pain. Medications included gabapentin, daily prednisone (20 mg/day), spironolactone, and omeprazole. Following her appendix surgery, she had been placed on moxifloxacin for five days. She had been on methotrexate for several years, but this was discontinued a few months prior due to elevation of liver enzymes.
At the time of presentation, she appeared ill, and her vitals included fluid responsive hypotension, tachypnea with respiratory rate of 22, and mild hypoxia with oxygen saturation 88-95% on room air. Physical exam was significant for bibasilar crackles, abdominal distension, and diffuse tenderness to palpation without peritoneal signs, diffusely tender joints, and erythema over the left elbow and the right knee that was warm to touch. Initial laboratory evaluation demonstrated a hemoglobin of 12.5 g/dL (reference range 12.0–15.5 g/dL), platelet count of 8 × 10(9)/L (reference range 149–375 × 10(9)/L), and white blood cell count (WBC) 2.7 × 10(9)/L (reference range 3.4–10.6 × 10(9)/L) with neutrophilic predominance (absolute neutrophil count (ANC), 2.05 × 10(9)/L (reference range 1.40–6.60 × 10(9)/L)). Electrolyte panel showed hyponatremia 131 mmol/L (reference range 135–145 mmol/L) but was otherwise normal, including creatinine 0.9 mg/dL (reference range 0.6–1.1 mg/dL). LFTs were elevated with alkaline phosphatase 318 U/L (reference range 55–142 U/L), alanine aminotransferase (ALT) 145 U/L (reference range 7–45 U/L), and aspartate aminotransferase (AST) 252 U/L (reference range 9–43 U/L). Most notably, her ferritin was drastically elevated at 27,300 mcg/L (reference range 11–307 mcg/L). Additionally, triglycerides were elevated at 272 mg/dL (reference range < 150 mg/dL), and fibrinogen was reduced at 120 mg/dL (reference range 200–430 mg/dL). Chest X-ray showed trace bilateral pleural effusions and small calcified granulomata in the upper lungs bilaterally. Given her diffusely tender joints, X-ray of the hands were performed and revealed numerous subchondral cysts and erosion, as well as subluxation of the right index finger distal phalanx, with sparing of the metacarpophalangeal joints consistent with rheumatoid arthritis. Due to tachypnea, leukopenia, and hemodynamic instability, she was diagnosed with sepsis.
She initially received broad spectrum antibiotics and underwent paracentesis which was negative for peritonitis. Bacterial and fungal cultures of the ascitic fluid showed no growth. Her significantly elevated ferritin prompted a bone marrow biopsy (BMB), which showed features of hemophagocytic lymphohistiocytosis (Figure 1(a)). Given her findings of pancytopenia, elevated ferritin and triglycerides, reduced fibrinogen, and evidence of hemophagocytosis on BMB, she was treated with high-dose steroids and intravenous fluids. After initiation of steroids, her thrombocytopenia and joint pain improved. However, her WBC count continued to drop, and the patient continued to spike fevers; thus, antibiotics were adjusted to cover for neutropenic fever. Without an identified infectious source, a CT of the brain, chest, abdomen, and pelvis was performed which showed bilateral pulmonary infiltrates but was otherwise unremarkable. Liver biopsy was considered but was deemed unsafe due to coagulopathy. Her respiratory status declined eventually requiring high-flow oxygen due to acute respiratory distress syndrome (ARDS) (Figure 1(b)), and she was treated with aggressive diuresis. Initially, she had adequate response but ultimately developed oliguria and renal failure.
On hospital day four, the ferritin had improved to 609 mcg/L (reference range 11–307 mcg/L); however, LFTs continued to rise, and resultant coagulopathy required daily cryoprecipitate transfusion to maintain safe fibrinogen levels. Due to worsening clinical status with multiorgan failure including the liver, kidney, respiratory, and bone marrow, it was decided to add etoposide for more aggressive treatment of HLH. Despite these efforts, her ferritin rapidly climbed to over 80,000 mcg/L (reference range 11–307 mcg/L). Infectious workup to date was negative including blood bacterial and fungal cultures, ascites bacterial and fungal cultures, and blood tests for HIV, HHV-6, EBV DNA, hepatitis A and E IgM, parvovirus B19, adenovirus, and tuberculosis quantiferon.
Infectious etiology was identified when her urine histoplasmosis antigen returned positive above the upper detectable limit. The bone marrow biopsy was stained for histoplasmosis and confirmed disseminated infection (Figure 1(c)). Amphotericin therapy was initiated as the patient began CRRT for worsening kidney failure. Over the next eight days, however, she did not show any clinical improvement and was treated supportively for ICU delirium, respiratory failure, anuria requiring intermittent hemodialysis, worsening coagulopathy and rising ammonia, and malnutrition requiring tube feeds. On day twelve, voriconazole was added for additional antifungal coverage.
Unfortunately, despite these efforts, the patient's blood counts continued to decline, and she developed massive melena on hospital day 13 with a hemoglobin of 4 g/dL (reference range 12.0–15.5 g/dL), WBC 0.1/L (reference range 3.4–10.6 × 10(9)/L), ANC 0.11/L (reference range 1.40–6.60 × 10(9)/L), and platelets 41/L (reference range 149–375 × 10(9)/L). At this point, the patient and her power of attorney elected to withdraw aggressive treatments, and she was transferred to inpatient hospice.
3. Case Report #2
A 41-year-old woman residing in Arizona with a history of ulcerative colitis from who was on Remicade up until one month earlier was admitted three times over a course of a month with a variety of symptoms without identifying etiology. Initially, she had nonspecific fevers, headache, neck pain, fatigue, nausea, vomiting, and arthralgias. She was found to have an edematous gallbladder (Figure 2(a)) and mild splenomegaly, with a negative infectious workup. With symptomatic care, her fevers were controlled, and she was discharged with a diagnosis of presumed viral syndrome versus Remicade toxicity. However, symptoms worsened, and she represented with fever, sepsis, cholestatic jaundice, acute kidney injury, pancytopenia, and multiple metabolic abnormalities requiring admission to the intensive care unit. Initially, she underwent ERCP with sphincterotomy, and common bile duct stent was placed. On endoscopy, the duodenal mucosa was noted to be friable, biopsy revealed reactive gastropathy, and H. pylori testing was negative. She then underwent laparoscopic cholecystectomy for acalculous cholecystitis. Postoperatively, she developed bloody secretions from the endotracheal tube followed by ARDS; thus, she was unable to be extubated. She also had episodes of epistaxis and melena through this time. Her clinical status quickly deteriorated to multiorgan failure including renal failure requiring dialysis, cholestatic liver failure, respiratory failure requiring mechanical ventilation, and critical pancytopenia requiring high-volume transfusions including 17 units of packed red blood cells, 17 units of platelets, and 6 units of cryoprecipitate.
Workup through this point revealed a markedly elevated ferritin of 73,469 mcg/L (reference range 11–307 mcg/L), elevated lactate dehydrogenase of 2,375 U/L (reference range 122–222 U/L), hypofibrinogenemia of 135 mg/dL (reference range 200-430 mg/dL), and hypertriglyceridemia 2,259 mg/dL (reference range < 150 mg/dL), raising suspicion for HLH. Bone marrow biopsy confirmed the diagnosis (Figures 2(b)–2(d)), and she was initiated on high-dose steroids and etoposide. She developed a severe diffuse rash to etoposide necessitating its discontinuation. Investigation for an underlying trigger included bronchoalveolar lavage (BAL) culture which returned positive for Histoplasma capsulatum, in addition to positive histoplasma urinary antigen. During the same hospitalization, she additionally underwent cholecystectomy, and cultured gallbladder tissue ultimately grew H. capsulatum. Based on history, this was likely acquired in the setting of prior Remicade use while exploring bat caves in Cancun, Mexico, two weeks prior to admission. The patient was born and lived in Arizona until her presentation and denied travel to any endemic areas. Her Aspergillus antigen was also positive from BAL, but this was felt to be a false positive as Aspergillus antigen testing cross-reacts with Histoplasma.
For treatment of disseminated histoplasmosis, she received intravenous AmBisome starting on day 4 of hospitalization and later transitioned to oral itraconazole. With these treatments, she recovered well and was eventually transferred out of the intensive care unit on day 18. She required one dose of Neupogen for leukopenia, but her white blood cell count recovered thereafter, and platelet count returned to normal. Her ferritin had dramatically decreased to 1,568 mcg/L (reference range 11–307 mcg/L). Her kidney and liver function recovered to the point where she could be safely discharged to acute rehabilitation after an approximately four weeks stay in the hospital. She continued to improve during a two-week rehabilitation stay and was then discharged home with an oral steroid taper and oral itraconazole for one year following diagnosis.
4. Discussion
The diagnosis and treatment of acquired HLH in adults are serious and challenging, as the clinical presentation can be fairly nonspecific and diagnosis is based on a collection of both clinical and laboratory abnormalities. In pediatric patients with familial HLH, an elevated ferritin greater than 10,000 μg/L is highly sensitive and specific for diagnosis [19]. In adults, however, elevated ferritin has been linked to various conditions including malignancy, liver dysfunction, infection, anemia of chronic disease, or iron overload [20]. Markedly elevated ferritin, however, is thought to be more specific for adult onset stills disease, macrophage activation syndrome, and HLH. In a retrospective study [20] of patients with ferritin levels greater than 50,000 μg/L, 19% were found to have HLH. The most frequently seen diagnosis in these patients was renal failure (73%), liver injury (61%), infections (52%), and hematologic malignancies (36%). No ferritin cut off level was found to be specific for HLH in this study. Currently, ferritin > 500 μg/L is included in the diagnostic criteria for HLH, although many prefer to use >3000 μg/L. Given the lack of specific criteria for diagnosis of adult acquired HLH, a scoring system which includes the above mentioned diagnostic criteria for HLH was developed and has been shown to be 90% sensitive and 79% specific, although specificity decreases as patients become less stable [21]. Once the diagnosis is confirmed, treatment must be initiated immediately. Additionally, a search must be undertaken to find an underlying trigger for HLH; as without treating the source, there is little chance for clinical improvement.
Here, we present two cases of HLH secondary to disseminated histoplasmosis. Previously, published cases of histoplasmosis associated HLH were reported in HIV [22], hematologic malignancy [16], and transplant patients on immunosuppression [18, 22]. Disseminated histoplasmosis by itself is also quite serious but generally treatable with antifungal therapy. Current IDSA guidelines for moderate to severe disease include liposomal amphotericin B (3.0 mg/kg daily) for 1-2 weeks, followed with oral itraconazole for at least 12 months [9]. Patients who have both disseminated histoplasmosis and HLH portend a worse prognosis. In a retrospective review of eleven cases of histoplasmosis associated HLH, 45% died within 30 days, and 63% died within 90 days [22]. The main challenge of caring for patients with histoplasmosis associated HLH is management of the multiorgan failure that can result from this combination of diseases. Both HLH and histoplasmosis can cause hematologic abnormalities, namely, pancytopenia, and both patients presented here required large volume transfusions. In addition, both patients developed respiratory failure from ARDS, renal failure requiring renal replacement therapy, liver failure, and gastrointestinal bleeding. Disseminated histoplasmosis involving the gastrointestinal system can cause cholecystitis and appendicitis leading to surgery, as well as melena and gastritis, which were seen in these cases.
The main risk factors for disseminated histoplasmosis leading to HLH in these cases were immunosuppressive medication (methotrexate and infliximab) and environmental exposure (bird or bat droppings, especially in caves). Interestingly, in both cases, the offending medication had been discontinued due to laboratory abnormalities 1-2 months prior to any presenting symptoms. It is unclear whether this may have been a risk factor for disease. Nevertheless, with a presentation of diffuse infectious symptoms without an identified etiology in the context of recent immunosuppressive medication, an exhaustive history and laboratory inquiry should be pursued to avoid delayed diagnosis for serious conditions such as disseminated fungal infection and HLH.
Data Availability
No datasets were used.
Conflicts of Interest
No authors have conflict of interest to disclose.
Authors' Contributions
All authors included have made substantial contributions to conception, design, data acquisition, drafting, and/or revising of the manuscript. All authors have read and approved the submission of this manuscript.
Figure 1 (a) Bone marrow aspirate reveals evidence of hemophagocytosis. (b) Chest X-ray reveals evidence of bilateral infiltrates, and patient then diagnosed with ARDS. (c) Bone marrow core biopsy GMS stain reveals histoplasmosis.
Figure 2 (a) CT abdomen on admission reveals edematous gallbladder which was later found to have evidence of Histoplasma capsulatum. (b, c) Bone marrow aspirate reveals hemophagocytosis. (d) GMS stain of bone marrow core biopsy positive for histoplasmosis. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33552603 | 18,974,854 | 2021 |
What was the dosage of drug 'METHOTREXATE SODIUM'? | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis in Rheumatologic Disease.
Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections.
Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.
1. Background
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune overactivation that can lead to tissue destruction and organ failure. As a primary disorder, it is typically seen in pediatrics and has several associated genetic mutations [1]. In adults, it presents as a secondary phenomenon, seen in conjunction with infection, malignancy, immunodeficiency, or another immune dysregulating event. The diagnosis is established by meeting five of eight criteria, including fever greater than 38.5 degrees Celsius; splenomegaly; peripheral cytopenia (at least two of hemoglobin < 9 g/dL, platelets < 100, 000/microL, absolute neutrophil count < 1000/microL); hypertriglyceridemia (fasting > 265 mg/dL) or hypofibrinogenemia (<150 mg/dL); hemophagocytosis in the bone marrow, spleen, lymph node, or liver; decreased natural killer cell activity; ferritin > 500 ng/mL; and elevated soluble CD25 (IL-2 receptor α) two standard deviations above age-adjusted norms [2, 3]. Laboratory evaluation of soluble CD25 and natural killer cell activity require specialized testing and therefore do not result in real time. Without treatment, prognosis is limited to a few months, and the greatest barrier to survival is delay in diagnosis. Treatment entails identification and treatment of the underlying trigger. With proper treatment and identification of triggering event, survival increases to 54% at 6.2 years [4, 5]. Prognosis is worse with higher ferritin levels, underlying malignancy, older age, and low serum albumin levels [6, 7].
Although rheumatologic disease by itself can be a trigger for HLH, this is rare. Among adults on biological therapies for rheumatologic disease, infection is the most common trigger [8]. Histoplasmosis is a serious fungal infection that is endemic to the Ohio and Mississippi River valleys in the United States, as well as parts of Central and South America. The infective agent, Histoplasma capsulatum, is most likely to be found in soil containing bird or bat droppings. Inhalation of the spores allows them to transform into yeast and travel throughout the lymphatic and vascular system. Pulmonary histoplasmosis can cause pneumonia, mediastinal or hilar masses, pulmonary nodules, cavitary lung disease, and pericarditis. Risk factors for disseminated histoplasmosis include AIDS, immunodeficiency, immunosuppressive medications, and extremes of age. Untreated diffuse histoplasmosis is fatal within weeks, but proper antifungal treatment with amphotericin B or itraconazole increases survival rates dramatically [9].
Cases of HLH secondary to disseminated histoplasmosis are rare and extremely serious. Several case reports in the literature describe patients with AIDS [10–15], malignancy [16], or immunosuppression due to medications [17, 18]. Below we present two cases of patients with HLH secondary to disseminated histoplasmosis, both in the setting of recent immunosuppressive medication for underlying autoimmune disease.
2. Case Report #1
A 66-year-old woman presented to an emergency department near her home in Mexico with fever and abdominal pain of two weeks duration. She also described two months of increased fatigue and malaise, as well as increased swelling around her feet and ankles that had more recently developed. Although she was born in the United States in Oregon, she had been living in Mexico for several years. She denied travel to any other regions. A CT scan demonstrated appendicitis, and she was admitted to a hospital in Mexico for appendectomy. However, over the subsequent five days, she continued to have worsening fevers and abdominal pain. At this point, she flew to Mayo Clinic Arizona for further evaluation.
Her past medical history was significant for rheumatoid arthritis and chronic low back pain. Medications included gabapentin, daily prednisone (20 mg/day), spironolactone, and omeprazole. Following her appendix surgery, she had been placed on moxifloxacin for five days. She had been on methotrexate for several years, but this was discontinued a few months prior due to elevation of liver enzymes.
At the time of presentation, she appeared ill, and her vitals included fluid responsive hypotension, tachypnea with respiratory rate of 22, and mild hypoxia with oxygen saturation 88-95% on room air. Physical exam was significant for bibasilar crackles, abdominal distension, and diffuse tenderness to palpation without peritoneal signs, diffusely tender joints, and erythema over the left elbow and the right knee that was warm to touch. Initial laboratory evaluation demonstrated a hemoglobin of 12.5 g/dL (reference range 12.0–15.5 g/dL), platelet count of 8 × 10(9)/L (reference range 149–375 × 10(9)/L), and white blood cell count (WBC) 2.7 × 10(9)/L (reference range 3.4–10.6 × 10(9)/L) with neutrophilic predominance (absolute neutrophil count (ANC), 2.05 × 10(9)/L (reference range 1.40–6.60 × 10(9)/L)). Electrolyte panel showed hyponatremia 131 mmol/L (reference range 135–145 mmol/L) but was otherwise normal, including creatinine 0.9 mg/dL (reference range 0.6–1.1 mg/dL). LFTs were elevated with alkaline phosphatase 318 U/L (reference range 55–142 U/L), alanine aminotransferase (ALT) 145 U/L (reference range 7–45 U/L), and aspartate aminotransferase (AST) 252 U/L (reference range 9–43 U/L). Most notably, her ferritin was drastically elevated at 27,300 mcg/L (reference range 11–307 mcg/L). Additionally, triglycerides were elevated at 272 mg/dL (reference range < 150 mg/dL), and fibrinogen was reduced at 120 mg/dL (reference range 200–430 mg/dL). Chest X-ray showed trace bilateral pleural effusions and small calcified granulomata in the upper lungs bilaterally. Given her diffusely tender joints, X-ray of the hands were performed and revealed numerous subchondral cysts and erosion, as well as subluxation of the right index finger distal phalanx, with sparing of the metacarpophalangeal joints consistent with rheumatoid arthritis. Due to tachypnea, leukopenia, and hemodynamic instability, she was diagnosed with sepsis.
She initially received broad spectrum antibiotics and underwent paracentesis which was negative for peritonitis. Bacterial and fungal cultures of the ascitic fluid showed no growth. Her significantly elevated ferritin prompted a bone marrow biopsy (BMB), which showed features of hemophagocytic lymphohistiocytosis (Figure 1(a)). Given her findings of pancytopenia, elevated ferritin and triglycerides, reduced fibrinogen, and evidence of hemophagocytosis on BMB, she was treated with high-dose steroids and intravenous fluids. After initiation of steroids, her thrombocytopenia and joint pain improved. However, her WBC count continued to drop, and the patient continued to spike fevers; thus, antibiotics were adjusted to cover for neutropenic fever. Without an identified infectious source, a CT of the brain, chest, abdomen, and pelvis was performed which showed bilateral pulmonary infiltrates but was otherwise unremarkable. Liver biopsy was considered but was deemed unsafe due to coagulopathy. Her respiratory status declined eventually requiring high-flow oxygen due to acute respiratory distress syndrome (ARDS) (Figure 1(b)), and she was treated with aggressive diuresis. Initially, she had adequate response but ultimately developed oliguria and renal failure.
On hospital day four, the ferritin had improved to 609 mcg/L (reference range 11–307 mcg/L); however, LFTs continued to rise, and resultant coagulopathy required daily cryoprecipitate transfusion to maintain safe fibrinogen levels. Due to worsening clinical status with multiorgan failure including the liver, kidney, respiratory, and bone marrow, it was decided to add etoposide for more aggressive treatment of HLH. Despite these efforts, her ferritin rapidly climbed to over 80,000 mcg/L (reference range 11–307 mcg/L). Infectious workup to date was negative including blood bacterial and fungal cultures, ascites bacterial and fungal cultures, and blood tests for HIV, HHV-6, EBV DNA, hepatitis A and E IgM, parvovirus B19, adenovirus, and tuberculosis quantiferon.
Infectious etiology was identified when her urine histoplasmosis antigen returned positive above the upper detectable limit. The bone marrow biopsy was stained for histoplasmosis and confirmed disseminated infection (Figure 1(c)). Amphotericin therapy was initiated as the patient began CRRT for worsening kidney failure. Over the next eight days, however, she did not show any clinical improvement and was treated supportively for ICU delirium, respiratory failure, anuria requiring intermittent hemodialysis, worsening coagulopathy and rising ammonia, and malnutrition requiring tube feeds. On day twelve, voriconazole was added for additional antifungal coverage.
Unfortunately, despite these efforts, the patient's blood counts continued to decline, and she developed massive melena on hospital day 13 with a hemoglobin of 4 g/dL (reference range 12.0–15.5 g/dL), WBC 0.1/L (reference range 3.4–10.6 × 10(9)/L), ANC 0.11/L (reference range 1.40–6.60 × 10(9)/L), and platelets 41/L (reference range 149–375 × 10(9)/L). At this point, the patient and her power of attorney elected to withdraw aggressive treatments, and she was transferred to inpatient hospice.
3. Case Report #2
A 41-year-old woman residing in Arizona with a history of ulcerative colitis from who was on Remicade up until one month earlier was admitted three times over a course of a month with a variety of symptoms without identifying etiology. Initially, she had nonspecific fevers, headache, neck pain, fatigue, nausea, vomiting, and arthralgias. She was found to have an edematous gallbladder (Figure 2(a)) and mild splenomegaly, with a negative infectious workup. With symptomatic care, her fevers were controlled, and she was discharged with a diagnosis of presumed viral syndrome versus Remicade toxicity. However, symptoms worsened, and she represented with fever, sepsis, cholestatic jaundice, acute kidney injury, pancytopenia, and multiple metabolic abnormalities requiring admission to the intensive care unit. Initially, she underwent ERCP with sphincterotomy, and common bile duct stent was placed. On endoscopy, the duodenal mucosa was noted to be friable, biopsy revealed reactive gastropathy, and H. pylori testing was negative. She then underwent laparoscopic cholecystectomy for acalculous cholecystitis. Postoperatively, she developed bloody secretions from the endotracheal tube followed by ARDS; thus, she was unable to be extubated. She also had episodes of epistaxis and melena through this time. Her clinical status quickly deteriorated to multiorgan failure including renal failure requiring dialysis, cholestatic liver failure, respiratory failure requiring mechanical ventilation, and critical pancytopenia requiring high-volume transfusions including 17 units of packed red blood cells, 17 units of platelets, and 6 units of cryoprecipitate.
Workup through this point revealed a markedly elevated ferritin of 73,469 mcg/L (reference range 11–307 mcg/L), elevated lactate dehydrogenase of 2,375 U/L (reference range 122–222 U/L), hypofibrinogenemia of 135 mg/dL (reference range 200-430 mg/dL), and hypertriglyceridemia 2,259 mg/dL (reference range < 150 mg/dL), raising suspicion for HLH. Bone marrow biopsy confirmed the diagnosis (Figures 2(b)–2(d)), and she was initiated on high-dose steroids and etoposide. She developed a severe diffuse rash to etoposide necessitating its discontinuation. Investigation for an underlying trigger included bronchoalveolar lavage (BAL) culture which returned positive for Histoplasma capsulatum, in addition to positive histoplasma urinary antigen. During the same hospitalization, she additionally underwent cholecystectomy, and cultured gallbladder tissue ultimately grew H. capsulatum. Based on history, this was likely acquired in the setting of prior Remicade use while exploring bat caves in Cancun, Mexico, two weeks prior to admission. The patient was born and lived in Arizona until her presentation and denied travel to any endemic areas. Her Aspergillus antigen was also positive from BAL, but this was felt to be a false positive as Aspergillus antigen testing cross-reacts with Histoplasma.
For treatment of disseminated histoplasmosis, she received intravenous AmBisome starting on day 4 of hospitalization and later transitioned to oral itraconazole. With these treatments, she recovered well and was eventually transferred out of the intensive care unit on day 18. She required one dose of Neupogen for leukopenia, but her white blood cell count recovered thereafter, and platelet count returned to normal. Her ferritin had dramatically decreased to 1,568 mcg/L (reference range 11–307 mcg/L). Her kidney and liver function recovered to the point where she could be safely discharged to acute rehabilitation after an approximately four weeks stay in the hospital. She continued to improve during a two-week rehabilitation stay and was then discharged home with an oral steroid taper and oral itraconazole for one year following diagnosis.
4. Discussion
The diagnosis and treatment of acquired HLH in adults are serious and challenging, as the clinical presentation can be fairly nonspecific and diagnosis is based on a collection of both clinical and laboratory abnormalities. In pediatric patients with familial HLH, an elevated ferritin greater than 10,000 μg/L is highly sensitive and specific for diagnosis [19]. In adults, however, elevated ferritin has been linked to various conditions including malignancy, liver dysfunction, infection, anemia of chronic disease, or iron overload [20]. Markedly elevated ferritin, however, is thought to be more specific for adult onset stills disease, macrophage activation syndrome, and HLH. In a retrospective study [20] of patients with ferritin levels greater than 50,000 μg/L, 19% were found to have HLH. The most frequently seen diagnosis in these patients was renal failure (73%), liver injury (61%), infections (52%), and hematologic malignancies (36%). No ferritin cut off level was found to be specific for HLH in this study. Currently, ferritin > 500 μg/L is included in the diagnostic criteria for HLH, although many prefer to use >3000 μg/L. Given the lack of specific criteria for diagnosis of adult acquired HLH, a scoring system which includes the above mentioned diagnostic criteria for HLH was developed and has been shown to be 90% sensitive and 79% specific, although specificity decreases as patients become less stable [21]. Once the diagnosis is confirmed, treatment must be initiated immediately. Additionally, a search must be undertaken to find an underlying trigger for HLH; as without treating the source, there is little chance for clinical improvement.
Here, we present two cases of HLH secondary to disseminated histoplasmosis. Previously, published cases of histoplasmosis associated HLH were reported in HIV [22], hematologic malignancy [16], and transplant patients on immunosuppression [18, 22]. Disseminated histoplasmosis by itself is also quite serious but generally treatable with antifungal therapy. Current IDSA guidelines for moderate to severe disease include liposomal amphotericin B (3.0 mg/kg daily) for 1-2 weeks, followed with oral itraconazole for at least 12 months [9]. Patients who have both disseminated histoplasmosis and HLH portend a worse prognosis. In a retrospective review of eleven cases of histoplasmosis associated HLH, 45% died within 30 days, and 63% died within 90 days [22]. The main challenge of caring for patients with histoplasmosis associated HLH is management of the multiorgan failure that can result from this combination of diseases. Both HLH and histoplasmosis can cause hematologic abnormalities, namely, pancytopenia, and both patients presented here required large volume transfusions. In addition, both patients developed respiratory failure from ARDS, renal failure requiring renal replacement therapy, liver failure, and gastrointestinal bleeding. Disseminated histoplasmosis involving the gastrointestinal system can cause cholecystitis and appendicitis leading to surgery, as well as melena and gastritis, which were seen in these cases.
The main risk factors for disseminated histoplasmosis leading to HLH in these cases were immunosuppressive medication (methotrexate and infliximab) and environmental exposure (bird or bat droppings, especially in caves). Interestingly, in both cases, the offending medication had been discontinued due to laboratory abnormalities 1-2 months prior to any presenting symptoms. It is unclear whether this may have been a risk factor for disease. Nevertheless, with a presentation of diffuse infectious symptoms without an identified etiology in the context of recent immunosuppressive medication, an exhaustive history and laboratory inquiry should be pursued to avoid delayed diagnosis for serious conditions such as disseminated fungal infection and HLH.
Data Availability
No datasets were used.
Conflicts of Interest
No authors have conflict of interest to disclose.
Authors' Contributions
All authors included have made substantial contributions to conception, design, data acquisition, drafting, and/or revising of the manuscript. All authors have read and approved the submission of this manuscript.
Figure 1 (a) Bone marrow aspirate reveals evidence of hemophagocytosis. (b) Chest X-ray reveals evidence of bilateral infiltrates, and patient then diagnosed with ARDS. (c) Bone marrow core biopsy GMS stain reveals histoplasmosis.
Figure 2 (a) CT abdomen on admission reveals edematous gallbladder which was later found to have evidence of Histoplasma capsulatum. (b, c) Bone marrow aspirate reveals hemophagocytosis. (d) GMS stain of bone marrow core biopsy positive for histoplasmosis. | FOR SEVERAL YEARS | DrugDosageText | CC BY | 33552603 | 18,967,567 | 2021 |
What was the dosage of drug 'MOXIFLOXACIN'? | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis in Rheumatologic Disease.
Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections.
Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.
1. Background
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune overactivation that can lead to tissue destruction and organ failure. As a primary disorder, it is typically seen in pediatrics and has several associated genetic mutations [1]. In adults, it presents as a secondary phenomenon, seen in conjunction with infection, malignancy, immunodeficiency, or another immune dysregulating event. The diagnosis is established by meeting five of eight criteria, including fever greater than 38.5 degrees Celsius; splenomegaly; peripheral cytopenia (at least two of hemoglobin < 9 g/dL, platelets < 100, 000/microL, absolute neutrophil count < 1000/microL); hypertriglyceridemia (fasting > 265 mg/dL) or hypofibrinogenemia (<150 mg/dL); hemophagocytosis in the bone marrow, spleen, lymph node, or liver; decreased natural killer cell activity; ferritin > 500 ng/mL; and elevated soluble CD25 (IL-2 receptor α) two standard deviations above age-adjusted norms [2, 3]. Laboratory evaluation of soluble CD25 and natural killer cell activity require specialized testing and therefore do not result in real time. Without treatment, prognosis is limited to a few months, and the greatest barrier to survival is delay in diagnosis. Treatment entails identification and treatment of the underlying trigger. With proper treatment and identification of triggering event, survival increases to 54% at 6.2 years [4, 5]. Prognosis is worse with higher ferritin levels, underlying malignancy, older age, and low serum albumin levels [6, 7].
Although rheumatologic disease by itself can be a trigger for HLH, this is rare. Among adults on biological therapies for rheumatologic disease, infection is the most common trigger [8]. Histoplasmosis is a serious fungal infection that is endemic to the Ohio and Mississippi River valleys in the United States, as well as parts of Central and South America. The infective agent, Histoplasma capsulatum, is most likely to be found in soil containing bird or bat droppings. Inhalation of the spores allows them to transform into yeast and travel throughout the lymphatic and vascular system. Pulmonary histoplasmosis can cause pneumonia, mediastinal or hilar masses, pulmonary nodules, cavitary lung disease, and pericarditis. Risk factors for disseminated histoplasmosis include AIDS, immunodeficiency, immunosuppressive medications, and extremes of age. Untreated diffuse histoplasmosis is fatal within weeks, but proper antifungal treatment with amphotericin B or itraconazole increases survival rates dramatically [9].
Cases of HLH secondary to disseminated histoplasmosis are rare and extremely serious. Several case reports in the literature describe patients with AIDS [10–15], malignancy [16], or immunosuppression due to medications [17, 18]. Below we present two cases of patients with HLH secondary to disseminated histoplasmosis, both in the setting of recent immunosuppressive medication for underlying autoimmune disease.
2. Case Report #1
A 66-year-old woman presented to an emergency department near her home in Mexico with fever and abdominal pain of two weeks duration. She also described two months of increased fatigue and malaise, as well as increased swelling around her feet and ankles that had more recently developed. Although she was born in the United States in Oregon, she had been living in Mexico for several years. She denied travel to any other regions. A CT scan demonstrated appendicitis, and she was admitted to a hospital in Mexico for appendectomy. However, over the subsequent five days, she continued to have worsening fevers and abdominal pain. At this point, she flew to Mayo Clinic Arizona for further evaluation.
Her past medical history was significant for rheumatoid arthritis and chronic low back pain. Medications included gabapentin, daily prednisone (20 mg/day), spironolactone, and omeprazole. Following her appendix surgery, she had been placed on moxifloxacin for five days. She had been on methotrexate for several years, but this was discontinued a few months prior due to elevation of liver enzymes.
At the time of presentation, she appeared ill, and her vitals included fluid responsive hypotension, tachypnea with respiratory rate of 22, and mild hypoxia with oxygen saturation 88-95% on room air. Physical exam was significant for bibasilar crackles, abdominal distension, and diffuse tenderness to palpation without peritoneal signs, diffusely tender joints, and erythema over the left elbow and the right knee that was warm to touch. Initial laboratory evaluation demonstrated a hemoglobin of 12.5 g/dL (reference range 12.0–15.5 g/dL), platelet count of 8 × 10(9)/L (reference range 149–375 × 10(9)/L), and white blood cell count (WBC) 2.7 × 10(9)/L (reference range 3.4–10.6 × 10(9)/L) with neutrophilic predominance (absolute neutrophil count (ANC), 2.05 × 10(9)/L (reference range 1.40–6.60 × 10(9)/L)). Electrolyte panel showed hyponatremia 131 mmol/L (reference range 135–145 mmol/L) but was otherwise normal, including creatinine 0.9 mg/dL (reference range 0.6–1.1 mg/dL). LFTs were elevated with alkaline phosphatase 318 U/L (reference range 55–142 U/L), alanine aminotransferase (ALT) 145 U/L (reference range 7–45 U/L), and aspartate aminotransferase (AST) 252 U/L (reference range 9–43 U/L). Most notably, her ferritin was drastically elevated at 27,300 mcg/L (reference range 11–307 mcg/L). Additionally, triglycerides were elevated at 272 mg/dL (reference range < 150 mg/dL), and fibrinogen was reduced at 120 mg/dL (reference range 200–430 mg/dL). Chest X-ray showed trace bilateral pleural effusions and small calcified granulomata in the upper lungs bilaterally. Given her diffusely tender joints, X-ray of the hands were performed and revealed numerous subchondral cysts and erosion, as well as subluxation of the right index finger distal phalanx, with sparing of the metacarpophalangeal joints consistent with rheumatoid arthritis. Due to tachypnea, leukopenia, and hemodynamic instability, she was diagnosed with sepsis.
She initially received broad spectrum antibiotics and underwent paracentesis which was negative for peritonitis. Bacterial and fungal cultures of the ascitic fluid showed no growth. Her significantly elevated ferritin prompted a bone marrow biopsy (BMB), which showed features of hemophagocytic lymphohistiocytosis (Figure 1(a)). Given her findings of pancytopenia, elevated ferritin and triglycerides, reduced fibrinogen, and evidence of hemophagocytosis on BMB, she was treated with high-dose steroids and intravenous fluids. After initiation of steroids, her thrombocytopenia and joint pain improved. However, her WBC count continued to drop, and the patient continued to spike fevers; thus, antibiotics were adjusted to cover for neutropenic fever. Without an identified infectious source, a CT of the brain, chest, abdomen, and pelvis was performed which showed bilateral pulmonary infiltrates but was otherwise unremarkable. Liver biopsy was considered but was deemed unsafe due to coagulopathy. Her respiratory status declined eventually requiring high-flow oxygen due to acute respiratory distress syndrome (ARDS) (Figure 1(b)), and she was treated with aggressive diuresis. Initially, she had adequate response but ultimately developed oliguria and renal failure.
On hospital day four, the ferritin had improved to 609 mcg/L (reference range 11–307 mcg/L); however, LFTs continued to rise, and resultant coagulopathy required daily cryoprecipitate transfusion to maintain safe fibrinogen levels. Due to worsening clinical status with multiorgan failure including the liver, kidney, respiratory, and bone marrow, it was decided to add etoposide for more aggressive treatment of HLH. Despite these efforts, her ferritin rapidly climbed to over 80,000 mcg/L (reference range 11–307 mcg/L). Infectious workup to date was negative including blood bacterial and fungal cultures, ascites bacterial and fungal cultures, and blood tests for HIV, HHV-6, EBV DNA, hepatitis A and E IgM, parvovirus B19, adenovirus, and tuberculosis quantiferon.
Infectious etiology was identified when her urine histoplasmosis antigen returned positive above the upper detectable limit. The bone marrow biopsy was stained for histoplasmosis and confirmed disseminated infection (Figure 1(c)). Amphotericin therapy was initiated as the patient began CRRT for worsening kidney failure. Over the next eight days, however, she did not show any clinical improvement and was treated supportively for ICU delirium, respiratory failure, anuria requiring intermittent hemodialysis, worsening coagulopathy and rising ammonia, and malnutrition requiring tube feeds. On day twelve, voriconazole was added for additional antifungal coverage.
Unfortunately, despite these efforts, the patient's blood counts continued to decline, and she developed massive melena on hospital day 13 with a hemoglobin of 4 g/dL (reference range 12.0–15.5 g/dL), WBC 0.1/L (reference range 3.4–10.6 × 10(9)/L), ANC 0.11/L (reference range 1.40–6.60 × 10(9)/L), and platelets 41/L (reference range 149–375 × 10(9)/L). At this point, the patient and her power of attorney elected to withdraw aggressive treatments, and she was transferred to inpatient hospice.
3. Case Report #2
A 41-year-old woman residing in Arizona with a history of ulcerative colitis from who was on Remicade up until one month earlier was admitted three times over a course of a month with a variety of symptoms without identifying etiology. Initially, she had nonspecific fevers, headache, neck pain, fatigue, nausea, vomiting, and arthralgias. She was found to have an edematous gallbladder (Figure 2(a)) and mild splenomegaly, with a negative infectious workup. With symptomatic care, her fevers were controlled, and she was discharged with a diagnosis of presumed viral syndrome versus Remicade toxicity. However, symptoms worsened, and she represented with fever, sepsis, cholestatic jaundice, acute kidney injury, pancytopenia, and multiple metabolic abnormalities requiring admission to the intensive care unit. Initially, she underwent ERCP with sphincterotomy, and common bile duct stent was placed. On endoscopy, the duodenal mucosa was noted to be friable, biopsy revealed reactive gastropathy, and H. pylori testing was negative. She then underwent laparoscopic cholecystectomy for acalculous cholecystitis. Postoperatively, she developed bloody secretions from the endotracheal tube followed by ARDS; thus, she was unable to be extubated. She also had episodes of epistaxis and melena through this time. Her clinical status quickly deteriorated to multiorgan failure including renal failure requiring dialysis, cholestatic liver failure, respiratory failure requiring mechanical ventilation, and critical pancytopenia requiring high-volume transfusions including 17 units of packed red blood cells, 17 units of platelets, and 6 units of cryoprecipitate.
Workup through this point revealed a markedly elevated ferritin of 73,469 mcg/L (reference range 11–307 mcg/L), elevated lactate dehydrogenase of 2,375 U/L (reference range 122–222 U/L), hypofibrinogenemia of 135 mg/dL (reference range 200-430 mg/dL), and hypertriglyceridemia 2,259 mg/dL (reference range < 150 mg/dL), raising suspicion for HLH. Bone marrow biopsy confirmed the diagnosis (Figures 2(b)–2(d)), and she was initiated on high-dose steroids and etoposide. She developed a severe diffuse rash to etoposide necessitating its discontinuation. Investigation for an underlying trigger included bronchoalveolar lavage (BAL) culture which returned positive for Histoplasma capsulatum, in addition to positive histoplasma urinary antigen. During the same hospitalization, she additionally underwent cholecystectomy, and cultured gallbladder tissue ultimately grew H. capsulatum. Based on history, this was likely acquired in the setting of prior Remicade use while exploring bat caves in Cancun, Mexico, two weeks prior to admission. The patient was born and lived in Arizona until her presentation and denied travel to any endemic areas. Her Aspergillus antigen was also positive from BAL, but this was felt to be a false positive as Aspergillus antigen testing cross-reacts with Histoplasma.
For treatment of disseminated histoplasmosis, she received intravenous AmBisome starting on day 4 of hospitalization and later transitioned to oral itraconazole. With these treatments, she recovered well and was eventually transferred out of the intensive care unit on day 18. She required one dose of Neupogen for leukopenia, but her white blood cell count recovered thereafter, and platelet count returned to normal. Her ferritin had dramatically decreased to 1,568 mcg/L (reference range 11–307 mcg/L). Her kidney and liver function recovered to the point where she could be safely discharged to acute rehabilitation after an approximately four weeks stay in the hospital. She continued to improve during a two-week rehabilitation stay and was then discharged home with an oral steroid taper and oral itraconazole for one year following diagnosis.
4. Discussion
The diagnosis and treatment of acquired HLH in adults are serious and challenging, as the clinical presentation can be fairly nonspecific and diagnosis is based on a collection of both clinical and laboratory abnormalities. In pediatric patients with familial HLH, an elevated ferritin greater than 10,000 μg/L is highly sensitive and specific for diagnosis [19]. In adults, however, elevated ferritin has been linked to various conditions including malignancy, liver dysfunction, infection, anemia of chronic disease, or iron overload [20]. Markedly elevated ferritin, however, is thought to be more specific for adult onset stills disease, macrophage activation syndrome, and HLH. In a retrospective study [20] of patients with ferritin levels greater than 50,000 μg/L, 19% were found to have HLH. The most frequently seen diagnosis in these patients was renal failure (73%), liver injury (61%), infections (52%), and hematologic malignancies (36%). No ferritin cut off level was found to be specific for HLH in this study. Currently, ferritin > 500 μg/L is included in the diagnostic criteria for HLH, although many prefer to use >3000 μg/L. Given the lack of specific criteria for diagnosis of adult acquired HLH, a scoring system which includes the above mentioned diagnostic criteria for HLH was developed and has been shown to be 90% sensitive and 79% specific, although specificity decreases as patients become less stable [21]. Once the diagnosis is confirmed, treatment must be initiated immediately. Additionally, a search must be undertaken to find an underlying trigger for HLH; as without treating the source, there is little chance for clinical improvement.
Here, we present two cases of HLH secondary to disseminated histoplasmosis. Previously, published cases of histoplasmosis associated HLH were reported in HIV [22], hematologic malignancy [16], and transplant patients on immunosuppression [18, 22]. Disseminated histoplasmosis by itself is also quite serious but generally treatable with antifungal therapy. Current IDSA guidelines for moderate to severe disease include liposomal amphotericin B (3.0 mg/kg daily) for 1-2 weeks, followed with oral itraconazole for at least 12 months [9]. Patients who have both disseminated histoplasmosis and HLH portend a worse prognosis. In a retrospective review of eleven cases of histoplasmosis associated HLH, 45% died within 30 days, and 63% died within 90 days [22]. The main challenge of caring for patients with histoplasmosis associated HLH is management of the multiorgan failure that can result from this combination of diseases. Both HLH and histoplasmosis can cause hematologic abnormalities, namely, pancytopenia, and both patients presented here required large volume transfusions. In addition, both patients developed respiratory failure from ARDS, renal failure requiring renal replacement therapy, liver failure, and gastrointestinal bleeding. Disseminated histoplasmosis involving the gastrointestinal system can cause cholecystitis and appendicitis leading to surgery, as well as melena and gastritis, which were seen in these cases.
The main risk factors for disseminated histoplasmosis leading to HLH in these cases were immunosuppressive medication (methotrexate and infliximab) and environmental exposure (bird or bat droppings, especially in caves). Interestingly, in both cases, the offending medication had been discontinued due to laboratory abnormalities 1-2 months prior to any presenting symptoms. It is unclear whether this may have been a risk factor for disease. Nevertheless, with a presentation of diffuse infectious symptoms without an identified etiology in the context of recent immunosuppressive medication, an exhaustive history and laboratory inquiry should be pursued to avoid delayed diagnosis for serious conditions such as disseminated fungal infection and HLH.
Data Availability
No datasets were used.
Conflicts of Interest
No authors have conflict of interest to disclose.
Authors' Contributions
All authors included have made substantial contributions to conception, design, data acquisition, drafting, and/or revising of the manuscript. All authors have read and approved the submission of this manuscript.
Figure 1 (a) Bone marrow aspirate reveals evidence of hemophagocytosis. (b) Chest X-ray reveals evidence of bilateral infiltrates, and patient then diagnosed with ARDS. (c) Bone marrow core biopsy GMS stain reveals histoplasmosis.
Figure 2 (a) CT abdomen on admission reveals edematous gallbladder which was later found to have evidence of Histoplasma capsulatum. (b, c) Bone marrow aspirate reveals hemophagocytosis. (d) GMS stain of bone marrow core biopsy positive for histoplasmosis. | FOR 5 DAYS | DrugDosageText | CC BY | 33552603 | 19,036,089 | 2021 |
What was the outcome of reaction 'Acute respiratory distress syndrome'? | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis in Rheumatologic Disease.
Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections.
Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.
1. Background
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune overactivation that can lead to tissue destruction and organ failure. As a primary disorder, it is typically seen in pediatrics and has several associated genetic mutations [1]. In adults, it presents as a secondary phenomenon, seen in conjunction with infection, malignancy, immunodeficiency, or another immune dysregulating event. The diagnosis is established by meeting five of eight criteria, including fever greater than 38.5 degrees Celsius; splenomegaly; peripheral cytopenia (at least two of hemoglobin < 9 g/dL, platelets < 100, 000/microL, absolute neutrophil count < 1000/microL); hypertriglyceridemia (fasting > 265 mg/dL) or hypofibrinogenemia (<150 mg/dL); hemophagocytosis in the bone marrow, spleen, lymph node, or liver; decreased natural killer cell activity; ferritin > 500 ng/mL; and elevated soluble CD25 (IL-2 receptor α) two standard deviations above age-adjusted norms [2, 3]. Laboratory evaluation of soluble CD25 and natural killer cell activity require specialized testing and therefore do not result in real time. Without treatment, prognosis is limited to a few months, and the greatest barrier to survival is delay in diagnosis. Treatment entails identification and treatment of the underlying trigger. With proper treatment and identification of triggering event, survival increases to 54% at 6.2 years [4, 5]. Prognosis is worse with higher ferritin levels, underlying malignancy, older age, and low serum albumin levels [6, 7].
Although rheumatologic disease by itself can be a trigger for HLH, this is rare. Among adults on biological therapies for rheumatologic disease, infection is the most common trigger [8]. Histoplasmosis is a serious fungal infection that is endemic to the Ohio and Mississippi River valleys in the United States, as well as parts of Central and South America. The infective agent, Histoplasma capsulatum, is most likely to be found in soil containing bird or bat droppings. Inhalation of the spores allows them to transform into yeast and travel throughout the lymphatic and vascular system. Pulmonary histoplasmosis can cause pneumonia, mediastinal or hilar masses, pulmonary nodules, cavitary lung disease, and pericarditis. Risk factors for disseminated histoplasmosis include AIDS, immunodeficiency, immunosuppressive medications, and extremes of age. Untreated diffuse histoplasmosis is fatal within weeks, but proper antifungal treatment with amphotericin B or itraconazole increases survival rates dramatically [9].
Cases of HLH secondary to disseminated histoplasmosis are rare and extremely serious. Several case reports in the literature describe patients with AIDS [10–15], malignancy [16], or immunosuppression due to medications [17, 18]. Below we present two cases of patients with HLH secondary to disseminated histoplasmosis, both in the setting of recent immunosuppressive medication for underlying autoimmune disease.
2. Case Report #1
A 66-year-old woman presented to an emergency department near her home in Mexico with fever and abdominal pain of two weeks duration. She also described two months of increased fatigue and malaise, as well as increased swelling around her feet and ankles that had more recently developed. Although she was born in the United States in Oregon, she had been living in Mexico for several years. She denied travel to any other regions. A CT scan demonstrated appendicitis, and she was admitted to a hospital in Mexico for appendectomy. However, over the subsequent five days, she continued to have worsening fevers and abdominal pain. At this point, she flew to Mayo Clinic Arizona for further evaluation.
Her past medical history was significant for rheumatoid arthritis and chronic low back pain. Medications included gabapentin, daily prednisone (20 mg/day), spironolactone, and omeprazole. Following her appendix surgery, she had been placed on moxifloxacin for five days. She had been on methotrexate for several years, but this was discontinued a few months prior due to elevation of liver enzymes.
At the time of presentation, she appeared ill, and her vitals included fluid responsive hypotension, tachypnea with respiratory rate of 22, and mild hypoxia with oxygen saturation 88-95% on room air. Physical exam was significant for bibasilar crackles, abdominal distension, and diffuse tenderness to palpation without peritoneal signs, diffusely tender joints, and erythema over the left elbow and the right knee that was warm to touch. Initial laboratory evaluation demonstrated a hemoglobin of 12.5 g/dL (reference range 12.0–15.5 g/dL), platelet count of 8 × 10(9)/L (reference range 149–375 × 10(9)/L), and white blood cell count (WBC) 2.7 × 10(9)/L (reference range 3.4–10.6 × 10(9)/L) with neutrophilic predominance (absolute neutrophil count (ANC), 2.05 × 10(9)/L (reference range 1.40–6.60 × 10(9)/L)). Electrolyte panel showed hyponatremia 131 mmol/L (reference range 135–145 mmol/L) but was otherwise normal, including creatinine 0.9 mg/dL (reference range 0.6–1.1 mg/dL). LFTs were elevated with alkaline phosphatase 318 U/L (reference range 55–142 U/L), alanine aminotransferase (ALT) 145 U/L (reference range 7–45 U/L), and aspartate aminotransferase (AST) 252 U/L (reference range 9–43 U/L). Most notably, her ferritin was drastically elevated at 27,300 mcg/L (reference range 11–307 mcg/L). Additionally, triglycerides were elevated at 272 mg/dL (reference range < 150 mg/dL), and fibrinogen was reduced at 120 mg/dL (reference range 200–430 mg/dL). Chest X-ray showed trace bilateral pleural effusions and small calcified granulomata in the upper lungs bilaterally. Given her diffusely tender joints, X-ray of the hands were performed and revealed numerous subchondral cysts and erosion, as well as subluxation of the right index finger distal phalanx, with sparing of the metacarpophalangeal joints consistent with rheumatoid arthritis. Due to tachypnea, leukopenia, and hemodynamic instability, she was diagnosed with sepsis.
She initially received broad spectrum antibiotics and underwent paracentesis which was negative for peritonitis. Bacterial and fungal cultures of the ascitic fluid showed no growth. Her significantly elevated ferritin prompted a bone marrow biopsy (BMB), which showed features of hemophagocytic lymphohistiocytosis (Figure 1(a)). Given her findings of pancytopenia, elevated ferritin and triglycerides, reduced fibrinogen, and evidence of hemophagocytosis on BMB, she was treated with high-dose steroids and intravenous fluids. After initiation of steroids, her thrombocytopenia and joint pain improved. However, her WBC count continued to drop, and the patient continued to spike fevers; thus, antibiotics were adjusted to cover for neutropenic fever. Without an identified infectious source, a CT of the brain, chest, abdomen, and pelvis was performed which showed bilateral pulmonary infiltrates but was otherwise unremarkable. Liver biopsy was considered but was deemed unsafe due to coagulopathy. Her respiratory status declined eventually requiring high-flow oxygen due to acute respiratory distress syndrome (ARDS) (Figure 1(b)), and she was treated with aggressive diuresis. Initially, she had adequate response but ultimately developed oliguria and renal failure.
On hospital day four, the ferritin had improved to 609 mcg/L (reference range 11–307 mcg/L); however, LFTs continued to rise, and resultant coagulopathy required daily cryoprecipitate transfusion to maintain safe fibrinogen levels. Due to worsening clinical status with multiorgan failure including the liver, kidney, respiratory, and bone marrow, it was decided to add etoposide for more aggressive treatment of HLH. Despite these efforts, her ferritin rapidly climbed to over 80,000 mcg/L (reference range 11–307 mcg/L). Infectious workup to date was negative including blood bacterial and fungal cultures, ascites bacterial and fungal cultures, and blood tests for HIV, HHV-6, EBV DNA, hepatitis A and E IgM, parvovirus B19, adenovirus, and tuberculosis quantiferon.
Infectious etiology was identified when her urine histoplasmosis antigen returned positive above the upper detectable limit. The bone marrow biopsy was stained for histoplasmosis and confirmed disseminated infection (Figure 1(c)). Amphotericin therapy was initiated as the patient began CRRT for worsening kidney failure. Over the next eight days, however, she did not show any clinical improvement and was treated supportively for ICU delirium, respiratory failure, anuria requiring intermittent hemodialysis, worsening coagulopathy and rising ammonia, and malnutrition requiring tube feeds. On day twelve, voriconazole was added for additional antifungal coverage.
Unfortunately, despite these efforts, the patient's blood counts continued to decline, and she developed massive melena on hospital day 13 with a hemoglobin of 4 g/dL (reference range 12.0–15.5 g/dL), WBC 0.1/L (reference range 3.4–10.6 × 10(9)/L), ANC 0.11/L (reference range 1.40–6.60 × 10(9)/L), and platelets 41/L (reference range 149–375 × 10(9)/L). At this point, the patient and her power of attorney elected to withdraw aggressive treatments, and she was transferred to inpatient hospice.
3. Case Report #2
A 41-year-old woman residing in Arizona with a history of ulcerative colitis from who was on Remicade up until one month earlier was admitted three times over a course of a month with a variety of symptoms without identifying etiology. Initially, she had nonspecific fevers, headache, neck pain, fatigue, nausea, vomiting, and arthralgias. She was found to have an edematous gallbladder (Figure 2(a)) and mild splenomegaly, with a negative infectious workup. With symptomatic care, her fevers were controlled, and she was discharged with a diagnosis of presumed viral syndrome versus Remicade toxicity. However, symptoms worsened, and she represented with fever, sepsis, cholestatic jaundice, acute kidney injury, pancytopenia, and multiple metabolic abnormalities requiring admission to the intensive care unit. Initially, she underwent ERCP with sphincterotomy, and common bile duct stent was placed. On endoscopy, the duodenal mucosa was noted to be friable, biopsy revealed reactive gastropathy, and H. pylori testing was negative. She then underwent laparoscopic cholecystectomy for acalculous cholecystitis. Postoperatively, she developed bloody secretions from the endotracheal tube followed by ARDS; thus, she was unable to be extubated. She also had episodes of epistaxis and melena through this time. Her clinical status quickly deteriorated to multiorgan failure including renal failure requiring dialysis, cholestatic liver failure, respiratory failure requiring mechanical ventilation, and critical pancytopenia requiring high-volume transfusions including 17 units of packed red blood cells, 17 units of platelets, and 6 units of cryoprecipitate.
Workup through this point revealed a markedly elevated ferritin of 73,469 mcg/L (reference range 11–307 mcg/L), elevated lactate dehydrogenase of 2,375 U/L (reference range 122–222 U/L), hypofibrinogenemia of 135 mg/dL (reference range 200-430 mg/dL), and hypertriglyceridemia 2,259 mg/dL (reference range < 150 mg/dL), raising suspicion for HLH. Bone marrow biopsy confirmed the diagnosis (Figures 2(b)–2(d)), and she was initiated on high-dose steroids and etoposide. She developed a severe diffuse rash to etoposide necessitating its discontinuation. Investigation for an underlying trigger included bronchoalveolar lavage (BAL) culture which returned positive for Histoplasma capsulatum, in addition to positive histoplasma urinary antigen. During the same hospitalization, she additionally underwent cholecystectomy, and cultured gallbladder tissue ultimately grew H. capsulatum. Based on history, this was likely acquired in the setting of prior Remicade use while exploring bat caves in Cancun, Mexico, two weeks prior to admission. The patient was born and lived in Arizona until her presentation and denied travel to any endemic areas. Her Aspergillus antigen was also positive from BAL, but this was felt to be a false positive as Aspergillus antigen testing cross-reacts with Histoplasma.
For treatment of disseminated histoplasmosis, she received intravenous AmBisome starting on day 4 of hospitalization and later transitioned to oral itraconazole. With these treatments, she recovered well and was eventually transferred out of the intensive care unit on day 18. She required one dose of Neupogen for leukopenia, but her white blood cell count recovered thereafter, and platelet count returned to normal. Her ferritin had dramatically decreased to 1,568 mcg/L (reference range 11–307 mcg/L). Her kidney and liver function recovered to the point where she could be safely discharged to acute rehabilitation after an approximately four weeks stay in the hospital. She continued to improve during a two-week rehabilitation stay and was then discharged home with an oral steroid taper and oral itraconazole for one year following diagnosis.
4. Discussion
The diagnosis and treatment of acquired HLH in adults are serious and challenging, as the clinical presentation can be fairly nonspecific and diagnosis is based on a collection of both clinical and laboratory abnormalities. In pediatric patients with familial HLH, an elevated ferritin greater than 10,000 μg/L is highly sensitive and specific for diagnosis [19]. In adults, however, elevated ferritin has been linked to various conditions including malignancy, liver dysfunction, infection, anemia of chronic disease, or iron overload [20]. Markedly elevated ferritin, however, is thought to be more specific for adult onset stills disease, macrophage activation syndrome, and HLH. In a retrospective study [20] of patients with ferritin levels greater than 50,000 μg/L, 19% were found to have HLH. The most frequently seen diagnosis in these patients was renal failure (73%), liver injury (61%), infections (52%), and hematologic malignancies (36%). No ferritin cut off level was found to be specific for HLH in this study. Currently, ferritin > 500 μg/L is included in the diagnostic criteria for HLH, although many prefer to use >3000 μg/L. Given the lack of specific criteria for diagnosis of adult acquired HLH, a scoring system which includes the above mentioned diagnostic criteria for HLH was developed and has been shown to be 90% sensitive and 79% specific, although specificity decreases as patients become less stable [21]. Once the diagnosis is confirmed, treatment must be initiated immediately. Additionally, a search must be undertaken to find an underlying trigger for HLH; as without treating the source, there is little chance for clinical improvement.
Here, we present two cases of HLH secondary to disseminated histoplasmosis. Previously, published cases of histoplasmosis associated HLH were reported in HIV [22], hematologic malignancy [16], and transplant patients on immunosuppression [18, 22]. Disseminated histoplasmosis by itself is also quite serious but generally treatable with antifungal therapy. Current IDSA guidelines for moderate to severe disease include liposomal amphotericin B (3.0 mg/kg daily) for 1-2 weeks, followed with oral itraconazole for at least 12 months [9]. Patients who have both disseminated histoplasmosis and HLH portend a worse prognosis. In a retrospective review of eleven cases of histoplasmosis associated HLH, 45% died within 30 days, and 63% died within 90 days [22]. The main challenge of caring for patients with histoplasmosis associated HLH is management of the multiorgan failure that can result from this combination of diseases. Both HLH and histoplasmosis can cause hematologic abnormalities, namely, pancytopenia, and both patients presented here required large volume transfusions. In addition, both patients developed respiratory failure from ARDS, renal failure requiring renal replacement therapy, liver failure, and gastrointestinal bleeding. Disseminated histoplasmosis involving the gastrointestinal system can cause cholecystitis and appendicitis leading to surgery, as well as melena and gastritis, which were seen in these cases.
The main risk factors for disseminated histoplasmosis leading to HLH in these cases were immunosuppressive medication (methotrexate and infliximab) and environmental exposure (bird or bat droppings, especially in caves). Interestingly, in both cases, the offending medication had been discontinued due to laboratory abnormalities 1-2 months prior to any presenting symptoms. It is unclear whether this may have been a risk factor for disease. Nevertheless, with a presentation of diffuse infectious symptoms without an identified etiology in the context of recent immunosuppressive medication, an exhaustive history and laboratory inquiry should be pursued to avoid delayed diagnosis for serious conditions such as disseminated fungal infection and HLH.
Data Availability
No datasets were used.
Conflicts of Interest
No authors have conflict of interest to disclose.
Authors' Contributions
All authors included have made substantial contributions to conception, design, data acquisition, drafting, and/or revising of the manuscript. All authors have read and approved the submission of this manuscript.
Figure 1 (a) Bone marrow aspirate reveals evidence of hemophagocytosis. (b) Chest X-ray reveals evidence of bilateral infiltrates, and patient then diagnosed with ARDS. (c) Bone marrow core biopsy GMS stain reveals histoplasmosis.
Figure 2 (a) CT abdomen on admission reveals edematous gallbladder which was later found to have evidence of Histoplasma capsulatum. (b, c) Bone marrow aspirate reveals hemophagocytosis. (d) GMS stain of bone marrow core biopsy positive for histoplasmosis. | Not recovered | ReactionOutcome | CC BY | 33552603 | 19,036,089 | 2021 |
What was the outcome of reaction 'Coagulopathy'? | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis in Rheumatologic Disease.
Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections.
Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.
1. Background
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune overactivation that can lead to tissue destruction and organ failure. As a primary disorder, it is typically seen in pediatrics and has several associated genetic mutations [1]. In adults, it presents as a secondary phenomenon, seen in conjunction with infection, malignancy, immunodeficiency, or another immune dysregulating event. The diagnosis is established by meeting five of eight criteria, including fever greater than 38.5 degrees Celsius; splenomegaly; peripheral cytopenia (at least two of hemoglobin < 9 g/dL, platelets < 100, 000/microL, absolute neutrophil count < 1000/microL); hypertriglyceridemia (fasting > 265 mg/dL) or hypofibrinogenemia (<150 mg/dL); hemophagocytosis in the bone marrow, spleen, lymph node, or liver; decreased natural killer cell activity; ferritin > 500 ng/mL; and elevated soluble CD25 (IL-2 receptor α) two standard deviations above age-adjusted norms [2, 3]. Laboratory evaluation of soluble CD25 and natural killer cell activity require specialized testing and therefore do not result in real time. Without treatment, prognosis is limited to a few months, and the greatest barrier to survival is delay in diagnosis. Treatment entails identification and treatment of the underlying trigger. With proper treatment and identification of triggering event, survival increases to 54% at 6.2 years [4, 5]. Prognosis is worse with higher ferritin levels, underlying malignancy, older age, and low serum albumin levels [6, 7].
Although rheumatologic disease by itself can be a trigger for HLH, this is rare. Among adults on biological therapies for rheumatologic disease, infection is the most common trigger [8]. Histoplasmosis is a serious fungal infection that is endemic to the Ohio and Mississippi River valleys in the United States, as well as parts of Central and South America. The infective agent, Histoplasma capsulatum, is most likely to be found in soil containing bird or bat droppings. Inhalation of the spores allows them to transform into yeast and travel throughout the lymphatic and vascular system. Pulmonary histoplasmosis can cause pneumonia, mediastinal or hilar masses, pulmonary nodules, cavitary lung disease, and pericarditis. Risk factors for disseminated histoplasmosis include AIDS, immunodeficiency, immunosuppressive medications, and extremes of age. Untreated diffuse histoplasmosis is fatal within weeks, but proper antifungal treatment with amphotericin B or itraconazole increases survival rates dramatically [9].
Cases of HLH secondary to disseminated histoplasmosis are rare and extremely serious. Several case reports in the literature describe patients with AIDS [10–15], malignancy [16], or immunosuppression due to medications [17, 18]. Below we present two cases of patients with HLH secondary to disseminated histoplasmosis, both in the setting of recent immunosuppressive medication for underlying autoimmune disease.
2. Case Report #1
A 66-year-old woman presented to an emergency department near her home in Mexico with fever and abdominal pain of two weeks duration. She also described two months of increased fatigue and malaise, as well as increased swelling around her feet and ankles that had more recently developed. Although she was born in the United States in Oregon, she had been living in Mexico for several years. She denied travel to any other regions. A CT scan demonstrated appendicitis, and she was admitted to a hospital in Mexico for appendectomy. However, over the subsequent five days, she continued to have worsening fevers and abdominal pain. At this point, she flew to Mayo Clinic Arizona for further evaluation.
Her past medical history was significant for rheumatoid arthritis and chronic low back pain. Medications included gabapentin, daily prednisone (20 mg/day), spironolactone, and omeprazole. Following her appendix surgery, she had been placed on moxifloxacin for five days. She had been on methotrexate for several years, but this was discontinued a few months prior due to elevation of liver enzymes.
At the time of presentation, she appeared ill, and her vitals included fluid responsive hypotension, tachypnea with respiratory rate of 22, and mild hypoxia with oxygen saturation 88-95% on room air. Physical exam was significant for bibasilar crackles, abdominal distension, and diffuse tenderness to palpation without peritoneal signs, diffusely tender joints, and erythema over the left elbow and the right knee that was warm to touch. Initial laboratory evaluation demonstrated a hemoglobin of 12.5 g/dL (reference range 12.0–15.5 g/dL), platelet count of 8 × 10(9)/L (reference range 149–375 × 10(9)/L), and white blood cell count (WBC) 2.7 × 10(9)/L (reference range 3.4–10.6 × 10(9)/L) with neutrophilic predominance (absolute neutrophil count (ANC), 2.05 × 10(9)/L (reference range 1.40–6.60 × 10(9)/L)). Electrolyte panel showed hyponatremia 131 mmol/L (reference range 135–145 mmol/L) but was otherwise normal, including creatinine 0.9 mg/dL (reference range 0.6–1.1 mg/dL). LFTs were elevated with alkaline phosphatase 318 U/L (reference range 55–142 U/L), alanine aminotransferase (ALT) 145 U/L (reference range 7–45 U/L), and aspartate aminotransferase (AST) 252 U/L (reference range 9–43 U/L). Most notably, her ferritin was drastically elevated at 27,300 mcg/L (reference range 11–307 mcg/L). Additionally, triglycerides were elevated at 272 mg/dL (reference range < 150 mg/dL), and fibrinogen was reduced at 120 mg/dL (reference range 200–430 mg/dL). Chest X-ray showed trace bilateral pleural effusions and small calcified granulomata in the upper lungs bilaterally. Given her diffusely tender joints, X-ray of the hands were performed and revealed numerous subchondral cysts and erosion, as well as subluxation of the right index finger distal phalanx, with sparing of the metacarpophalangeal joints consistent with rheumatoid arthritis. Due to tachypnea, leukopenia, and hemodynamic instability, she was diagnosed with sepsis.
She initially received broad spectrum antibiotics and underwent paracentesis which was negative for peritonitis. Bacterial and fungal cultures of the ascitic fluid showed no growth. Her significantly elevated ferritin prompted a bone marrow biopsy (BMB), which showed features of hemophagocytic lymphohistiocytosis (Figure 1(a)). Given her findings of pancytopenia, elevated ferritin and triglycerides, reduced fibrinogen, and evidence of hemophagocytosis on BMB, she was treated with high-dose steroids and intravenous fluids. After initiation of steroids, her thrombocytopenia and joint pain improved. However, her WBC count continued to drop, and the patient continued to spike fevers; thus, antibiotics were adjusted to cover for neutropenic fever. Without an identified infectious source, a CT of the brain, chest, abdomen, and pelvis was performed which showed bilateral pulmonary infiltrates but was otherwise unremarkable. Liver biopsy was considered but was deemed unsafe due to coagulopathy. Her respiratory status declined eventually requiring high-flow oxygen due to acute respiratory distress syndrome (ARDS) (Figure 1(b)), and she was treated with aggressive diuresis. Initially, she had adequate response but ultimately developed oliguria and renal failure.
On hospital day four, the ferritin had improved to 609 mcg/L (reference range 11–307 mcg/L); however, LFTs continued to rise, and resultant coagulopathy required daily cryoprecipitate transfusion to maintain safe fibrinogen levels. Due to worsening clinical status with multiorgan failure including the liver, kidney, respiratory, and bone marrow, it was decided to add etoposide for more aggressive treatment of HLH. Despite these efforts, her ferritin rapidly climbed to over 80,000 mcg/L (reference range 11–307 mcg/L). Infectious workup to date was negative including blood bacterial and fungal cultures, ascites bacterial and fungal cultures, and blood tests for HIV, HHV-6, EBV DNA, hepatitis A and E IgM, parvovirus B19, adenovirus, and tuberculosis quantiferon.
Infectious etiology was identified when her urine histoplasmosis antigen returned positive above the upper detectable limit. The bone marrow biopsy was stained for histoplasmosis and confirmed disseminated infection (Figure 1(c)). Amphotericin therapy was initiated as the patient began CRRT for worsening kidney failure. Over the next eight days, however, she did not show any clinical improvement and was treated supportively for ICU delirium, respiratory failure, anuria requiring intermittent hemodialysis, worsening coagulopathy and rising ammonia, and malnutrition requiring tube feeds. On day twelve, voriconazole was added for additional antifungal coverage.
Unfortunately, despite these efforts, the patient's blood counts continued to decline, and she developed massive melena on hospital day 13 with a hemoglobin of 4 g/dL (reference range 12.0–15.5 g/dL), WBC 0.1/L (reference range 3.4–10.6 × 10(9)/L), ANC 0.11/L (reference range 1.40–6.60 × 10(9)/L), and platelets 41/L (reference range 149–375 × 10(9)/L). At this point, the patient and her power of attorney elected to withdraw aggressive treatments, and she was transferred to inpatient hospice.
3. Case Report #2
A 41-year-old woman residing in Arizona with a history of ulcerative colitis from who was on Remicade up until one month earlier was admitted three times over a course of a month with a variety of symptoms without identifying etiology. Initially, she had nonspecific fevers, headache, neck pain, fatigue, nausea, vomiting, and arthralgias. She was found to have an edematous gallbladder (Figure 2(a)) and mild splenomegaly, with a negative infectious workup. With symptomatic care, her fevers were controlled, and she was discharged with a diagnosis of presumed viral syndrome versus Remicade toxicity. However, symptoms worsened, and she represented with fever, sepsis, cholestatic jaundice, acute kidney injury, pancytopenia, and multiple metabolic abnormalities requiring admission to the intensive care unit. Initially, she underwent ERCP with sphincterotomy, and common bile duct stent was placed. On endoscopy, the duodenal mucosa was noted to be friable, biopsy revealed reactive gastropathy, and H. pylori testing was negative. She then underwent laparoscopic cholecystectomy for acalculous cholecystitis. Postoperatively, she developed bloody secretions from the endotracheal tube followed by ARDS; thus, she was unable to be extubated. She also had episodes of epistaxis and melena through this time. Her clinical status quickly deteriorated to multiorgan failure including renal failure requiring dialysis, cholestatic liver failure, respiratory failure requiring mechanical ventilation, and critical pancytopenia requiring high-volume transfusions including 17 units of packed red blood cells, 17 units of platelets, and 6 units of cryoprecipitate.
Workup through this point revealed a markedly elevated ferritin of 73,469 mcg/L (reference range 11–307 mcg/L), elevated lactate dehydrogenase of 2,375 U/L (reference range 122–222 U/L), hypofibrinogenemia of 135 mg/dL (reference range 200-430 mg/dL), and hypertriglyceridemia 2,259 mg/dL (reference range < 150 mg/dL), raising suspicion for HLH. Bone marrow biopsy confirmed the diagnosis (Figures 2(b)–2(d)), and she was initiated on high-dose steroids and etoposide. She developed a severe diffuse rash to etoposide necessitating its discontinuation. Investigation for an underlying trigger included bronchoalveolar lavage (BAL) culture which returned positive for Histoplasma capsulatum, in addition to positive histoplasma urinary antigen. During the same hospitalization, she additionally underwent cholecystectomy, and cultured gallbladder tissue ultimately grew H. capsulatum. Based on history, this was likely acquired in the setting of prior Remicade use while exploring bat caves in Cancun, Mexico, two weeks prior to admission. The patient was born and lived in Arizona until her presentation and denied travel to any endemic areas. Her Aspergillus antigen was also positive from BAL, but this was felt to be a false positive as Aspergillus antigen testing cross-reacts with Histoplasma.
For treatment of disseminated histoplasmosis, she received intravenous AmBisome starting on day 4 of hospitalization and later transitioned to oral itraconazole. With these treatments, she recovered well and was eventually transferred out of the intensive care unit on day 18. She required one dose of Neupogen for leukopenia, but her white blood cell count recovered thereafter, and platelet count returned to normal. Her ferritin had dramatically decreased to 1,568 mcg/L (reference range 11–307 mcg/L). Her kidney and liver function recovered to the point where she could be safely discharged to acute rehabilitation after an approximately four weeks stay in the hospital. She continued to improve during a two-week rehabilitation stay and was then discharged home with an oral steroid taper and oral itraconazole for one year following diagnosis.
4. Discussion
The diagnosis and treatment of acquired HLH in adults are serious and challenging, as the clinical presentation can be fairly nonspecific and diagnosis is based on a collection of both clinical and laboratory abnormalities. In pediatric patients with familial HLH, an elevated ferritin greater than 10,000 μg/L is highly sensitive and specific for diagnosis [19]. In adults, however, elevated ferritin has been linked to various conditions including malignancy, liver dysfunction, infection, anemia of chronic disease, or iron overload [20]. Markedly elevated ferritin, however, is thought to be more specific for adult onset stills disease, macrophage activation syndrome, and HLH. In a retrospective study [20] of patients with ferritin levels greater than 50,000 μg/L, 19% were found to have HLH. The most frequently seen diagnosis in these patients was renal failure (73%), liver injury (61%), infections (52%), and hematologic malignancies (36%). No ferritin cut off level was found to be specific for HLH in this study. Currently, ferritin > 500 μg/L is included in the diagnostic criteria for HLH, although many prefer to use >3000 μg/L. Given the lack of specific criteria for diagnosis of adult acquired HLH, a scoring system which includes the above mentioned diagnostic criteria for HLH was developed and has been shown to be 90% sensitive and 79% specific, although specificity decreases as patients become less stable [21]. Once the diagnosis is confirmed, treatment must be initiated immediately. Additionally, a search must be undertaken to find an underlying trigger for HLH; as without treating the source, there is little chance for clinical improvement.
Here, we present two cases of HLH secondary to disseminated histoplasmosis. Previously, published cases of histoplasmosis associated HLH were reported in HIV [22], hematologic malignancy [16], and transplant patients on immunosuppression [18, 22]. Disseminated histoplasmosis by itself is also quite serious but generally treatable with antifungal therapy. Current IDSA guidelines for moderate to severe disease include liposomal amphotericin B (3.0 mg/kg daily) for 1-2 weeks, followed with oral itraconazole for at least 12 months [9]. Patients who have both disseminated histoplasmosis and HLH portend a worse prognosis. In a retrospective review of eleven cases of histoplasmosis associated HLH, 45% died within 30 days, and 63% died within 90 days [22]. The main challenge of caring for patients with histoplasmosis associated HLH is management of the multiorgan failure that can result from this combination of diseases. Both HLH and histoplasmosis can cause hematologic abnormalities, namely, pancytopenia, and both patients presented here required large volume transfusions. In addition, both patients developed respiratory failure from ARDS, renal failure requiring renal replacement therapy, liver failure, and gastrointestinal bleeding. Disseminated histoplasmosis involving the gastrointestinal system can cause cholecystitis and appendicitis leading to surgery, as well as melena and gastritis, which were seen in these cases.
The main risk factors for disseminated histoplasmosis leading to HLH in these cases were immunosuppressive medication (methotrexate and infliximab) and environmental exposure (bird or bat droppings, especially in caves). Interestingly, in both cases, the offending medication had been discontinued due to laboratory abnormalities 1-2 months prior to any presenting symptoms. It is unclear whether this may have been a risk factor for disease. Nevertheless, with a presentation of diffuse infectious symptoms without an identified etiology in the context of recent immunosuppressive medication, an exhaustive history and laboratory inquiry should be pursued to avoid delayed diagnosis for serious conditions such as disseminated fungal infection and HLH.
Data Availability
No datasets were used.
Conflicts of Interest
No authors have conflict of interest to disclose.
Authors' Contributions
All authors included have made substantial contributions to conception, design, data acquisition, drafting, and/or revising of the manuscript. All authors have read and approved the submission of this manuscript.
Figure 1 (a) Bone marrow aspirate reveals evidence of hemophagocytosis. (b) Chest X-ray reveals evidence of bilateral infiltrates, and patient then diagnosed with ARDS. (c) Bone marrow core biopsy GMS stain reveals histoplasmosis.
Figure 2 (a) CT abdomen on admission reveals edematous gallbladder which was later found to have evidence of Histoplasma capsulatum. (b, c) Bone marrow aspirate reveals hemophagocytosis. (d) GMS stain of bone marrow core biopsy positive for histoplasmosis. | Not recovered | ReactionOutcome | CC BY | 33552603 | 19,036,089 | 2021 |
What was the outcome of reaction 'Delirium'? | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis in Rheumatologic Disease.
Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections.
Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.
1. Background
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune overactivation that can lead to tissue destruction and organ failure. As a primary disorder, it is typically seen in pediatrics and has several associated genetic mutations [1]. In adults, it presents as a secondary phenomenon, seen in conjunction with infection, malignancy, immunodeficiency, or another immune dysregulating event. The diagnosis is established by meeting five of eight criteria, including fever greater than 38.5 degrees Celsius; splenomegaly; peripheral cytopenia (at least two of hemoglobin < 9 g/dL, platelets < 100, 000/microL, absolute neutrophil count < 1000/microL); hypertriglyceridemia (fasting > 265 mg/dL) or hypofibrinogenemia (<150 mg/dL); hemophagocytosis in the bone marrow, spleen, lymph node, or liver; decreased natural killer cell activity; ferritin > 500 ng/mL; and elevated soluble CD25 (IL-2 receptor α) two standard deviations above age-adjusted norms [2, 3]. Laboratory evaluation of soluble CD25 and natural killer cell activity require specialized testing and therefore do not result in real time. Without treatment, prognosis is limited to a few months, and the greatest barrier to survival is delay in diagnosis. Treatment entails identification and treatment of the underlying trigger. With proper treatment and identification of triggering event, survival increases to 54% at 6.2 years [4, 5]. Prognosis is worse with higher ferritin levels, underlying malignancy, older age, and low serum albumin levels [6, 7].
Although rheumatologic disease by itself can be a trigger for HLH, this is rare. Among adults on biological therapies for rheumatologic disease, infection is the most common trigger [8]. Histoplasmosis is a serious fungal infection that is endemic to the Ohio and Mississippi River valleys in the United States, as well as parts of Central and South America. The infective agent, Histoplasma capsulatum, is most likely to be found in soil containing bird or bat droppings. Inhalation of the spores allows them to transform into yeast and travel throughout the lymphatic and vascular system. Pulmonary histoplasmosis can cause pneumonia, mediastinal or hilar masses, pulmonary nodules, cavitary lung disease, and pericarditis. Risk factors for disseminated histoplasmosis include AIDS, immunodeficiency, immunosuppressive medications, and extremes of age. Untreated diffuse histoplasmosis is fatal within weeks, but proper antifungal treatment with amphotericin B or itraconazole increases survival rates dramatically [9].
Cases of HLH secondary to disseminated histoplasmosis are rare and extremely serious. Several case reports in the literature describe patients with AIDS [10–15], malignancy [16], or immunosuppression due to medications [17, 18]. Below we present two cases of patients with HLH secondary to disseminated histoplasmosis, both in the setting of recent immunosuppressive medication for underlying autoimmune disease.
2. Case Report #1
A 66-year-old woman presented to an emergency department near her home in Mexico with fever and abdominal pain of two weeks duration. She also described two months of increased fatigue and malaise, as well as increased swelling around her feet and ankles that had more recently developed. Although she was born in the United States in Oregon, she had been living in Mexico for several years. She denied travel to any other regions. A CT scan demonstrated appendicitis, and she was admitted to a hospital in Mexico for appendectomy. However, over the subsequent five days, she continued to have worsening fevers and abdominal pain. At this point, she flew to Mayo Clinic Arizona for further evaluation.
Her past medical history was significant for rheumatoid arthritis and chronic low back pain. Medications included gabapentin, daily prednisone (20 mg/day), spironolactone, and omeprazole. Following her appendix surgery, she had been placed on moxifloxacin for five days. She had been on methotrexate for several years, but this was discontinued a few months prior due to elevation of liver enzymes.
At the time of presentation, she appeared ill, and her vitals included fluid responsive hypotension, tachypnea with respiratory rate of 22, and mild hypoxia with oxygen saturation 88-95% on room air. Physical exam was significant for bibasilar crackles, abdominal distension, and diffuse tenderness to palpation without peritoneal signs, diffusely tender joints, and erythema over the left elbow and the right knee that was warm to touch. Initial laboratory evaluation demonstrated a hemoglobin of 12.5 g/dL (reference range 12.0–15.5 g/dL), platelet count of 8 × 10(9)/L (reference range 149–375 × 10(9)/L), and white blood cell count (WBC) 2.7 × 10(9)/L (reference range 3.4–10.6 × 10(9)/L) with neutrophilic predominance (absolute neutrophil count (ANC), 2.05 × 10(9)/L (reference range 1.40–6.60 × 10(9)/L)). Electrolyte panel showed hyponatremia 131 mmol/L (reference range 135–145 mmol/L) but was otherwise normal, including creatinine 0.9 mg/dL (reference range 0.6–1.1 mg/dL). LFTs were elevated with alkaline phosphatase 318 U/L (reference range 55–142 U/L), alanine aminotransferase (ALT) 145 U/L (reference range 7–45 U/L), and aspartate aminotransferase (AST) 252 U/L (reference range 9–43 U/L). Most notably, her ferritin was drastically elevated at 27,300 mcg/L (reference range 11–307 mcg/L). Additionally, triglycerides were elevated at 272 mg/dL (reference range < 150 mg/dL), and fibrinogen was reduced at 120 mg/dL (reference range 200–430 mg/dL). Chest X-ray showed trace bilateral pleural effusions and small calcified granulomata in the upper lungs bilaterally. Given her diffusely tender joints, X-ray of the hands were performed and revealed numerous subchondral cysts and erosion, as well as subluxation of the right index finger distal phalanx, with sparing of the metacarpophalangeal joints consistent with rheumatoid arthritis. Due to tachypnea, leukopenia, and hemodynamic instability, she was diagnosed with sepsis.
She initially received broad spectrum antibiotics and underwent paracentesis which was negative for peritonitis. Bacterial and fungal cultures of the ascitic fluid showed no growth. Her significantly elevated ferritin prompted a bone marrow biopsy (BMB), which showed features of hemophagocytic lymphohistiocytosis (Figure 1(a)). Given her findings of pancytopenia, elevated ferritin and triglycerides, reduced fibrinogen, and evidence of hemophagocytosis on BMB, she was treated with high-dose steroids and intravenous fluids. After initiation of steroids, her thrombocytopenia and joint pain improved. However, her WBC count continued to drop, and the patient continued to spike fevers; thus, antibiotics were adjusted to cover for neutropenic fever. Without an identified infectious source, a CT of the brain, chest, abdomen, and pelvis was performed which showed bilateral pulmonary infiltrates but was otherwise unremarkable. Liver biopsy was considered but was deemed unsafe due to coagulopathy. Her respiratory status declined eventually requiring high-flow oxygen due to acute respiratory distress syndrome (ARDS) (Figure 1(b)), and she was treated with aggressive diuresis. Initially, she had adequate response but ultimately developed oliguria and renal failure.
On hospital day four, the ferritin had improved to 609 mcg/L (reference range 11–307 mcg/L); however, LFTs continued to rise, and resultant coagulopathy required daily cryoprecipitate transfusion to maintain safe fibrinogen levels. Due to worsening clinical status with multiorgan failure including the liver, kidney, respiratory, and bone marrow, it was decided to add etoposide for more aggressive treatment of HLH. Despite these efforts, her ferritin rapidly climbed to over 80,000 mcg/L (reference range 11–307 mcg/L). Infectious workup to date was negative including blood bacterial and fungal cultures, ascites bacterial and fungal cultures, and blood tests for HIV, HHV-6, EBV DNA, hepatitis A and E IgM, parvovirus B19, adenovirus, and tuberculosis quantiferon.
Infectious etiology was identified when her urine histoplasmosis antigen returned positive above the upper detectable limit. The bone marrow biopsy was stained for histoplasmosis and confirmed disseminated infection (Figure 1(c)). Amphotericin therapy was initiated as the patient began CRRT for worsening kidney failure. Over the next eight days, however, she did not show any clinical improvement and was treated supportively for ICU delirium, respiratory failure, anuria requiring intermittent hemodialysis, worsening coagulopathy and rising ammonia, and malnutrition requiring tube feeds. On day twelve, voriconazole was added for additional antifungal coverage.
Unfortunately, despite these efforts, the patient's blood counts continued to decline, and she developed massive melena on hospital day 13 with a hemoglobin of 4 g/dL (reference range 12.0–15.5 g/dL), WBC 0.1/L (reference range 3.4–10.6 × 10(9)/L), ANC 0.11/L (reference range 1.40–6.60 × 10(9)/L), and platelets 41/L (reference range 149–375 × 10(9)/L). At this point, the patient and her power of attorney elected to withdraw aggressive treatments, and she was transferred to inpatient hospice.
3. Case Report #2
A 41-year-old woman residing in Arizona with a history of ulcerative colitis from who was on Remicade up until one month earlier was admitted three times over a course of a month with a variety of symptoms without identifying etiology. Initially, she had nonspecific fevers, headache, neck pain, fatigue, nausea, vomiting, and arthralgias. She was found to have an edematous gallbladder (Figure 2(a)) and mild splenomegaly, with a negative infectious workup. With symptomatic care, her fevers were controlled, and she was discharged with a diagnosis of presumed viral syndrome versus Remicade toxicity. However, symptoms worsened, and she represented with fever, sepsis, cholestatic jaundice, acute kidney injury, pancytopenia, and multiple metabolic abnormalities requiring admission to the intensive care unit. Initially, she underwent ERCP with sphincterotomy, and common bile duct stent was placed. On endoscopy, the duodenal mucosa was noted to be friable, biopsy revealed reactive gastropathy, and H. pylori testing was negative. She then underwent laparoscopic cholecystectomy for acalculous cholecystitis. Postoperatively, she developed bloody secretions from the endotracheal tube followed by ARDS; thus, she was unable to be extubated. She also had episodes of epistaxis and melena through this time. Her clinical status quickly deteriorated to multiorgan failure including renal failure requiring dialysis, cholestatic liver failure, respiratory failure requiring mechanical ventilation, and critical pancytopenia requiring high-volume transfusions including 17 units of packed red blood cells, 17 units of platelets, and 6 units of cryoprecipitate.
Workup through this point revealed a markedly elevated ferritin of 73,469 mcg/L (reference range 11–307 mcg/L), elevated lactate dehydrogenase of 2,375 U/L (reference range 122–222 U/L), hypofibrinogenemia of 135 mg/dL (reference range 200-430 mg/dL), and hypertriglyceridemia 2,259 mg/dL (reference range < 150 mg/dL), raising suspicion for HLH. Bone marrow biopsy confirmed the diagnosis (Figures 2(b)–2(d)), and she was initiated on high-dose steroids and etoposide. She developed a severe diffuse rash to etoposide necessitating its discontinuation. Investigation for an underlying trigger included bronchoalveolar lavage (BAL) culture which returned positive for Histoplasma capsulatum, in addition to positive histoplasma urinary antigen. During the same hospitalization, she additionally underwent cholecystectomy, and cultured gallbladder tissue ultimately grew H. capsulatum. Based on history, this was likely acquired in the setting of prior Remicade use while exploring bat caves in Cancun, Mexico, two weeks prior to admission. The patient was born and lived in Arizona until her presentation and denied travel to any endemic areas. Her Aspergillus antigen was also positive from BAL, but this was felt to be a false positive as Aspergillus antigen testing cross-reacts with Histoplasma.
For treatment of disseminated histoplasmosis, she received intravenous AmBisome starting on day 4 of hospitalization and later transitioned to oral itraconazole. With these treatments, she recovered well and was eventually transferred out of the intensive care unit on day 18. She required one dose of Neupogen for leukopenia, but her white blood cell count recovered thereafter, and platelet count returned to normal. Her ferritin had dramatically decreased to 1,568 mcg/L (reference range 11–307 mcg/L). Her kidney and liver function recovered to the point where she could be safely discharged to acute rehabilitation after an approximately four weeks stay in the hospital. She continued to improve during a two-week rehabilitation stay and was then discharged home with an oral steroid taper and oral itraconazole for one year following diagnosis.
4. Discussion
The diagnosis and treatment of acquired HLH in adults are serious and challenging, as the clinical presentation can be fairly nonspecific and diagnosis is based on a collection of both clinical and laboratory abnormalities. In pediatric patients with familial HLH, an elevated ferritin greater than 10,000 μg/L is highly sensitive and specific for diagnosis [19]. In adults, however, elevated ferritin has been linked to various conditions including malignancy, liver dysfunction, infection, anemia of chronic disease, or iron overload [20]. Markedly elevated ferritin, however, is thought to be more specific for adult onset stills disease, macrophage activation syndrome, and HLH. In a retrospective study [20] of patients with ferritin levels greater than 50,000 μg/L, 19% were found to have HLH. The most frequently seen diagnosis in these patients was renal failure (73%), liver injury (61%), infections (52%), and hematologic malignancies (36%). No ferritin cut off level was found to be specific for HLH in this study. Currently, ferritin > 500 μg/L is included in the diagnostic criteria for HLH, although many prefer to use >3000 μg/L. Given the lack of specific criteria for diagnosis of adult acquired HLH, a scoring system which includes the above mentioned diagnostic criteria for HLH was developed and has been shown to be 90% sensitive and 79% specific, although specificity decreases as patients become less stable [21]. Once the diagnosis is confirmed, treatment must be initiated immediately. Additionally, a search must be undertaken to find an underlying trigger for HLH; as without treating the source, there is little chance for clinical improvement.
Here, we present two cases of HLH secondary to disseminated histoplasmosis. Previously, published cases of histoplasmosis associated HLH were reported in HIV [22], hematologic malignancy [16], and transplant patients on immunosuppression [18, 22]. Disseminated histoplasmosis by itself is also quite serious but generally treatable with antifungal therapy. Current IDSA guidelines for moderate to severe disease include liposomal amphotericin B (3.0 mg/kg daily) for 1-2 weeks, followed with oral itraconazole for at least 12 months [9]. Patients who have both disseminated histoplasmosis and HLH portend a worse prognosis. In a retrospective review of eleven cases of histoplasmosis associated HLH, 45% died within 30 days, and 63% died within 90 days [22]. The main challenge of caring for patients with histoplasmosis associated HLH is management of the multiorgan failure that can result from this combination of diseases. Both HLH and histoplasmosis can cause hematologic abnormalities, namely, pancytopenia, and both patients presented here required large volume transfusions. In addition, both patients developed respiratory failure from ARDS, renal failure requiring renal replacement therapy, liver failure, and gastrointestinal bleeding. Disseminated histoplasmosis involving the gastrointestinal system can cause cholecystitis and appendicitis leading to surgery, as well as melena and gastritis, which were seen in these cases.
The main risk factors for disseminated histoplasmosis leading to HLH in these cases were immunosuppressive medication (methotrexate and infliximab) and environmental exposure (bird or bat droppings, especially in caves). Interestingly, in both cases, the offending medication had been discontinued due to laboratory abnormalities 1-2 months prior to any presenting symptoms. It is unclear whether this may have been a risk factor for disease. Nevertheless, with a presentation of diffuse infectious symptoms without an identified etiology in the context of recent immunosuppressive medication, an exhaustive history and laboratory inquiry should be pursued to avoid delayed diagnosis for serious conditions such as disseminated fungal infection and HLH.
Data Availability
No datasets were used.
Conflicts of Interest
No authors have conflict of interest to disclose.
Authors' Contributions
All authors included have made substantial contributions to conception, design, data acquisition, drafting, and/or revising of the manuscript. All authors have read and approved the submission of this manuscript.
Figure 1 (a) Bone marrow aspirate reveals evidence of hemophagocytosis. (b) Chest X-ray reveals evidence of bilateral infiltrates, and patient then diagnosed with ARDS. (c) Bone marrow core biopsy GMS stain reveals histoplasmosis.
Figure 2 (a) CT abdomen on admission reveals edematous gallbladder which was later found to have evidence of Histoplasma capsulatum. (b, c) Bone marrow aspirate reveals hemophagocytosis. (d) GMS stain of bone marrow core biopsy positive for histoplasmosis. | Not recovered | ReactionOutcome | CC BY | 33552603 | 19,036,089 | 2021 |
What was the outcome of reaction 'Drug ineffective for unapproved indication'? | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis in Rheumatologic Disease.
Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections.
Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.
1. Background
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune overactivation that can lead to tissue destruction and organ failure. As a primary disorder, it is typically seen in pediatrics and has several associated genetic mutations [1]. In adults, it presents as a secondary phenomenon, seen in conjunction with infection, malignancy, immunodeficiency, or another immune dysregulating event. The diagnosis is established by meeting five of eight criteria, including fever greater than 38.5 degrees Celsius; splenomegaly; peripheral cytopenia (at least two of hemoglobin < 9 g/dL, platelets < 100, 000/microL, absolute neutrophil count < 1000/microL); hypertriglyceridemia (fasting > 265 mg/dL) or hypofibrinogenemia (<150 mg/dL); hemophagocytosis in the bone marrow, spleen, lymph node, or liver; decreased natural killer cell activity; ferritin > 500 ng/mL; and elevated soluble CD25 (IL-2 receptor α) two standard deviations above age-adjusted norms [2, 3]. Laboratory evaluation of soluble CD25 and natural killer cell activity require specialized testing and therefore do not result in real time. Without treatment, prognosis is limited to a few months, and the greatest barrier to survival is delay in diagnosis. Treatment entails identification and treatment of the underlying trigger. With proper treatment and identification of triggering event, survival increases to 54% at 6.2 years [4, 5]. Prognosis is worse with higher ferritin levels, underlying malignancy, older age, and low serum albumin levels [6, 7].
Although rheumatologic disease by itself can be a trigger for HLH, this is rare. Among adults on biological therapies for rheumatologic disease, infection is the most common trigger [8]. Histoplasmosis is a serious fungal infection that is endemic to the Ohio and Mississippi River valleys in the United States, as well as parts of Central and South America. The infective agent, Histoplasma capsulatum, is most likely to be found in soil containing bird or bat droppings. Inhalation of the spores allows them to transform into yeast and travel throughout the lymphatic and vascular system. Pulmonary histoplasmosis can cause pneumonia, mediastinal or hilar masses, pulmonary nodules, cavitary lung disease, and pericarditis. Risk factors for disseminated histoplasmosis include AIDS, immunodeficiency, immunosuppressive medications, and extremes of age. Untreated diffuse histoplasmosis is fatal within weeks, but proper antifungal treatment with amphotericin B or itraconazole increases survival rates dramatically [9].
Cases of HLH secondary to disseminated histoplasmosis are rare and extremely serious. Several case reports in the literature describe patients with AIDS [10–15], malignancy [16], or immunosuppression due to medications [17, 18]. Below we present two cases of patients with HLH secondary to disseminated histoplasmosis, both in the setting of recent immunosuppressive medication for underlying autoimmune disease.
2. Case Report #1
A 66-year-old woman presented to an emergency department near her home in Mexico with fever and abdominal pain of two weeks duration. She also described two months of increased fatigue and malaise, as well as increased swelling around her feet and ankles that had more recently developed. Although she was born in the United States in Oregon, she had been living in Mexico for several years. She denied travel to any other regions. A CT scan demonstrated appendicitis, and she was admitted to a hospital in Mexico for appendectomy. However, over the subsequent five days, she continued to have worsening fevers and abdominal pain. At this point, she flew to Mayo Clinic Arizona for further evaluation.
Her past medical history was significant for rheumatoid arthritis and chronic low back pain. Medications included gabapentin, daily prednisone (20 mg/day), spironolactone, and omeprazole. Following her appendix surgery, she had been placed on moxifloxacin for five days. She had been on methotrexate for several years, but this was discontinued a few months prior due to elevation of liver enzymes.
At the time of presentation, she appeared ill, and her vitals included fluid responsive hypotension, tachypnea with respiratory rate of 22, and mild hypoxia with oxygen saturation 88-95% on room air. Physical exam was significant for bibasilar crackles, abdominal distension, and diffuse tenderness to palpation without peritoneal signs, diffusely tender joints, and erythema over the left elbow and the right knee that was warm to touch. Initial laboratory evaluation demonstrated a hemoglobin of 12.5 g/dL (reference range 12.0–15.5 g/dL), platelet count of 8 × 10(9)/L (reference range 149–375 × 10(9)/L), and white blood cell count (WBC) 2.7 × 10(9)/L (reference range 3.4–10.6 × 10(9)/L) with neutrophilic predominance (absolute neutrophil count (ANC), 2.05 × 10(9)/L (reference range 1.40–6.60 × 10(9)/L)). Electrolyte panel showed hyponatremia 131 mmol/L (reference range 135–145 mmol/L) but was otherwise normal, including creatinine 0.9 mg/dL (reference range 0.6–1.1 mg/dL). LFTs were elevated with alkaline phosphatase 318 U/L (reference range 55–142 U/L), alanine aminotransferase (ALT) 145 U/L (reference range 7–45 U/L), and aspartate aminotransferase (AST) 252 U/L (reference range 9–43 U/L). Most notably, her ferritin was drastically elevated at 27,300 mcg/L (reference range 11–307 mcg/L). Additionally, triglycerides were elevated at 272 mg/dL (reference range < 150 mg/dL), and fibrinogen was reduced at 120 mg/dL (reference range 200–430 mg/dL). Chest X-ray showed trace bilateral pleural effusions and small calcified granulomata in the upper lungs bilaterally. Given her diffusely tender joints, X-ray of the hands were performed and revealed numerous subchondral cysts and erosion, as well as subluxation of the right index finger distal phalanx, with sparing of the metacarpophalangeal joints consistent with rheumatoid arthritis. Due to tachypnea, leukopenia, and hemodynamic instability, she was diagnosed with sepsis.
She initially received broad spectrum antibiotics and underwent paracentesis which was negative for peritonitis. Bacterial and fungal cultures of the ascitic fluid showed no growth. Her significantly elevated ferritin prompted a bone marrow biopsy (BMB), which showed features of hemophagocytic lymphohistiocytosis (Figure 1(a)). Given her findings of pancytopenia, elevated ferritin and triglycerides, reduced fibrinogen, and evidence of hemophagocytosis on BMB, she was treated with high-dose steroids and intravenous fluids. After initiation of steroids, her thrombocytopenia and joint pain improved. However, her WBC count continued to drop, and the patient continued to spike fevers; thus, antibiotics were adjusted to cover for neutropenic fever. Without an identified infectious source, a CT of the brain, chest, abdomen, and pelvis was performed which showed bilateral pulmonary infiltrates but was otherwise unremarkable. Liver biopsy was considered but was deemed unsafe due to coagulopathy. Her respiratory status declined eventually requiring high-flow oxygen due to acute respiratory distress syndrome (ARDS) (Figure 1(b)), and she was treated with aggressive diuresis. Initially, she had adequate response but ultimately developed oliguria and renal failure.
On hospital day four, the ferritin had improved to 609 mcg/L (reference range 11–307 mcg/L); however, LFTs continued to rise, and resultant coagulopathy required daily cryoprecipitate transfusion to maintain safe fibrinogen levels. Due to worsening clinical status with multiorgan failure including the liver, kidney, respiratory, and bone marrow, it was decided to add etoposide for more aggressive treatment of HLH. Despite these efforts, her ferritin rapidly climbed to over 80,000 mcg/L (reference range 11–307 mcg/L). Infectious workup to date was negative including blood bacterial and fungal cultures, ascites bacterial and fungal cultures, and blood tests for HIV, HHV-6, EBV DNA, hepatitis A and E IgM, parvovirus B19, adenovirus, and tuberculosis quantiferon.
Infectious etiology was identified when her urine histoplasmosis antigen returned positive above the upper detectable limit. The bone marrow biopsy was stained for histoplasmosis and confirmed disseminated infection (Figure 1(c)). Amphotericin therapy was initiated as the patient began CRRT for worsening kidney failure. Over the next eight days, however, she did not show any clinical improvement and was treated supportively for ICU delirium, respiratory failure, anuria requiring intermittent hemodialysis, worsening coagulopathy and rising ammonia, and malnutrition requiring tube feeds. On day twelve, voriconazole was added for additional antifungal coverage.
Unfortunately, despite these efforts, the patient's blood counts continued to decline, and she developed massive melena on hospital day 13 with a hemoglobin of 4 g/dL (reference range 12.0–15.5 g/dL), WBC 0.1/L (reference range 3.4–10.6 × 10(9)/L), ANC 0.11/L (reference range 1.40–6.60 × 10(9)/L), and platelets 41/L (reference range 149–375 × 10(9)/L). At this point, the patient and her power of attorney elected to withdraw aggressive treatments, and she was transferred to inpatient hospice.
3. Case Report #2
A 41-year-old woman residing in Arizona with a history of ulcerative colitis from who was on Remicade up until one month earlier was admitted three times over a course of a month with a variety of symptoms without identifying etiology. Initially, she had nonspecific fevers, headache, neck pain, fatigue, nausea, vomiting, and arthralgias. She was found to have an edematous gallbladder (Figure 2(a)) and mild splenomegaly, with a negative infectious workup. With symptomatic care, her fevers were controlled, and she was discharged with a diagnosis of presumed viral syndrome versus Remicade toxicity. However, symptoms worsened, and she represented with fever, sepsis, cholestatic jaundice, acute kidney injury, pancytopenia, and multiple metabolic abnormalities requiring admission to the intensive care unit. Initially, she underwent ERCP with sphincterotomy, and common bile duct stent was placed. On endoscopy, the duodenal mucosa was noted to be friable, biopsy revealed reactive gastropathy, and H. pylori testing was negative. She then underwent laparoscopic cholecystectomy for acalculous cholecystitis. Postoperatively, she developed bloody secretions from the endotracheal tube followed by ARDS; thus, she was unable to be extubated. She also had episodes of epistaxis and melena through this time. Her clinical status quickly deteriorated to multiorgan failure including renal failure requiring dialysis, cholestatic liver failure, respiratory failure requiring mechanical ventilation, and critical pancytopenia requiring high-volume transfusions including 17 units of packed red blood cells, 17 units of platelets, and 6 units of cryoprecipitate.
Workup through this point revealed a markedly elevated ferritin of 73,469 mcg/L (reference range 11–307 mcg/L), elevated lactate dehydrogenase of 2,375 U/L (reference range 122–222 U/L), hypofibrinogenemia of 135 mg/dL (reference range 200-430 mg/dL), and hypertriglyceridemia 2,259 mg/dL (reference range < 150 mg/dL), raising suspicion for HLH. Bone marrow biopsy confirmed the diagnosis (Figures 2(b)–2(d)), and she was initiated on high-dose steroids and etoposide. She developed a severe diffuse rash to etoposide necessitating its discontinuation. Investigation for an underlying trigger included bronchoalveolar lavage (BAL) culture which returned positive for Histoplasma capsulatum, in addition to positive histoplasma urinary antigen. During the same hospitalization, she additionally underwent cholecystectomy, and cultured gallbladder tissue ultimately grew H. capsulatum. Based on history, this was likely acquired in the setting of prior Remicade use while exploring bat caves in Cancun, Mexico, two weeks prior to admission. The patient was born and lived in Arizona until her presentation and denied travel to any endemic areas. Her Aspergillus antigen was also positive from BAL, but this was felt to be a false positive as Aspergillus antigen testing cross-reacts with Histoplasma.
For treatment of disseminated histoplasmosis, she received intravenous AmBisome starting on day 4 of hospitalization and later transitioned to oral itraconazole. With these treatments, she recovered well and was eventually transferred out of the intensive care unit on day 18. She required one dose of Neupogen for leukopenia, but her white blood cell count recovered thereafter, and platelet count returned to normal. Her ferritin had dramatically decreased to 1,568 mcg/L (reference range 11–307 mcg/L). Her kidney and liver function recovered to the point where she could be safely discharged to acute rehabilitation after an approximately four weeks stay in the hospital. She continued to improve during a two-week rehabilitation stay and was then discharged home with an oral steroid taper and oral itraconazole for one year following diagnosis.
4. Discussion
The diagnosis and treatment of acquired HLH in adults are serious and challenging, as the clinical presentation can be fairly nonspecific and diagnosis is based on a collection of both clinical and laboratory abnormalities. In pediatric patients with familial HLH, an elevated ferritin greater than 10,000 μg/L is highly sensitive and specific for diagnosis [19]. In adults, however, elevated ferritin has been linked to various conditions including malignancy, liver dysfunction, infection, anemia of chronic disease, or iron overload [20]. Markedly elevated ferritin, however, is thought to be more specific for adult onset stills disease, macrophage activation syndrome, and HLH. In a retrospective study [20] of patients with ferritin levels greater than 50,000 μg/L, 19% were found to have HLH. The most frequently seen diagnosis in these patients was renal failure (73%), liver injury (61%), infections (52%), and hematologic malignancies (36%). No ferritin cut off level was found to be specific for HLH in this study. Currently, ferritin > 500 μg/L is included in the diagnostic criteria for HLH, although many prefer to use >3000 μg/L. Given the lack of specific criteria for diagnosis of adult acquired HLH, a scoring system which includes the above mentioned diagnostic criteria for HLH was developed and has been shown to be 90% sensitive and 79% specific, although specificity decreases as patients become less stable [21]. Once the diagnosis is confirmed, treatment must be initiated immediately. Additionally, a search must be undertaken to find an underlying trigger for HLH; as without treating the source, there is little chance for clinical improvement.
Here, we present two cases of HLH secondary to disseminated histoplasmosis. Previously, published cases of histoplasmosis associated HLH were reported in HIV [22], hematologic malignancy [16], and transplant patients on immunosuppression [18, 22]. Disseminated histoplasmosis by itself is also quite serious but generally treatable with antifungal therapy. Current IDSA guidelines for moderate to severe disease include liposomal amphotericin B (3.0 mg/kg daily) for 1-2 weeks, followed with oral itraconazole for at least 12 months [9]. Patients who have both disseminated histoplasmosis and HLH portend a worse prognosis. In a retrospective review of eleven cases of histoplasmosis associated HLH, 45% died within 30 days, and 63% died within 90 days [22]. The main challenge of caring for patients with histoplasmosis associated HLH is management of the multiorgan failure that can result from this combination of diseases. Both HLH and histoplasmosis can cause hematologic abnormalities, namely, pancytopenia, and both patients presented here required large volume transfusions. In addition, both patients developed respiratory failure from ARDS, renal failure requiring renal replacement therapy, liver failure, and gastrointestinal bleeding. Disseminated histoplasmosis involving the gastrointestinal system can cause cholecystitis and appendicitis leading to surgery, as well as melena and gastritis, which were seen in these cases.
The main risk factors for disseminated histoplasmosis leading to HLH in these cases were immunosuppressive medication (methotrexate and infliximab) and environmental exposure (bird or bat droppings, especially in caves). Interestingly, in both cases, the offending medication had been discontinued due to laboratory abnormalities 1-2 months prior to any presenting symptoms. It is unclear whether this may have been a risk factor for disease. Nevertheless, with a presentation of diffuse infectious symptoms without an identified etiology in the context of recent immunosuppressive medication, an exhaustive history and laboratory inquiry should be pursued to avoid delayed diagnosis for serious conditions such as disseminated fungal infection and HLH.
Data Availability
No datasets were used.
Conflicts of Interest
No authors have conflict of interest to disclose.
Authors' Contributions
All authors included have made substantial contributions to conception, design, data acquisition, drafting, and/or revising of the manuscript. All authors have read and approved the submission of this manuscript.
Figure 1 (a) Bone marrow aspirate reveals evidence of hemophagocytosis. (b) Chest X-ray reveals evidence of bilateral infiltrates, and patient then diagnosed with ARDS. (c) Bone marrow core biopsy GMS stain reveals histoplasmosis.
Figure 2 (a) CT abdomen on admission reveals edematous gallbladder which was later found to have evidence of Histoplasma capsulatum. (b, c) Bone marrow aspirate reveals hemophagocytosis. (d) GMS stain of bone marrow core biopsy positive for histoplasmosis. | Not recovered | ReactionOutcome | CC BY | 33552603 | 18,986,270 | 2021 |
What was the outcome of reaction 'Drug ineffective'? | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis in Rheumatologic Disease.
Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections.
Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.
1. Background
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune overactivation that can lead to tissue destruction and organ failure. As a primary disorder, it is typically seen in pediatrics and has several associated genetic mutations [1]. In adults, it presents as a secondary phenomenon, seen in conjunction with infection, malignancy, immunodeficiency, or another immune dysregulating event. The diagnosis is established by meeting five of eight criteria, including fever greater than 38.5 degrees Celsius; splenomegaly; peripheral cytopenia (at least two of hemoglobin < 9 g/dL, platelets < 100, 000/microL, absolute neutrophil count < 1000/microL); hypertriglyceridemia (fasting > 265 mg/dL) or hypofibrinogenemia (<150 mg/dL); hemophagocytosis in the bone marrow, spleen, lymph node, or liver; decreased natural killer cell activity; ferritin > 500 ng/mL; and elevated soluble CD25 (IL-2 receptor α) two standard deviations above age-adjusted norms [2, 3]. Laboratory evaluation of soluble CD25 and natural killer cell activity require specialized testing and therefore do not result in real time. Without treatment, prognosis is limited to a few months, and the greatest barrier to survival is delay in diagnosis. Treatment entails identification and treatment of the underlying trigger. With proper treatment and identification of triggering event, survival increases to 54% at 6.2 years [4, 5]. Prognosis is worse with higher ferritin levels, underlying malignancy, older age, and low serum albumin levels [6, 7].
Although rheumatologic disease by itself can be a trigger for HLH, this is rare. Among adults on biological therapies for rheumatologic disease, infection is the most common trigger [8]. Histoplasmosis is a serious fungal infection that is endemic to the Ohio and Mississippi River valleys in the United States, as well as parts of Central and South America. The infective agent, Histoplasma capsulatum, is most likely to be found in soil containing bird or bat droppings. Inhalation of the spores allows them to transform into yeast and travel throughout the lymphatic and vascular system. Pulmonary histoplasmosis can cause pneumonia, mediastinal or hilar masses, pulmonary nodules, cavitary lung disease, and pericarditis. Risk factors for disseminated histoplasmosis include AIDS, immunodeficiency, immunosuppressive medications, and extremes of age. Untreated diffuse histoplasmosis is fatal within weeks, but proper antifungal treatment with amphotericin B or itraconazole increases survival rates dramatically [9].
Cases of HLH secondary to disseminated histoplasmosis are rare and extremely serious. Several case reports in the literature describe patients with AIDS [10–15], malignancy [16], or immunosuppression due to medications [17, 18]. Below we present two cases of patients with HLH secondary to disseminated histoplasmosis, both in the setting of recent immunosuppressive medication for underlying autoimmune disease.
2. Case Report #1
A 66-year-old woman presented to an emergency department near her home in Mexico with fever and abdominal pain of two weeks duration. She also described two months of increased fatigue and malaise, as well as increased swelling around her feet and ankles that had more recently developed. Although she was born in the United States in Oregon, she had been living in Mexico for several years. She denied travel to any other regions. A CT scan demonstrated appendicitis, and she was admitted to a hospital in Mexico for appendectomy. However, over the subsequent five days, she continued to have worsening fevers and abdominal pain. At this point, she flew to Mayo Clinic Arizona for further evaluation.
Her past medical history was significant for rheumatoid arthritis and chronic low back pain. Medications included gabapentin, daily prednisone (20 mg/day), spironolactone, and omeprazole. Following her appendix surgery, she had been placed on moxifloxacin for five days. She had been on methotrexate for several years, but this was discontinued a few months prior due to elevation of liver enzymes.
At the time of presentation, she appeared ill, and her vitals included fluid responsive hypotension, tachypnea with respiratory rate of 22, and mild hypoxia with oxygen saturation 88-95% on room air. Physical exam was significant for bibasilar crackles, abdominal distension, and diffuse tenderness to palpation without peritoneal signs, diffusely tender joints, and erythema over the left elbow and the right knee that was warm to touch. Initial laboratory evaluation demonstrated a hemoglobin of 12.5 g/dL (reference range 12.0–15.5 g/dL), platelet count of 8 × 10(9)/L (reference range 149–375 × 10(9)/L), and white blood cell count (WBC) 2.7 × 10(9)/L (reference range 3.4–10.6 × 10(9)/L) with neutrophilic predominance (absolute neutrophil count (ANC), 2.05 × 10(9)/L (reference range 1.40–6.60 × 10(9)/L)). Electrolyte panel showed hyponatremia 131 mmol/L (reference range 135–145 mmol/L) but was otherwise normal, including creatinine 0.9 mg/dL (reference range 0.6–1.1 mg/dL). LFTs were elevated with alkaline phosphatase 318 U/L (reference range 55–142 U/L), alanine aminotransferase (ALT) 145 U/L (reference range 7–45 U/L), and aspartate aminotransferase (AST) 252 U/L (reference range 9–43 U/L). Most notably, her ferritin was drastically elevated at 27,300 mcg/L (reference range 11–307 mcg/L). Additionally, triglycerides were elevated at 272 mg/dL (reference range < 150 mg/dL), and fibrinogen was reduced at 120 mg/dL (reference range 200–430 mg/dL). Chest X-ray showed trace bilateral pleural effusions and small calcified granulomata in the upper lungs bilaterally. Given her diffusely tender joints, X-ray of the hands were performed and revealed numerous subchondral cysts and erosion, as well as subluxation of the right index finger distal phalanx, with sparing of the metacarpophalangeal joints consistent with rheumatoid arthritis. Due to tachypnea, leukopenia, and hemodynamic instability, she was diagnosed with sepsis.
She initially received broad spectrum antibiotics and underwent paracentesis which was negative for peritonitis. Bacterial and fungal cultures of the ascitic fluid showed no growth. Her significantly elevated ferritin prompted a bone marrow biopsy (BMB), which showed features of hemophagocytic lymphohistiocytosis (Figure 1(a)). Given her findings of pancytopenia, elevated ferritin and triglycerides, reduced fibrinogen, and evidence of hemophagocytosis on BMB, she was treated with high-dose steroids and intravenous fluids. After initiation of steroids, her thrombocytopenia and joint pain improved. However, her WBC count continued to drop, and the patient continued to spike fevers; thus, antibiotics were adjusted to cover for neutropenic fever. Without an identified infectious source, a CT of the brain, chest, abdomen, and pelvis was performed which showed bilateral pulmonary infiltrates but was otherwise unremarkable. Liver biopsy was considered but was deemed unsafe due to coagulopathy. Her respiratory status declined eventually requiring high-flow oxygen due to acute respiratory distress syndrome (ARDS) (Figure 1(b)), and she was treated with aggressive diuresis. Initially, she had adequate response but ultimately developed oliguria and renal failure.
On hospital day four, the ferritin had improved to 609 mcg/L (reference range 11–307 mcg/L); however, LFTs continued to rise, and resultant coagulopathy required daily cryoprecipitate transfusion to maintain safe fibrinogen levels. Due to worsening clinical status with multiorgan failure including the liver, kidney, respiratory, and bone marrow, it was decided to add etoposide for more aggressive treatment of HLH. Despite these efforts, her ferritin rapidly climbed to over 80,000 mcg/L (reference range 11–307 mcg/L). Infectious workup to date was negative including blood bacterial and fungal cultures, ascites bacterial and fungal cultures, and blood tests for HIV, HHV-6, EBV DNA, hepatitis A and E IgM, parvovirus B19, adenovirus, and tuberculosis quantiferon.
Infectious etiology was identified when her urine histoplasmosis antigen returned positive above the upper detectable limit. The bone marrow biopsy was stained for histoplasmosis and confirmed disseminated infection (Figure 1(c)). Amphotericin therapy was initiated as the patient began CRRT for worsening kidney failure. Over the next eight days, however, she did not show any clinical improvement and was treated supportively for ICU delirium, respiratory failure, anuria requiring intermittent hemodialysis, worsening coagulopathy and rising ammonia, and malnutrition requiring tube feeds. On day twelve, voriconazole was added for additional antifungal coverage.
Unfortunately, despite these efforts, the patient's blood counts continued to decline, and she developed massive melena on hospital day 13 with a hemoglobin of 4 g/dL (reference range 12.0–15.5 g/dL), WBC 0.1/L (reference range 3.4–10.6 × 10(9)/L), ANC 0.11/L (reference range 1.40–6.60 × 10(9)/L), and platelets 41/L (reference range 149–375 × 10(9)/L). At this point, the patient and her power of attorney elected to withdraw aggressive treatments, and she was transferred to inpatient hospice.
3. Case Report #2
A 41-year-old woman residing in Arizona with a history of ulcerative colitis from who was on Remicade up until one month earlier was admitted three times over a course of a month with a variety of symptoms without identifying etiology. Initially, she had nonspecific fevers, headache, neck pain, fatigue, nausea, vomiting, and arthralgias. She was found to have an edematous gallbladder (Figure 2(a)) and mild splenomegaly, with a negative infectious workup. With symptomatic care, her fevers were controlled, and she was discharged with a diagnosis of presumed viral syndrome versus Remicade toxicity. However, symptoms worsened, and she represented with fever, sepsis, cholestatic jaundice, acute kidney injury, pancytopenia, and multiple metabolic abnormalities requiring admission to the intensive care unit. Initially, she underwent ERCP with sphincterotomy, and common bile duct stent was placed. On endoscopy, the duodenal mucosa was noted to be friable, biopsy revealed reactive gastropathy, and H. pylori testing was negative. She then underwent laparoscopic cholecystectomy for acalculous cholecystitis. Postoperatively, she developed bloody secretions from the endotracheal tube followed by ARDS; thus, she was unable to be extubated. She also had episodes of epistaxis and melena through this time. Her clinical status quickly deteriorated to multiorgan failure including renal failure requiring dialysis, cholestatic liver failure, respiratory failure requiring mechanical ventilation, and critical pancytopenia requiring high-volume transfusions including 17 units of packed red blood cells, 17 units of platelets, and 6 units of cryoprecipitate.
Workup through this point revealed a markedly elevated ferritin of 73,469 mcg/L (reference range 11–307 mcg/L), elevated lactate dehydrogenase of 2,375 U/L (reference range 122–222 U/L), hypofibrinogenemia of 135 mg/dL (reference range 200-430 mg/dL), and hypertriglyceridemia 2,259 mg/dL (reference range < 150 mg/dL), raising suspicion for HLH. Bone marrow biopsy confirmed the diagnosis (Figures 2(b)–2(d)), and she was initiated on high-dose steroids and etoposide. She developed a severe diffuse rash to etoposide necessitating its discontinuation. Investigation for an underlying trigger included bronchoalveolar lavage (BAL) culture which returned positive for Histoplasma capsulatum, in addition to positive histoplasma urinary antigen. During the same hospitalization, she additionally underwent cholecystectomy, and cultured gallbladder tissue ultimately grew H. capsulatum. Based on history, this was likely acquired in the setting of prior Remicade use while exploring bat caves in Cancun, Mexico, two weeks prior to admission. The patient was born and lived in Arizona until her presentation and denied travel to any endemic areas. Her Aspergillus antigen was also positive from BAL, but this was felt to be a false positive as Aspergillus antigen testing cross-reacts with Histoplasma.
For treatment of disseminated histoplasmosis, she received intravenous AmBisome starting on day 4 of hospitalization and later transitioned to oral itraconazole. With these treatments, she recovered well and was eventually transferred out of the intensive care unit on day 18. She required one dose of Neupogen for leukopenia, but her white blood cell count recovered thereafter, and platelet count returned to normal. Her ferritin had dramatically decreased to 1,568 mcg/L (reference range 11–307 mcg/L). Her kidney and liver function recovered to the point where she could be safely discharged to acute rehabilitation after an approximately four weeks stay in the hospital. She continued to improve during a two-week rehabilitation stay and was then discharged home with an oral steroid taper and oral itraconazole for one year following diagnosis.
4. Discussion
The diagnosis and treatment of acquired HLH in adults are serious and challenging, as the clinical presentation can be fairly nonspecific and diagnosis is based on a collection of both clinical and laboratory abnormalities. In pediatric patients with familial HLH, an elevated ferritin greater than 10,000 μg/L is highly sensitive and specific for diagnosis [19]. In adults, however, elevated ferritin has been linked to various conditions including malignancy, liver dysfunction, infection, anemia of chronic disease, or iron overload [20]. Markedly elevated ferritin, however, is thought to be more specific for adult onset stills disease, macrophage activation syndrome, and HLH. In a retrospective study [20] of patients with ferritin levels greater than 50,000 μg/L, 19% were found to have HLH. The most frequently seen diagnosis in these patients was renal failure (73%), liver injury (61%), infections (52%), and hematologic malignancies (36%). No ferritin cut off level was found to be specific for HLH in this study. Currently, ferritin > 500 μg/L is included in the diagnostic criteria for HLH, although many prefer to use >3000 μg/L. Given the lack of specific criteria for diagnosis of adult acquired HLH, a scoring system which includes the above mentioned diagnostic criteria for HLH was developed and has been shown to be 90% sensitive and 79% specific, although specificity decreases as patients become less stable [21]. Once the diagnosis is confirmed, treatment must be initiated immediately. Additionally, a search must be undertaken to find an underlying trigger for HLH; as without treating the source, there is little chance for clinical improvement.
Here, we present two cases of HLH secondary to disseminated histoplasmosis. Previously, published cases of histoplasmosis associated HLH were reported in HIV [22], hematologic malignancy [16], and transplant patients on immunosuppression [18, 22]. Disseminated histoplasmosis by itself is also quite serious but generally treatable with antifungal therapy. Current IDSA guidelines for moderate to severe disease include liposomal amphotericin B (3.0 mg/kg daily) for 1-2 weeks, followed with oral itraconazole for at least 12 months [9]. Patients who have both disseminated histoplasmosis and HLH portend a worse prognosis. In a retrospective review of eleven cases of histoplasmosis associated HLH, 45% died within 30 days, and 63% died within 90 days [22]. The main challenge of caring for patients with histoplasmosis associated HLH is management of the multiorgan failure that can result from this combination of diseases. Both HLH and histoplasmosis can cause hematologic abnormalities, namely, pancytopenia, and both patients presented here required large volume transfusions. In addition, both patients developed respiratory failure from ARDS, renal failure requiring renal replacement therapy, liver failure, and gastrointestinal bleeding. Disseminated histoplasmosis involving the gastrointestinal system can cause cholecystitis and appendicitis leading to surgery, as well as melena and gastritis, which were seen in these cases.
The main risk factors for disseminated histoplasmosis leading to HLH in these cases were immunosuppressive medication (methotrexate and infliximab) and environmental exposure (bird or bat droppings, especially in caves). Interestingly, in both cases, the offending medication had been discontinued due to laboratory abnormalities 1-2 months prior to any presenting symptoms. It is unclear whether this may have been a risk factor for disease. Nevertheless, with a presentation of diffuse infectious symptoms without an identified etiology in the context of recent immunosuppressive medication, an exhaustive history and laboratory inquiry should be pursued to avoid delayed diagnosis for serious conditions such as disseminated fungal infection and HLH.
Data Availability
No datasets were used.
Conflicts of Interest
No authors have conflict of interest to disclose.
Authors' Contributions
All authors included have made substantial contributions to conception, design, data acquisition, drafting, and/or revising of the manuscript. All authors have read and approved the submission of this manuscript.
Figure 1 (a) Bone marrow aspirate reveals evidence of hemophagocytosis. (b) Chest X-ray reveals evidence of bilateral infiltrates, and patient then diagnosed with ARDS. (c) Bone marrow core biopsy GMS stain reveals histoplasmosis.
Figure 2 (a) CT abdomen on admission reveals edematous gallbladder which was later found to have evidence of Histoplasma capsulatum. (b, c) Bone marrow aspirate reveals hemophagocytosis. (d) GMS stain of bone marrow core biopsy positive for histoplasmosis. | Not recovered | ReactionOutcome | CC BY | 33552603 | 19,036,089 | 2021 |
What was the outcome of reaction 'Haemodynamic instability'? | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis in Rheumatologic Disease.
Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections.
Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.
1. Background
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune overactivation that can lead to tissue destruction and organ failure. As a primary disorder, it is typically seen in pediatrics and has several associated genetic mutations [1]. In adults, it presents as a secondary phenomenon, seen in conjunction with infection, malignancy, immunodeficiency, or another immune dysregulating event. The diagnosis is established by meeting five of eight criteria, including fever greater than 38.5 degrees Celsius; splenomegaly; peripheral cytopenia (at least two of hemoglobin < 9 g/dL, platelets < 100, 000/microL, absolute neutrophil count < 1000/microL); hypertriglyceridemia (fasting > 265 mg/dL) or hypofibrinogenemia (<150 mg/dL); hemophagocytosis in the bone marrow, spleen, lymph node, or liver; decreased natural killer cell activity; ferritin > 500 ng/mL; and elevated soluble CD25 (IL-2 receptor α) two standard deviations above age-adjusted norms [2, 3]. Laboratory evaluation of soluble CD25 and natural killer cell activity require specialized testing and therefore do not result in real time. Without treatment, prognosis is limited to a few months, and the greatest barrier to survival is delay in diagnosis. Treatment entails identification and treatment of the underlying trigger. With proper treatment and identification of triggering event, survival increases to 54% at 6.2 years [4, 5]. Prognosis is worse with higher ferritin levels, underlying malignancy, older age, and low serum albumin levels [6, 7].
Although rheumatologic disease by itself can be a trigger for HLH, this is rare. Among adults on biological therapies for rheumatologic disease, infection is the most common trigger [8]. Histoplasmosis is a serious fungal infection that is endemic to the Ohio and Mississippi River valleys in the United States, as well as parts of Central and South America. The infective agent, Histoplasma capsulatum, is most likely to be found in soil containing bird or bat droppings. Inhalation of the spores allows them to transform into yeast and travel throughout the lymphatic and vascular system. Pulmonary histoplasmosis can cause pneumonia, mediastinal or hilar masses, pulmonary nodules, cavitary lung disease, and pericarditis. Risk factors for disseminated histoplasmosis include AIDS, immunodeficiency, immunosuppressive medications, and extremes of age. Untreated diffuse histoplasmosis is fatal within weeks, but proper antifungal treatment with amphotericin B or itraconazole increases survival rates dramatically [9].
Cases of HLH secondary to disseminated histoplasmosis are rare and extremely serious. Several case reports in the literature describe patients with AIDS [10–15], malignancy [16], or immunosuppression due to medications [17, 18]. Below we present two cases of patients with HLH secondary to disseminated histoplasmosis, both in the setting of recent immunosuppressive medication for underlying autoimmune disease.
2. Case Report #1
A 66-year-old woman presented to an emergency department near her home in Mexico with fever and abdominal pain of two weeks duration. She also described two months of increased fatigue and malaise, as well as increased swelling around her feet and ankles that had more recently developed. Although she was born in the United States in Oregon, she had been living in Mexico for several years. She denied travel to any other regions. A CT scan demonstrated appendicitis, and she was admitted to a hospital in Mexico for appendectomy. However, over the subsequent five days, she continued to have worsening fevers and abdominal pain. At this point, she flew to Mayo Clinic Arizona for further evaluation.
Her past medical history was significant for rheumatoid arthritis and chronic low back pain. Medications included gabapentin, daily prednisone (20 mg/day), spironolactone, and omeprazole. Following her appendix surgery, she had been placed on moxifloxacin for five days. She had been on methotrexate for several years, but this was discontinued a few months prior due to elevation of liver enzymes.
At the time of presentation, she appeared ill, and her vitals included fluid responsive hypotension, tachypnea with respiratory rate of 22, and mild hypoxia with oxygen saturation 88-95% on room air. Physical exam was significant for bibasilar crackles, abdominal distension, and diffuse tenderness to palpation without peritoneal signs, diffusely tender joints, and erythema over the left elbow and the right knee that was warm to touch. Initial laboratory evaluation demonstrated a hemoglobin of 12.5 g/dL (reference range 12.0–15.5 g/dL), platelet count of 8 × 10(9)/L (reference range 149–375 × 10(9)/L), and white blood cell count (WBC) 2.7 × 10(9)/L (reference range 3.4–10.6 × 10(9)/L) with neutrophilic predominance (absolute neutrophil count (ANC), 2.05 × 10(9)/L (reference range 1.40–6.60 × 10(9)/L)). Electrolyte panel showed hyponatremia 131 mmol/L (reference range 135–145 mmol/L) but was otherwise normal, including creatinine 0.9 mg/dL (reference range 0.6–1.1 mg/dL). LFTs were elevated with alkaline phosphatase 318 U/L (reference range 55–142 U/L), alanine aminotransferase (ALT) 145 U/L (reference range 7–45 U/L), and aspartate aminotransferase (AST) 252 U/L (reference range 9–43 U/L). Most notably, her ferritin was drastically elevated at 27,300 mcg/L (reference range 11–307 mcg/L). Additionally, triglycerides were elevated at 272 mg/dL (reference range < 150 mg/dL), and fibrinogen was reduced at 120 mg/dL (reference range 200–430 mg/dL). Chest X-ray showed trace bilateral pleural effusions and small calcified granulomata in the upper lungs bilaterally. Given her diffusely tender joints, X-ray of the hands were performed and revealed numerous subchondral cysts and erosion, as well as subluxation of the right index finger distal phalanx, with sparing of the metacarpophalangeal joints consistent with rheumatoid arthritis. Due to tachypnea, leukopenia, and hemodynamic instability, she was diagnosed with sepsis.
She initially received broad spectrum antibiotics and underwent paracentesis which was negative for peritonitis. Bacterial and fungal cultures of the ascitic fluid showed no growth. Her significantly elevated ferritin prompted a bone marrow biopsy (BMB), which showed features of hemophagocytic lymphohistiocytosis (Figure 1(a)). Given her findings of pancytopenia, elevated ferritin and triglycerides, reduced fibrinogen, and evidence of hemophagocytosis on BMB, she was treated with high-dose steroids and intravenous fluids. After initiation of steroids, her thrombocytopenia and joint pain improved. However, her WBC count continued to drop, and the patient continued to spike fevers; thus, antibiotics were adjusted to cover for neutropenic fever. Without an identified infectious source, a CT of the brain, chest, abdomen, and pelvis was performed which showed bilateral pulmonary infiltrates but was otherwise unremarkable. Liver biopsy was considered but was deemed unsafe due to coagulopathy. Her respiratory status declined eventually requiring high-flow oxygen due to acute respiratory distress syndrome (ARDS) (Figure 1(b)), and she was treated with aggressive diuresis. Initially, she had adequate response but ultimately developed oliguria and renal failure.
On hospital day four, the ferritin had improved to 609 mcg/L (reference range 11–307 mcg/L); however, LFTs continued to rise, and resultant coagulopathy required daily cryoprecipitate transfusion to maintain safe fibrinogen levels. Due to worsening clinical status with multiorgan failure including the liver, kidney, respiratory, and bone marrow, it was decided to add etoposide for more aggressive treatment of HLH. Despite these efforts, her ferritin rapidly climbed to over 80,000 mcg/L (reference range 11–307 mcg/L). Infectious workup to date was negative including blood bacterial and fungal cultures, ascites bacterial and fungal cultures, and blood tests for HIV, HHV-6, EBV DNA, hepatitis A and E IgM, parvovirus B19, adenovirus, and tuberculosis quantiferon.
Infectious etiology was identified when her urine histoplasmosis antigen returned positive above the upper detectable limit. The bone marrow biopsy was stained for histoplasmosis and confirmed disseminated infection (Figure 1(c)). Amphotericin therapy was initiated as the patient began CRRT for worsening kidney failure. Over the next eight days, however, she did not show any clinical improvement and was treated supportively for ICU delirium, respiratory failure, anuria requiring intermittent hemodialysis, worsening coagulopathy and rising ammonia, and malnutrition requiring tube feeds. On day twelve, voriconazole was added for additional antifungal coverage.
Unfortunately, despite these efforts, the patient's blood counts continued to decline, and she developed massive melena on hospital day 13 with a hemoglobin of 4 g/dL (reference range 12.0–15.5 g/dL), WBC 0.1/L (reference range 3.4–10.6 × 10(9)/L), ANC 0.11/L (reference range 1.40–6.60 × 10(9)/L), and platelets 41/L (reference range 149–375 × 10(9)/L). At this point, the patient and her power of attorney elected to withdraw aggressive treatments, and she was transferred to inpatient hospice.
3. Case Report #2
A 41-year-old woman residing in Arizona with a history of ulcerative colitis from who was on Remicade up until one month earlier was admitted three times over a course of a month with a variety of symptoms without identifying etiology. Initially, she had nonspecific fevers, headache, neck pain, fatigue, nausea, vomiting, and arthralgias. She was found to have an edematous gallbladder (Figure 2(a)) and mild splenomegaly, with a negative infectious workup. With symptomatic care, her fevers were controlled, and she was discharged with a diagnosis of presumed viral syndrome versus Remicade toxicity. However, symptoms worsened, and she represented with fever, sepsis, cholestatic jaundice, acute kidney injury, pancytopenia, and multiple metabolic abnormalities requiring admission to the intensive care unit. Initially, she underwent ERCP with sphincterotomy, and common bile duct stent was placed. On endoscopy, the duodenal mucosa was noted to be friable, biopsy revealed reactive gastropathy, and H. pylori testing was negative. She then underwent laparoscopic cholecystectomy for acalculous cholecystitis. Postoperatively, she developed bloody secretions from the endotracheal tube followed by ARDS; thus, she was unable to be extubated. She also had episodes of epistaxis and melena through this time. Her clinical status quickly deteriorated to multiorgan failure including renal failure requiring dialysis, cholestatic liver failure, respiratory failure requiring mechanical ventilation, and critical pancytopenia requiring high-volume transfusions including 17 units of packed red blood cells, 17 units of platelets, and 6 units of cryoprecipitate.
Workup through this point revealed a markedly elevated ferritin of 73,469 mcg/L (reference range 11–307 mcg/L), elevated lactate dehydrogenase of 2,375 U/L (reference range 122–222 U/L), hypofibrinogenemia of 135 mg/dL (reference range 200-430 mg/dL), and hypertriglyceridemia 2,259 mg/dL (reference range < 150 mg/dL), raising suspicion for HLH. Bone marrow biopsy confirmed the diagnosis (Figures 2(b)–2(d)), and she was initiated on high-dose steroids and etoposide. She developed a severe diffuse rash to etoposide necessitating its discontinuation. Investigation for an underlying trigger included bronchoalveolar lavage (BAL) culture which returned positive for Histoplasma capsulatum, in addition to positive histoplasma urinary antigen. During the same hospitalization, she additionally underwent cholecystectomy, and cultured gallbladder tissue ultimately grew H. capsulatum. Based on history, this was likely acquired in the setting of prior Remicade use while exploring bat caves in Cancun, Mexico, two weeks prior to admission. The patient was born and lived in Arizona until her presentation and denied travel to any endemic areas. Her Aspergillus antigen was also positive from BAL, but this was felt to be a false positive as Aspergillus antigen testing cross-reacts with Histoplasma.
For treatment of disseminated histoplasmosis, she received intravenous AmBisome starting on day 4 of hospitalization and later transitioned to oral itraconazole. With these treatments, she recovered well and was eventually transferred out of the intensive care unit on day 18. She required one dose of Neupogen for leukopenia, but her white blood cell count recovered thereafter, and platelet count returned to normal. Her ferritin had dramatically decreased to 1,568 mcg/L (reference range 11–307 mcg/L). Her kidney and liver function recovered to the point where she could be safely discharged to acute rehabilitation after an approximately four weeks stay in the hospital. She continued to improve during a two-week rehabilitation stay and was then discharged home with an oral steroid taper and oral itraconazole for one year following diagnosis.
4. Discussion
The diagnosis and treatment of acquired HLH in adults are serious and challenging, as the clinical presentation can be fairly nonspecific and diagnosis is based on a collection of both clinical and laboratory abnormalities. In pediatric patients with familial HLH, an elevated ferritin greater than 10,000 μg/L is highly sensitive and specific for diagnosis [19]. In adults, however, elevated ferritin has been linked to various conditions including malignancy, liver dysfunction, infection, anemia of chronic disease, or iron overload [20]. Markedly elevated ferritin, however, is thought to be more specific for adult onset stills disease, macrophage activation syndrome, and HLH. In a retrospective study [20] of patients with ferritin levels greater than 50,000 μg/L, 19% were found to have HLH. The most frequently seen diagnosis in these patients was renal failure (73%), liver injury (61%), infections (52%), and hematologic malignancies (36%). No ferritin cut off level was found to be specific for HLH in this study. Currently, ferritin > 500 μg/L is included in the diagnostic criteria for HLH, although many prefer to use >3000 μg/L. Given the lack of specific criteria for diagnosis of adult acquired HLH, a scoring system which includes the above mentioned diagnostic criteria for HLH was developed and has been shown to be 90% sensitive and 79% specific, although specificity decreases as patients become less stable [21]. Once the diagnosis is confirmed, treatment must be initiated immediately. Additionally, a search must be undertaken to find an underlying trigger for HLH; as without treating the source, there is little chance for clinical improvement.
Here, we present two cases of HLH secondary to disseminated histoplasmosis. Previously, published cases of histoplasmosis associated HLH were reported in HIV [22], hematologic malignancy [16], and transplant patients on immunosuppression [18, 22]. Disseminated histoplasmosis by itself is also quite serious but generally treatable with antifungal therapy. Current IDSA guidelines for moderate to severe disease include liposomal amphotericin B (3.0 mg/kg daily) for 1-2 weeks, followed with oral itraconazole for at least 12 months [9]. Patients who have both disseminated histoplasmosis and HLH portend a worse prognosis. In a retrospective review of eleven cases of histoplasmosis associated HLH, 45% died within 30 days, and 63% died within 90 days [22]. The main challenge of caring for patients with histoplasmosis associated HLH is management of the multiorgan failure that can result from this combination of diseases. Both HLH and histoplasmosis can cause hematologic abnormalities, namely, pancytopenia, and both patients presented here required large volume transfusions. In addition, both patients developed respiratory failure from ARDS, renal failure requiring renal replacement therapy, liver failure, and gastrointestinal bleeding. Disseminated histoplasmosis involving the gastrointestinal system can cause cholecystitis and appendicitis leading to surgery, as well as melena and gastritis, which were seen in these cases.
The main risk factors for disseminated histoplasmosis leading to HLH in these cases were immunosuppressive medication (methotrexate and infliximab) and environmental exposure (bird or bat droppings, especially in caves). Interestingly, in both cases, the offending medication had been discontinued due to laboratory abnormalities 1-2 months prior to any presenting symptoms. It is unclear whether this may have been a risk factor for disease. Nevertheless, with a presentation of diffuse infectious symptoms without an identified etiology in the context of recent immunosuppressive medication, an exhaustive history and laboratory inquiry should be pursued to avoid delayed diagnosis for serious conditions such as disseminated fungal infection and HLH.
Data Availability
No datasets were used.
Conflicts of Interest
No authors have conflict of interest to disclose.
Authors' Contributions
All authors included have made substantial contributions to conception, design, data acquisition, drafting, and/or revising of the manuscript. All authors have read and approved the submission of this manuscript.
Figure 1 (a) Bone marrow aspirate reveals evidence of hemophagocytosis. (b) Chest X-ray reveals evidence of bilateral infiltrates, and patient then diagnosed with ARDS. (c) Bone marrow core biopsy GMS stain reveals histoplasmosis.
Figure 2 (a) CT abdomen on admission reveals edematous gallbladder which was later found to have evidence of Histoplasma capsulatum. (b, c) Bone marrow aspirate reveals hemophagocytosis. (d) GMS stain of bone marrow core biopsy positive for histoplasmosis. | Not recovered | ReactionOutcome | CC BY | 33552603 | 19,036,089 | 2021 |
What was the outcome of reaction 'Haemoglobin decreased'? | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis in Rheumatologic Disease.
Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections.
Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.
1. Background
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune overactivation that can lead to tissue destruction and organ failure. As a primary disorder, it is typically seen in pediatrics and has several associated genetic mutations [1]. In adults, it presents as a secondary phenomenon, seen in conjunction with infection, malignancy, immunodeficiency, or another immune dysregulating event. The diagnosis is established by meeting five of eight criteria, including fever greater than 38.5 degrees Celsius; splenomegaly; peripheral cytopenia (at least two of hemoglobin < 9 g/dL, platelets < 100, 000/microL, absolute neutrophil count < 1000/microL); hypertriglyceridemia (fasting > 265 mg/dL) or hypofibrinogenemia (<150 mg/dL); hemophagocytosis in the bone marrow, spleen, lymph node, or liver; decreased natural killer cell activity; ferritin > 500 ng/mL; and elevated soluble CD25 (IL-2 receptor α) two standard deviations above age-adjusted norms [2, 3]. Laboratory evaluation of soluble CD25 and natural killer cell activity require specialized testing and therefore do not result in real time. Without treatment, prognosis is limited to a few months, and the greatest barrier to survival is delay in diagnosis. Treatment entails identification and treatment of the underlying trigger. With proper treatment and identification of triggering event, survival increases to 54% at 6.2 years [4, 5]. Prognosis is worse with higher ferritin levels, underlying malignancy, older age, and low serum albumin levels [6, 7].
Although rheumatologic disease by itself can be a trigger for HLH, this is rare. Among adults on biological therapies for rheumatologic disease, infection is the most common trigger [8]. Histoplasmosis is a serious fungal infection that is endemic to the Ohio and Mississippi River valleys in the United States, as well as parts of Central and South America. The infective agent, Histoplasma capsulatum, is most likely to be found in soil containing bird or bat droppings. Inhalation of the spores allows them to transform into yeast and travel throughout the lymphatic and vascular system. Pulmonary histoplasmosis can cause pneumonia, mediastinal or hilar masses, pulmonary nodules, cavitary lung disease, and pericarditis. Risk factors for disseminated histoplasmosis include AIDS, immunodeficiency, immunosuppressive medications, and extremes of age. Untreated diffuse histoplasmosis is fatal within weeks, but proper antifungal treatment with amphotericin B or itraconazole increases survival rates dramatically [9].
Cases of HLH secondary to disseminated histoplasmosis are rare and extremely serious. Several case reports in the literature describe patients with AIDS [10–15], malignancy [16], or immunosuppression due to medications [17, 18]. Below we present two cases of patients with HLH secondary to disseminated histoplasmosis, both in the setting of recent immunosuppressive medication for underlying autoimmune disease.
2. Case Report #1
A 66-year-old woman presented to an emergency department near her home in Mexico with fever and abdominal pain of two weeks duration. She also described two months of increased fatigue and malaise, as well as increased swelling around her feet and ankles that had more recently developed. Although she was born in the United States in Oregon, she had been living in Mexico for several years. She denied travel to any other regions. A CT scan demonstrated appendicitis, and she was admitted to a hospital in Mexico for appendectomy. However, over the subsequent five days, she continued to have worsening fevers and abdominal pain. At this point, she flew to Mayo Clinic Arizona for further evaluation.
Her past medical history was significant for rheumatoid arthritis and chronic low back pain. Medications included gabapentin, daily prednisone (20 mg/day), spironolactone, and omeprazole. Following her appendix surgery, she had been placed on moxifloxacin for five days. She had been on methotrexate for several years, but this was discontinued a few months prior due to elevation of liver enzymes.
At the time of presentation, she appeared ill, and her vitals included fluid responsive hypotension, tachypnea with respiratory rate of 22, and mild hypoxia with oxygen saturation 88-95% on room air. Physical exam was significant for bibasilar crackles, abdominal distension, and diffuse tenderness to palpation without peritoneal signs, diffusely tender joints, and erythema over the left elbow and the right knee that was warm to touch. Initial laboratory evaluation demonstrated a hemoglobin of 12.5 g/dL (reference range 12.0–15.5 g/dL), platelet count of 8 × 10(9)/L (reference range 149–375 × 10(9)/L), and white blood cell count (WBC) 2.7 × 10(9)/L (reference range 3.4–10.6 × 10(9)/L) with neutrophilic predominance (absolute neutrophil count (ANC), 2.05 × 10(9)/L (reference range 1.40–6.60 × 10(9)/L)). Electrolyte panel showed hyponatremia 131 mmol/L (reference range 135–145 mmol/L) but was otherwise normal, including creatinine 0.9 mg/dL (reference range 0.6–1.1 mg/dL). LFTs were elevated with alkaline phosphatase 318 U/L (reference range 55–142 U/L), alanine aminotransferase (ALT) 145 U/L (reference range 7–45 U/L), and aspartate aminotransferase (AST) 252 U/L (reference range 9–43 U/L). Most notably, her ferritin was drastically elevated at 27,300 mcg/L (reference range 11–307 mcg/L). Additionally, triglycerides were elevated at 272 mg/dL (reference range < 150 mg/dL), and fibrinogen was reduced at 120 mg/dL (reference range 200–430 mg/dL). Chest X-ray showed trace bilateral pleural effusions and small calcified granulomata in the upper lungs bilaterally. Given her diffusely tender joints, X-ray of the hands were performed and revealed numerous subchondral cysts and erosion, as well as subluxation of the right index finger distal phalanx, with sparing of the metacarpophalangeal joints consistent with rheumatoid arthritis. Due to tachypnea, leukopenia, and hemodynamic instability, she was diagnosed with sepsis.
She initially received broad spectrum antibiotics and underwent paracentesis which was negative for peritonitis. Bacterial and fungal cultures of the ascitic fluid showed no growth. Her significantly elevated ferritin prompted a bone marrow biopsy (BMB), which showed features of hemophagocytic lymphohistiocytosis (Figure 1(a)). Given her findings of pancytopenia, elevated ferritin and triglycerides, reduced fibrinogen, and evidence of hemophagocytosis on BMB, she was treated with high-dose steroids and intravenous fluids. After initiation of steroids, her thrombocytopenia and joint pain improved. However, her WBC count continued to drop, and the patient continued to spike fevers; thus, antibiotics were adjusted to cover for neutropenic fever. Without an identified infectious source, a CT of the brain, chest, abdomen, and pelvis was performed which showed bilateral pulmonary infiltrates but was otherwise unremarkable. Liver biopsy was considered but was deemed unsafe due to coagulopathy. Her respiratory status declined eventually requiring high-flow oxygen due to acute respiratory distress syndrome (ARDS) (Figure 1(b)), and she was treated with aggressive diuresis. Initially, she had adequate response but ultimately developed oliguria and renal failure.
On hospital day four, the ferritin had improved to 609 mcg/L (reference range 11–307 mcg/L); however, LFTs continued to rise, and resultant coagulopathy required daily cryoprecipitate transfusion to maintain safe fibrinogen levels. Due to worsening clinical status with multiorgan failure including the liver, kidney, respiratory, and bone marrow, it was decided to add etoposide for more aggressive treatment of HLH. Despite these efforts, her ferritin rapidly climbed to over 80,000 mcg/L (reference range 11–307 mcg/L). Infectious workup to date was negative including blood bacterial and fungal cultures, ascites bacterial and fungal cultures, and blood tests for HIV, HHV-6, EBV DNA, hepatitis A and E IgM, parvovirus B19, adenovirus, and tuberculosis quantiferon.
Infectious etiology was identified when her urine histoplasmosis antigen returned positive above the upper detectable limit. The bone marrow biopsy was stained for histoplasmosis and confirmed disseminated infection (Figure 1(c)). Amphotericin therapy was initiated as the patient began CRRT for worsening kidney failure. Over the next eight days, however, she did not show any clinical improvement and was treated supportively for ICU delirium, respiratory failure, anuria requiring intermittent hemodialysis, worsening coagulopathy and rising ammonia, and malnutrition requiring tube feeds. On day twelve, voriconazole was added for additional antifungal coverage.
Unfortunately, despite these efforts, the patient's blood counts continued to decline, and she developed massive melena on hospital day 13 with a hemoglobin of 4 g/dL (reference range 12.0–15.5 g/dL), WBC 0.1/L (reference range 3.4–10.6 × 10(9)/L), ANC 0.11/L (reference range 1.40–6.60 × 10(9)/L), and platelets 41/L (reference range 149–375 × 10(9)/L). At this point, the patient and her power of attorney elected to withdraw aggressive treatments, and she was transferred to inpatient hospice.
3. Case Report #2
A 41-year-old woman residing in Arizona with a history of ulcerative colitis from who was on Remicade up until one month earlier was admitted three times over a course of a month with a variety of symptoms without identifying etiology. Initially, she had nonspecific fevers, headache, neck pain, fatigue, nausea, vomiting, and arthralgias. She was found to have an edematous gallbladder (Figure 2(a)) and mild splenomegaly, with a negative infectious workup. With symptomatic care, her fevers were controlled, and she was discharged with a diagnosis of presumed viral syndrome versus Remicade toxicity. However, symptoms worsened, and she represented with fever, sepsis, cholestatic jaundice, acute kidney injury, pancytopenia, and multiple metabolic abnormalities requiring admission to the intensive care unit. Initially, she underwent ERCP with sphincterotomy, and common bile duct stent was placed. On endoscopy, the duodenal mucosa was noted to be friable, biopsy revealed reactive gastropathy, and H. pylori testing was negative. She then underwent laparoscopic cholecystectomy for acalculous cholecystitis. Postoperatively, she developed bloody secretions from the endotracheal tube followed by ARDS; thus, she was unable to be extubated. She also had episodes of epistaxis and melena through this time. Her clinical status quickly deteriorated to multiorgan failure including renal failure requiring dialysis, cholestatic liver failure, respiratory failure requiring mechanical ventilation, and critical pancytopenia requiring high-volume transfusions including 17 units of packed red blood cells, 17 units of platelets, and 6 units of cryoprecipitate.
Workup through this point revealed a markedly elevated ferritin of 73,469 mcg/L (reference range 11–307 mcg/L), elevated lactate dehydrogenase of 2,375 U/L (reference range 122–222 U/L), hypofibrinogenemia of 135 mg/dL (reference range 200-430 mg/dL), and hypertriglyceridemia 2,259 mg/dL (reference range < 150 mg/dL), raising suspicion for HLH. Bone marrow biopsy confirmed the diagnosis (Figures 2(b)–2(d)), and she was initiated on high-dose steroids and etoposide. She developed a severe diffuse rash to etoposide necessitating its discontinuation. Investigation for an underlying trigger included bronchoalveolar lavage (BAL) culture which returned positive for Histoplasma capsulatum, in addition to positive histoplasma urinary antigen. During the same hospitalization, she additionally underwent cholecystectomy, and cultured gallbladder tissue ultimately grew H. capsulatum. Based on history, this was likely acquired in the setting of prior Remicade use while exploring bat caves in Cancun, Mexico, two weeks prior to admission. The patient was born and lived in Arizona until her presentation and denied travel to any endemic areas. Her Aspergillus antigen was also positive from BAL, but this was felt to be a false positive as Aspergillus antigen testing cross-reacts with Histoplasma.
For treatment of disseminated histoplasmosis, she received intravenous AmBisome starting on day 4 of hospitalization and later transitioned to oral itraconazole. With these treatments, she recovered well and was eventually transferred out of the intensive care unit on day 18. She required one dose of Neupogen for leukopenia, but her white blood cell count recovered thereafter, and platelet count returned to normal. Her ferritin had dramatically decreased to 1,568 mcg/L (reference range 11–307 mcg/L). Her kidney and liver function recovered to the point where she could be safely discharged to acute rehabilitation after an approximately four weeks stay in the hospital. She continued to improve during a two-week rehabilitation stay and was then discharged home with an oral steroid taper and oral itraconazole for one year following diagnosis.
4. Discussion
The diagnosis and treatment of acquired HLH in adults are serious and challenging, as the clinical presentation can be fairly nonspecific and diagnosis is based on a collection of both clinical and laboratory abnormalities. In pediatric patients with familial HLH, an elevated ferritin greater than 10,000 μg/L is highly sensitive and specific for diagnosis [19]. In adults, however, elevated ferritin has been linked to various conditions including malignancy, liver dysfunction, infection, anemia of chronic disease, or iron overload [20]. Markedly elevated ferritin, however, is thought to be more specific for adult onset stills disease, macrophage activation syndrome, and HLH. In a retrospective study [20] of patients with ferritin levels greater than 50,000 μg/L, 19% were found to have HLH. The most frequently seen diagnosis in these patients was renal failure (73%), liver injury (61%), infections (52%), and hematologic malignancies (36%). No ferritin cut off level was found to be specific for HLH in this study. Currently, ferritin > 500 μg/L is included in the diagnostic criteria for HLH, although many prefer to use >3000 μg/L. Given the lack of specific criteria for diagnosis of adult acquired HLH, a scoring system which includes the above mentioned diagnostic criteria for HLH was developed and has been shown to be 90% sensitive and 79% specific, although specificity decreases as patients become less stable [21]. Once the diagnosis is confirmed, treatment must be initiated immediately. Additionally, a search must be undertaken to find an underlying trigger for HLH; as without treating the source, there is little chance for clinical improvement.
Here, we present two cases of HLH secondary to disseminated histoplasmosis. Previously, published cases of histoplasmosis associated HLH were reported in HIV [22], hematologic malignancy [16], and transplant patients on immunosuppression [18, 22]. Disseminated histoplasmosis by itself is also quite serious but generally treatable with antifungal therapy. Current IDSA guidelines for moderate to severe disease include liposomal amphotericin B (3.0 mg/kg daily) for 1-2 weeks, followed with oral itraconazole for at least 12 months [9]. Patients who have both disseminated histoplasmosis and HLH portend a worse prognosis. In a retrospective review of eleven cases of histoplasmosis associated HLH, 45% died within 30 days, and 63% died within 90 days [22]. The main challenge of caring for patients with histoplasmosis associated HLH is management of the multiorgan failure that can result from this combination of diseases. Both HLH and histoplasmosis can cause hematologic abnormalities, namely, pancytopenia, and both patients presented here required large volume transfusions. In addition, both patients developed respiratory failure from ARDS, renal failure requiring renal replacement therapy, liver failure, and gastrointestinal bleeding. Disseminated histoplasmosis involving the gastrointestinal system can cause cholecystitis and appendicitis leading to surgery, as well as melena and gastritis, which were seen in these cases.
The main risk factors for disseminated histoplasmosis leading to HLH in these cases were immunosuppressive medication (methotrexate and infliximab) and environmental exposure (bird or bat droppings, especially in caves). Interestingly, in both cases, the offending medication had been discontinued due to laboratory abnormalities 1-2 months prior to any presenting symptoms. It is unclear whether this may have been a risk factor for disease. Nevertheless, with a presentation of diffuse infectious symptoms without an identified etiology in the context of recent immunosuppressive medication, an exhaustive history and laboratory inquiry should be pursued to avoid delayed diagnosis for serious conditions such as disseminated fungal infection and HLH.
Data Availability
No datasets were used.
Conflicts of Interest
No authors have conflict of interest to disclose.
Authors' Contributions
All authors included have made substantial contributions to conception, design, data acquisition, drafting, and/or revising of the manuscript. All authors have read and approved the submission of this manuscript.
Figure 1 (a) Bone marrow aspirate reveals evidence of hemophagocytosis. (b) Chest X-ray reveals evidence of bilateral infiltrates, and patient then diagnosed with ARDS. (c) Bone marrow core biopsy GMS stain reveals histoplasmosis.
Figure 2 (a) CT abdomen on admission reveals edematous gallbladder which was later found to have evidence of Histoplasma capsulatum. (b, c) Bone marrow aspirate reveals hemophagocytosis. (d) GMS stain of bone marrow core biopsy positive for histoplasmosis. | Not recovered | ReactionOutcome | CC BY | 33552603 | 19,036,089 | 2021 |
What was the outcome of reaction 'Malnutrition'? | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis in Rheumatologic Disease.
Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections.
Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.
1. Background
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune overactivation that can lead to tissue destruction and organ failure. As a primary disorder, it is typically seen in pediatrics and has several associated genetic mutations [1]. In adults, it presents as a secondary phenomenon, seen in conjunction with infection, malignancy, immunodeficiency, or another immune dysregulating event. The diagnosis is established by meeting five of eight criteria, including fever greater than 38.5 degrees Celsius; splenomegaly; peripheral cytopenia (at least two of hemoglobin < 9 g/dL, platelets < 100, 000/microL, absolute neutrophil count < 1000/microL); hypertriglyceridemia (fasting > 265 mg/dL) or hypofibrinogenemia (<150 mg/dL); hemophagocytosis in the bone marrow, spleen, lymph node, or liver; decreased natural killer cell activity; ferritin > 500 ng/mL; and elevated soluble CD25 (IL-2 receptor α) two standard deviations above age-adjusted norms [2, 3]. Laboratory evaluation of soluble CD25 and natural killer cell activity require specialized testing and therefore do not result in real time. Without treatment, prognosis is limited to a few months, and the greatest barrier to survival is delay in diagnosis. Treatment entails identification and treatment of the underlying trigger. With proper treatment and identification of triggering event, survival increases to 54% at 6.2 years [4, 5]. Prognosis is worse with higher ferritin levels, underlying malignancy, older age, and low serum albumin levels [6, 7].
Although rheumatologic disease by itself can be a trigger for HLH, this is rare. Among adults on biological therapies for rheumatologic disease, infection is the most common trigger [8]. Histoplasmosis is a serious fungal infection that is endemic to the Ohio and Mississippi River valleys in the United States, as well as parts of Central and South America. The infective agent, Histoplasma capsulatum, is most likely to be found in soil containing bird or bat droppings. Inhalation of the spores allows them to transform into yeast and travel throughout the lymphatic and vascular system. Pulmonary histoplasmosis can cause pneumonia, mediastinal or hilar masses, pulmonary nodules, cavitary lung disease, and pericarditis. Risk factors for disseminated histoplasmosis include AIDS, immunodeficiency, immunosuppressive medications, and extremes of age. Untreated diffuse histoplasmosis is fatal within weeks, but proper antifungal treatment with amphotericin B or itraconazole increases survival rates dramatically [9].
Cases of HLH secondary to disseminated histoplasmosis are rare and extremely serious. Several case reports in the literature describe patients with AIDS [10–15], malignancy [16], or immunosuppression due to medications [17, 18]. Below we present two cases of patients with HLH secondary to disseminated histoplasmosis, both in the setting of recent immunosuppressive medication for underlying autoimmune disease.
2. Case Report #1
A 66-year-old woman presented to an emergency department near her home in Mexico with fever and abdominal pain of two weeks duration. She also described two months of increased fatigue and malaise, as well as increased swelling around her feet and ankles that had more recently developed. Although she was born in the United States in Oregon, she had been living in Mexico for several years. She denied travel to any other regions. A CT scan demonstrated appendicitis, and she was admitted to a hospital in Mexico for appendectomy. However, over the subsequent five days, she continued to have worsening fevers and abdominal pain. At this point, she flew to Mayo Clinic Arizona for further evaluation.
Her past medical history was significant for rheumatoid arthritis and chronic low back pain. Medications included gabapentin, daily prednisone (20 mg/day), spironolactone, and omeprazole. Following her appendix surgery, she had been placed on moxifloxacin for five days. She had been on methotrexate for several years, but this was discontinued a few months prior due to elevation of liver enzymes.
At the time of presentation, she appeared ill, and her vitals included fluid responsive hypotension, tachypnea with respiratory rate of 22, and mild hypoxia with oxygen saturation 88-95% on room air. Physical exam was significant for bibasilar crackles, abdominal distension, and diffuse tenderness to palpation without peritoneal signs, diffusely tender joints, and erythema over the left elbow and the right knee that was warm to touch. Initial laboratory evaluation demonstrated a hemoglobin of 12.5 g/dL (reference range 12.0–15.5 g/dL), platelet count of 8 × 10(9)/L (reference range 149–375 × 10(9)/L), and white blood cell count (WBC) 2.7 × 10(9)/L (reference range 3.4–10.6 × 10(9)/L) with neutrophilic predominance (absolute neutrophil count (ANC), 2.05 × 10(9)/L (reference range 1.40–6.60 × 10(9)/L)). Electrolyte panel showed hyponatremia 131 mmol/L (reference range 135–145 mmol/L) but was otherwise normal, including creatinine 0.9 mg/dL (reference range 0.6–1.1 mg/dL). LFTs were elevated with alkaline phosphatase 318 U/L (reference range 55–142 U/L), alanine aminotransferase (ALT) 145 U/L (reference range 7–45 U/L), and aspartate aminotransferase (AST) 252 U/L (reference range 9–43 U/L). Most notably, her ferritin was drastically elevated at 27,300 mcg/L (reference range 11–307 mcg/L). Additionally, triglycerides were elevated at 272 mg/dL (reference range < 150 mg/dL), and fibrinogen was reduced at 120 mg/dL (reference range 200–430 mg/dL). Chest X-ray showed trace bilateral pleural effusions and small calcified granulomata in the upper lungs bilaterally. Given her diffusely tender joints, X-ray of the hands were performed and revealed numerous subchondral cysts and erosion, as well as subluxation of the right index finger distal phalanx, with sparing of the metacarpophalangeal joints consistent with rheumatoid arthritis. Due to tachypnea, leukopenia, and hemodynamic instability, she was diagnosed with sepsis.
She initially received broad spectrum antibiotics and underwent paracentesis which was negative for peritonitis. Bacterial and fungal cultures of the ascitic fluid showed no growth. Her significantly elevated ferritin prompted a bone marrow biopsy (BMB), which showed features of hemophagocytic lymphohistiocytosis (Figure 1(a)). Given her findings of pancytopenia, elevated ferritin and triglycerides, reduced fibrinogen, and evidence of hemophagocytosis on BMB, she was treated with high-dose steroids and intravenous fluids. After initiation of steroids, her thrombocytopenia and joint pain improved. However, her WBC count continued to drop, and the patient continued to spike fevers; thus, antibiotics were adjusted to cover for neutropenic fever. Without an identified infectious source, a CT of the brain, chest, abdomen, and pelvis was performed which showed bilateral pulmonary infiltrates but was otherwise unremarkable. Liver biopsy was considered but was deemed unsafe due to coagulopathy. Her respiratory status declined eventually requiring high-flow oxygen due to acute respiratory distress syndrome (ARDS) (Figure 1(b)), and she was treated with aggressive diuresis. Initially, she had adequate response but ultimately developed oliguria and renal failure.
On hospital day four, the ferritin had improved to 609 mcg/L (reference range 11–307 mcg/L); however, LFTs continued to rise, and resultant coagulopathy required daily cryoprecipitate transfusion to maintain safe fibrinogen levels. Due to worsening clinical status with multiorgan failure including the liver, kidney, respiratory, and bone marrow, it was decided to add etoposide for more aggressive treatment of HLH. Despite these efforts, her ferritin rapidly climbed to over 80,000 mcg/L (reference range 11–307 mcg/L). Infectious workup to date was negative including blood bacterial and fungal cultures, ascites bacterial and fungal cultures, and blood tests for HIV, HHV-6, EBV DNA, hepatitis A and E IgM, parvovirus B19, adenovirus, and tuberculosis quantiferon.
Infectious etiology was identified when her urine histoplasmosis antigen returned positive above the upper detectable limit. The bone marrow biopsy was stained for histoplasmosis and confirmed disseminated infection (Figure 1(c)). Amphotericin therapy was initiated as the patient began CRRT for worsening kidney failure. Over the next eight days, however, she did not show any clinical improvement and was treated supportively for ICU delirium, respiratory failure, anuria requiring intermittent hemodialysis, worsening coagulopathy and rising ammonia, and malnutrition requiring tube feeds. On day twelve, voriconazole was added for additional antifungal coverage.
Unfortunately, despite these efforts, the patient's blood counts continued to decline, and she developed massive melena on hospital day 13 with a hemoglobin of 4 g/dL (reference range 12.0–15.5 g/dL), WBC 0.1/L (reference range 3.4–10.6 × 10(9)/L), ANC 0.11/L (reference range 1.40–6.60 × 10(9)/L), and platelets 41/L (reference range 149–375 × 10(9)/L). At this point, the patient and her power of attorney elected to withdraw aggressive treatments, and she was transferred to inpatient hospice.
3. Case Report #2
A 41-year-old woman residing in Arizona with a history of ulcerative colitis from who was on Remicade up until one month earlier was admitted three times over a course of a month with a variety of symptoms without identifying etiology. Initially, she had nonspecific fevers, headache, neck pain, fatigue, nausea, vomiting, and arthralgias. She was found to have an edematous gallbladder (Figure 2(a)) and mild splenomegaly, with a negative infectious workup. With symptomatic care, her fevers were controlled, and she was discharged with a diagnosis of presumed viral syndrome versus Remicade toxicity. However, symptoms worsened, and she represented with fever, sepsis, cholestatic jaundice, acute kidney injury, pancytopenia, and multiple metabolic abnormalities requiring admission to the intensive care unit. Initially, she underwent ERCP with sphincterotomy, and common bile duct stent was placed. On endoscopy, the duodenal mucosa was noted to be friable, biopsy revealed reactive gastropathy, and H. pylori testing was negative. She then underwent laparoscopic cholecystectomy for acalculous cholecystitis. Postoperatively, she developed bloody secretions from the endotracheal tube followed by ARDS; thus, she was unable to be extubated. She also had episodes of epistaxis and melena through this time. Her clinical status quickly deteriorated to multiorgan failure including renal failure requiring dialysis, cholestatic liver failure, respiratory failure requiring mechanical ventilation, and critical pancytopenia requiring high-volume transfusions including 17 units of packed red blood cells, 17 units of platelets, and 6 units of cryoprecipitate.
Workup through this point revealed a markedly elevated ferritin of 73,469 mcg/L (reference range 11–307 mcg/L), elevated lactate dehydrogenase of 2,375 U/L (reference range 122–222 U/L), hypofibrinogenemia of 135 mg/dL (reference range 200-430 mg/dL), and hypertriglyceridemia 2,259 mg/dL (reference range < 150 mg/dL), raising suspicion for HLH. Bone marrow biopsy confirmed the diagnosis (Figures 2(b)–2(d)), and she was initiated on high-dose steroids and etoposide. She developed a severe diffuse rash to etoposide necessitating its discontinuation. Investigation for an underlying trigger included bronchoalveolar lavage (BAL) culture which returned positive for Histoplasma capsulatum, in addition to positive histoplasma urinary antigen. During the same hospitalization, she additionally underwent cholecystectomy, and cultured gallbladder tissue ultimately grew H. capsulatum. Based on history, this was likely acquired in the setting of prior Remicade use while exploring bat caves in Cancun, Mexico, two weeks prior to admission. The patient was born and lived in Arizona until her presentation and denied travel to any endemic areas. Her Aspergillus antigen was also positive from BAL, but this was felt to be a false positive as Aspergillus antigen testing cross-reacts with Histoplasma.
For treatment of disseminated histoplasmosis, she received intravenous AmBisome starting on day 4 of hospitalization and later transitioned to oral itraconazole. With these treatments, she recovered well and was eventually transferred out of the intensive care unit on day 18. She required one dose of Neupogen for leukopenia, but her white blood cell count recovered thereafter, and platelet count returned to normal. Her ferritin had dramatically decreased to 1,568 mcg/L (reference range 11–307 mcg/L). Her kidney and liver function recovered to the point where she could be safely discharged to acute rehabilitation after an approximately four weeks stay in the hospital. She continued to improve during a two-week rehabilitation stay and was then discharged home with an oral steroid taper and oral itraconazole for one year following diagnosis.
4. Discussion
The diagnosis and treatment of acquired HLH in adults are serious and challenging, as the clinical presentation can be fairly nonspecific and diagnosis is based on a collection of both clinical and laboratory abnormalities. In pediatric patients with familial HLH, an elevated ferritin greater than 10,000 μg/L is highly sensitive and specific for diagnosis [19]. In adults, however, elevated ferritin has been linked to various conditions including malignancy, liver dysfunction, infection, anemia of chronic disease, or iron overload [20]. Markedly elevated ferritin, however, is thought to be more specific for adult onset stills disease, macrophage activation syndrome, and HLH. In a retrospective study [20] of patients with ferritin levels greater than 50,000 μg/L, 19% were found to have HLH. The most frequently seen diagnosis in these patients was renal failure (73%), liver injury (61%), infections (52%), and hematologic malignancies (36%). No ferritin cut off level was found to be specific for HLH in this study. Currently, ferritin > 500 μg/L is included in the diagnostic criteria for HLH, although many prefer to use >3000 μg/L. Given the lack of specific criteria for diagnosis of adult acquired HLH, a scoring system which includes the above mentioned diagnostic criteria for HLH was developed and has been shown to be 90% sensitive and 79% specific, although specificity decreases as patients become less stable [21]. Once the diagnosis is confirmed, treatment must be initiated immediately. Additionally, a search must be undertaken to find an underlying trigger for HLH; as without treating the source, there is little chance for clinical improvement.
Here, we present two cases of HLH secondary to disseminated histoplasmosis. Previously, published cases of histoplasmosis associated HLH were reported in HIV [22], hematologic malignancy [16], and transplant patients on immunosuppression [18, 22]. Disseminated histoplasmosis by itself is also quite serious but generally treatable with antifungal therapy. Current IDSA guidelines for moderate to severe disease include liposomal amphotericin B (3.0 mg/kg daily) for 1-2 weeks, followed with oral itraconazole for at least 12 months [9]. Patients who have both disseminated histoplasmosis and HLH portend a worse prognosis. In a retrospective review of eleven cases of histoplasmosis associated HLH, 45% died within 30 days, and 63% died within 90 days [22]. The main challenge of caring for patients with histoplasmosis associated HLH is management of the multiorgan failure that can result from this combination of diseases. Both HLH and histoplasmosis can cause hematologic abnormalities, namely, pancytopenia, and both patients presented here required large volume transfusions. In addition, both patients developed respiratory failure from ARDS, renal failure requiring renal replacement therapy, liver failure, and gastrointestinal bleeding. Disseminated histoplasmosis involving the gastrointestinal system can cause cholecystitis and appendicitis leading to surgery, as well as melena and gastritis, which were seen in these cases.
The main risk factors for disseminated histoplasmosis leading to HLH in these cases were immunosuppressive medication (methotrexate and infliximab) and environmental exposure (bird or bat droppings, especially in caves). Interestingly, in both cases, the offending medication had been discontinued due to laboratory abnormalities 1-2 months prior to any presenting symptoms. It is unclear whether this may have been a risk factor for disease. Nevertheless, with a presentation of diffuse infectious symptoms without an identified etiology in the context of recent immunosuppressive medication, an exhaustive history and laboratory inquiry should be pursued to avoid delayed diagnosis for serious conditions such as disseminated fungal infection and HLH.
Data Availability
No datasets were used.
Conflicts of Interest
No authors have conflict of interest to disclose.
Authors' Contributions
All authors included have made substantial contributions to conception, design, data acquisition, drafting, and/or revising of the manuscript. All authors have read and approved the submission of this manuscript.
Figure 1 (a) Bone marrow aspirate reveals evidence of hemophagocytosis. (b) Chest X-ray reveals evidence of bilateral infiltrates, and patient then diagnosed with ARDS. (c) Bone marrow core biopsy GMS stain reveals histoplasmosis.
Figure 2 (a) CT abdomen on admission reveals edematous gallbladder which was later found to have evidence of Histoplasma capsulatum. (b, c) Bone marrow aspirate reveals hemophagocytosis. (d) GMS stain of bone marrow core biopsy positive for histoplasmosis. | Not recovered | ReactionOutcome | CC BY | 33552603 | 19,036,089 | 2021 |
What was the outcome of reaction 'Melaena'? | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis in Rheumatologic Disease.
Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections.
Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.
1. Background
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune overactivation that can lead to tissue destruction and organ failure. As a primary disorder, it is typically seen in pediatrics and has several associated genetic mutations [1]. In adults, it presents as a secondary phenomenon, seen in conjunction with infection, malignancy, immunodeficiency, or another immune dysregulating event. The diagnosis is established by meeting five of eight criteria, including fever greater than 38.5 degrees Celsius; splenomegaly; peripheral cytopenia (at least two of hemoglobin < 9 g/dL, platelets < 100, 000/microL, absolute neutrophil count < 1000/microL); hypertriglyceridemia (fasting > 265 mg/dL) or hypofibrinogenemia (<150 mg/dL); hemophagocytosis in the bone marrow, spleen, lymph node, or liver; decreased natural killer cell activity; ferritin > 500 ng/mL; and elevated soluble CD25 (IL-2 receptor α) two standard deviations above age-adjusted norms [2, 3]. Laboratory evaluation of soluble CD25 and natural killer cell activity require specialized testing and therefore do not result in real time. Without treatment, prognosis is limited to a few months, and the greatest barrier to survival is delay in diagnosis. Treatment entails identification and treatment of the underlying trigger. With proper treatment and identification of triggering event, survival increases to 54% at 6.2 years [4, 5]. Prognosis is worse with higher ferritin levels, underlying malignancy, older age, and low serum albumin levels [6, 7].
Although rheumatologic disease by itself can be a trigger for HLH, this is rare. Among adults on biological therapies for rheumatologic disease, infection is the most common trigger [8]. Histoplasmosis is a serious fungal infection that is endemic to the Ohio and Mississippi River valleys in the United States, as well as parts of Central and South America. The infective agent, Histoplasma capsulatum, is most likely to be found in soil containing bird or bat droppings. Inhalation of the spores allows them to transform into yeast and travel throughout the lymphatic and vascular system. Pulmonary histoplasmosis can cause pneumonia, mediastinal or hilar masses, pulmonary nodules, cavitary lung disease, and pericarditis. Risk factors for disseminated histoplasmosis include AIDS, immunodeficiency, immunosuppressive medications, and extremes of age. Untreated diffuse histoplasmosis is fatal within weeks, but proper antifungal treatment with amphotericin B or itraconazole increases survival rates dramatically [9].
Cases of HLH secondary to disseminated histoplasmosis are rare and extremely serious. Several case reports in the literature describe patients with AIDS [10–15], malignancy [16], or immunosuppression due to medications [17, 18]. Below we present two cases of patients with HLH secondary to disseminated histoplasmosis, both in the setting of recent immunosuppressive medication for underlying autoimmune disease.
2. Case Report #1
A 66-year-old woman presented to an emergency department near her home in Mexico with fever and abdominal pain of two weeks duration. She also described two months of increased fatigue and malaise, as well as increased swelling around her feet and ankles that had more recently developed. Although she was born in the United States in Oregon, she had been living in Mexico for several years. She denied travel to any other regions. A CT scan demonstrated appendicitis, and she was admitted to a hospital in Mexico for appendectomy. However, over the subsequent five days, she continued to have worsening fevers and abdominal pain. At this point, she flew to Mayo Clinic Arizona for further evaluation.
Her past medical history was significant for rheumatoid arthritis and chronic low back pain. Medications included gabapentin, daily prednisone (20 mg/day), spironolactone, and omeprazole. Following her appendix surgery, she had been placed on moxifloxacin for five days. She had been on methotrexate for several years, but this was discontinued a few months prior due to elevation of liver enzymes.
At the time of presentation, she appeared ill, and her vitals included fluid responsive hypotension, tachypnea with respiratory rate of 22, and mild hypoxia with oxygen saturation 88-95% on room air. Physical exam was significant for bibasilar crackles, abdominal distension, and diffuse tenderness to palpation without peritoneal signs, diffusely tender joints, and erythema over the left elbow and the right knee that was warm to touch. Initial laboratory evaluation demonstrated a hemoglobin of 12.5 g/dL (reference range 12.0–15.5 g/dL), platelet count of 8 × 10(9)/L (reference range 149–375 × 10(9)/L), and white blood cell count (WBC) 2.7 × 10(9)/L (reference range 3.4–10.6 × 10(9)/L) with neutrophilic predominance (absolute neutrophil count (ANC), 2.05 × 10(9)/L (reference range 1.40–6.60 × 10(9)/L)). Electrolyte panel showed hyponatremia 131 mmol/L (reference range 135–145 mmol/L) but was otherwise normal, including creatinine 0.9 mg/dL (reference range 0.6–1.1 mg/dL). LFTs were elevated with alkaline phosphatase 318 U/L (reference range 55–142 U/L), alanine aminotransferase (ALT) 145 U/L (reference range 7–45 U/L), and aspartate aminotransferase (AST) 252 U/L (reference range 9–43 U/L). Most notably, her ferritin was drastically elevated at 27,300 mcg/L (reference range 11–307 mcg/L). Additionally, triglycerides were elevated at 272 mg/dL (reference range < 150 mg/dL), and fibrinogen was reduced at 120 mg/dL (reference range 200–430 mg/dL). Chest X-ray showed trace bilateral pleural effusions and small calcified granulomata in the upper lungs bilaterally. Given her diffusely tender joints, X-ray of the hands were performed and revealed numerous subchondral cysts and erosion, as well as subluxation of the right index finger distal phalanx, with sparing of the metacarpophalangeal joints consistent with rheumatoid arthritis. Due to tachypnea, leukopenia, and hemodynamic instability, she was diagnosed with sepsis.
She initially received broad spectrum antibiotics and underwent paracentesis which was negative for peritonitis. Bacterial and fungal cultures of the ascitic fluid showed no growth. Her significantly elevated ferritin prompted a bone marrow biopsy (BMB), which showed features of hemophagocytic lymphohistiocytosis (Figure 1(a)). Given her findings of pancytopenia, elevated ferritin and triglycerides, reduced fibrinogen, and evidence of hemophagocytosis on BMB, she was treated with high-dose steroids and intravenous fluids. After initiation of steroids, her thrombocytopenia and joint pain improved. However, her WBC count continued to drop, and the patient continued to spike fevers; thus, antibiotics were adjusted to cover for neutropenic fever. Without an identified infectious source, a CT of the brain, chest, abdomen, and pelvis was performed which showed bilateral pulmonary infiltrates but was otherwise unremarkable. Liver biopsy was considered but was deemed unsafe due to coagulopathy. Her respiratory status declined eventually requiring high-flow oxygen due to acute respiratory distress syndrome (ARDS) (Figure 1(b)), and she was treated with aggressive diuresis. Initially, she had adequate response but ultimately developed oliguria and renal failure.
On hospital day four, the ferritin had improved to 609 mcg/L (reference range 11–307 mcg/L); however, LFTs continued to rise, and resultant coagulopathy required daily cryoprecipitate transfusion to maintain safe fibrinogen levels. Due to worsening clinical status with multiorgan failure including the liver, kidney, respiratory, and bone marrow, it was decided to add etoposide for more aggressive treatment of HLH. Despite these efforts, her ferritin rapidly climbed to over 80,000 mcg/L (reference range 11–307 mcg/L). Infectious workup to date was negative including blood bacterial and fungal cultures, ascites bacterial and fungal cultures, and blood tests for HIV, HHV-6, EBV DNA, hepatitis A and E IgM, parvovirus B19, adenovirus, and tuberculosis quantiferon.
Infectious etiology was identified when her urine histoplasmosis antigen returned positive above the upper detectable limit. The bone marrow biopsy was stained for histoplasmosis and confirmed disseminated infection (Figure 1(c)). Amphotericin therapy was initiated as the patient began CRRT for worsening kidney failure. Over the next eight days, however, she did not show any clinical improvement and was treated supportively for ICU delirium, respiratory failure, anuria requiring intermittent hemodialysis, worsening coagulopathy and rising ammonia, and malnutrition requiring tube feeds. On day twelve, voriconazole was added for additional antifungal coverage.
Unfortunately, despite these efforts, the patient's blood counts continued to decline, and she developed massive melena on hospital day 13 with a hemoglobin of 4 g/dL (reference range 12.0–15.5 g/dL), WBC 0.1/L (reference range 3.4–10.6 × 10(9)/L), ANC 0.11/L (reference range 1.40–6.60 × 10(9)/L), and platelets 41/L (reference range 149–375 × 10(9)/L). At this point, the patient and her power of attorney elected to withdraw aggressive treatments, and she was transferred to inpatient hospice.
3. Case Report #2
A 41-year-old woman residing in Arizona with a history of ulcerative colitis from who was on Remicade up until one month earlier was admitted three times over a course of a month with a variety of symptoms without identifying etiology. Initially, she had nonspecific fevers, headache, neck pain, fatigue, nausea, vomiting, and arthralgias. She was found to have an edematous gallbladder (Figure 2(a)) and mild splenomegaly, with a negative infectious workup. With symptomatic care, her fevers were controlled, and she was discharged with a diagnosis of presumed viral syndrome versus Remicade toxicity. However, symptoms worsened, and she represented with fever, sepsis, cholestatic jaundice, acute kidney injury, pancytopenia, and multiple metabolic abnormalities requiring admission to the intensive care unit. Initially, she underwent ERCP with sphincterotomy, and common bile duct stent was placed. On endoscopy, the duodenal mucosa was noted to be friable, biopsy revealed reactive gastropathy, and H. pylori testing was negative. She then underwent laparoscopic cholecystectomy for acalculous cholecystitis. Postoperatively, she developed bloody secretions from the endotracheal tube followed by ARDS; thus, she was unable to be extubated. She also had episodes of epistaxis and melena through this time. Her clinical status quickly deteriorated to multiorgan failure including renal failure requiring dialysis, cholestatic liver failure, respiratory failure requiring mechanical ventilation, and critical pancytopenia requiring high-volume transfusions including 17 units of packed red blood cells, 17 units of platelets, and 6 units of cryoprecipitate.
Workup through this point revealed a markedly elevated ferritin of 73,469 mcg/L (reference range 11–307 mcg/L), elevated lactate dehydrogenase of 2,375 U/L (reference range 122–222 U/L), hypofibrinogenemia of 135 mg/dL (reference range 200-430 mg/dL), and hypertriglyceridemia 2,259 mg/dL (reference range < 150 mg/dL), raising suspicion for HLH. Bone marrow biopsy confirmed the diagnosis (Figures 2(b)–2(d)), and she was initiated on high-dose steroids and etoposide. She developed a severe diffuse rash to etoposide necessitating its discontinuation. Investigation for an underlying trigger included bronchoalveolar lavage (BAL) culture which returned positive for Histoplasma capsulatum, in addition to positive histoplasma urinary antigen. During the same hospitalization, she additionally underwent cholecystectomy, and cultured gallbladder tissue ultimately grew H. capsulatum. Based on history, this was likely acquired in the setting of prior Remicade use while exploring bat caves in Cancun, Mexico, two weeks prior to admission. The patient was born and lived in Arizona until her presentation and denied travel to any endemic areas. Her Aspergillus antigen was also positive from BAL, but this was felt to be a false positive as Aspergillus antigen testing cross-reacts with Histoplasma.
For treatment of disseminated histoplasmosis, she received intravenous AmBisome starting on day 4 of hospitalization and later transitioned to oral itraconazole. With these treatments, she recovered well and was eventually transferred out of the intensive care unit on day 18. She required one dose of Neupogen for leukopenia, but her white blood cell count recovered thereafter, and platelet count returned to normal. Her ferritin had dramatically decreased to 1,568 mcg/L (reference range 11–307 mcg/L). Her kidney and liver function recovered to the point where she could be safely discharged to acute rehabilitation after an approximately four weeks stay in the hospital. She continued to improve during a two-week rehabilitation stay and was then discharged home with an oral steroid taper and oral itraconazole for one year following diagnosis.
4. Discussion
The diagnosis and treatment of acquired HLH in adults are serious and challenging, as the clinical presentation can be fairly nonspecific and diagnosis is based on a collection of both clinical and laboratory abnormalities. In pediatric patients with familial HLH, an elevated ferritin greater than 10,000 μg/L is highly sensitive and specific for diagnosis [19]. In adults, however, elevated ferritin has been linked to various conditions including malignancy, liver dysfunction, infection, anemia of chronic disease, or iron overload [20]. Markedly elevated ferritin, however, is thought to be more specific for adult onset stills disease, macrophage activation syndrome, and HLH. In a retrospective study [20] of patients with ferritin levels greater than 50,000 μg/L, 19% were found to have HLH. The most frequently seen diagnosis in these patients was renal failure (73%), liver injury (61%), infections (52%), and hematologic malignancies (36%). No ferritin cut off level was found to be specific for HLH in this study. Currently, ferritin > 500 μg/L is included in the diagnostic criteria for HLH, although many prefer to use >3000 μg/L. Given the lack of specific criteria for diagnosis of adult acquired HLH, a scoring system which includes the above mentioned diagnostic criteria for HLH was developed and has been shown to be 90% sensitive and 79% specific, although specificity decreases as patients become less stable [21]. Once the diagnosis is confirmed, treatment must be initiated immediately. Additionally, a search must be undertaken to find an underlying trigger for HLH; as without treating the source, there is little chance for clinical improvement.
Here, we present two cases of HLH secondary to disseminated histoplasmosis. Previously, published cases of histoplasmosis associated HLH were reported in HIV [22], hematologic malignancy [16], and transplant patients on immunosuppression [18, 22]. Disseminated histoplasmosis by itself is also quite serious but generally treatable with antifungal therapy. Current IDSA guidelines for moderate to severe disease include liposomal amphotericin B (3.0 mg/kg daily) for 1-2 weeks, followed with oral itraconazole for at least 12 months [9]. Patients who have both disseminated histoplasmosis and HLH portend a worse prognosis. In a retrospective review of eleven cases of histoplasmosis associated HLH, 45% died within 30 days, and 63% died within 90 days [22]. The main challenge of caring for patients with histoplasmosis associated HLH is management of the multiorgan failure that can result from this combination of diseases. Both HLH and histoplasmosis can cause hematologic abnormalities, namely, pancytopenia, and both patients presented here required large volume transfusions. In addition, both patients developed respiratory failure from ARDS, renal failure requiring renal replacement therapy, liver failure, and gastrointestinal bleeding. Disseminated histoplasmosis involving the gastrointestinal system can cause cholecystitis and appendicitis leading to surgery, as well as melena and gastritis, which were seen in these cases.
The main risk factors for disseminated histoplasmosis leading to HLH in these cases were immunosuppressive medication (methotrexate and infliximab) and environmental exposure (bird or bat droppings, especially in caves). Interestingly, in both cases, the offending medication had been discontinued due to laboratory abnormalities 1-2 months prior to any presenting symptoms. It is unclear whether this may have been a risk factor for disease. Nevertheless, with a presentation of diffuse infectious symptoms without an identified etiology in the context of recent immunosuppressive medication, an exhaustive history and laboratory inquiry should be pursued to avoid delayed diagnosis for serious conditions such as disseminated fungal infection and HLH.
Data Availability
No datasets were used.
Conflicts of Interest
No authors have conflict of interest to disclose.
Authors' Contributions
All authors included have made substantial contributions to conception, design, data acquisition, drafting, and/or revising of the manuscript. All authors have read and approved the submission of this manuscript.
Figure 1 (a) Bone marrow aspirate reveals evidence of hemophagocytosis. (b) Chest X-ray reveals evidence of bilateral infiltrates, and patient then diagnosed with ARDS. (c) Bone marrow core biopsy GMS stain reveals histoplasmosis.
Figure 2 (a) CT abdomen on admission reveals edematous gallbladder which was later found to have evidence of Histoplasma capsulatum. (b, c) Bone marrow aspirate reveals hemophagocytosis. (d) GMS stain of bone marrow core biopsy positive for histoplasmosis. | Not recovered | ReactionOutcome | CC BY | 33552603 | 19,036,089 | 2021 |
What was the outcome of reaction 'Multiple organ dysfunction syndrome'? | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis in Rheumatologic Disease.
Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections.
Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.
1. Background
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune overactivation that can lead to tissue destruction and organ failure. As a primary disorder, it is typically seen in pediatrics and has several associated genetic mutations [1]. In adults, it presents as a secondary phenomenon, seen in conjunction with infection, malignancy, immunodeficiency, or another immune dysregulating event. The diagnosis is established by meeting five of eight criteria, including fever greater than 38.5 degrees Celsius; splenomegaly; peripheral cytopenia (at least two of hemoglobin < 9 g/dL, platelets < 100, 000/microL, absolute neutrophil count < 1000/microL); hypertriglyceridemia (fasting > 265 mg/dL) or hypofibrinogenemia (<150 mg/dL); hemophagocytosis in the bone marrow, spleen, lymph node, or liver; decreased natural killer cell activity; ferritin > 500 ng/mL; and elevated soluble CD25 (IL-2 receptor α) two standard deviations above age-adjusted norms [2, 3]. Laboratory evaluation of soluble CD25 and natural killer cell activity require specialized testing and therefore do not result in real time. Without treatment, prognosis is limited to a few months, and the greatest barrier to survival is delay in diagnosis. Treatment entails identification and treatment of the underlying trigger. With proper treatment and identification of triggering event, survival increases to 54% at 6.2 years [4, 5]. Prognosis is worse with higher ferritin levels, underlying malignancy, older age, and low serum albumin levels [6, 7].
Although rheumatologic disease by itself can be a trigger for HLH, this is rare. Among adults on biological therapies for rheumatologic disease, infection is the most common trigger [8]. Histoplasmosis is a serious fungal infection that is endemic to the Ohio and Mississippi River valleys in the United States, as well as parts of Central and South America. The infective agent, Histoplasma capsulatum, is most likely to be found in soil containing bird or bat droppings. Inhalation of the spores allows them to transform into yeast and travel throughout the lymphatic and vascular system. Pulmonary histoplasmosis can cause pneumonia, mediastinal or hilar masses, pulmonary nodules, cavitary lung disease, and pericarditis. Risk factors for disseminated histoplasmosis include AIDS, immunodeficiency, immunosuppressive medications, and extremes of age. Untreated diffuse histoplasmosis is fatal within weeks, but proper antifungal treatment with amphotericin B or itraconazole increases survival rates dramatically [9].
Cases of HLH secondary to disseminated histoplasmosis are rare and extremely serious. Several case reports in the literature describe patients with AIDS [10–15], malignancy [16], or immunosuppression due to medications [17, 18]. Below we present two cases of patients with HLH secondary to disseminated histoplasmosis, both in the setting of recent immunosuppressive medication for underlying autoimmune disease.
2. Case Report #1
A 66-year-old woman presented to an emergency department near her home in Mexico with fever and abdominal pain of two weeks duration. She also described two months of increased fatigue and malaise, as well as increased swelling around her feet and ankles that had more recently developed. Although she was born in the United States in Oregon, she had been living in Mexico for several years. She denied travel to any other regions. A CT scan demonstrated appendicitis, and she was admitted to a hospital in Mexico for appendectomy. However, over the subsequent five days, she continued to have worsening fevers and abdominal pain. At this point, she flew to Mayo Clinic Arizona for further evaluation.
Her past medical history was significant for rheumatoid arthritis and chronic low back pain. Medications included gabapentin, daily prednisone (20 mg/day), spironolactone, and omeprazole. Following her appendix surgery, she had been placed on moxifloxacin for five days. She had been on methotrexate for several years, but this was discontinued a few months prior due to elevation of liver enzymes.
At the time of presentation, she appeared ill, and her vitals included fluid responsive hypotension, tachypnea with respiratory rate of 22, and mild hypoxia with oxygen saturation 88-95% on room air. Physical exam was significant for bibasilar crackles, abdominal distension, and diffuse tenderness to palpation without peritoneal signs, diffusely tender joints, and erythema over the left elbow and the right knee that was warm to touch. Initial laboratory evaluation demonstrated a hemoglobin of 12.5 g/dL (reference range 12.0–15.5 g/dL), platelet count of 8 × 10(9)/L (reference range 149–375 × 10(9)/L), and white blood cell count (WBC) 2.7 × 10(9)/L (reference range 3.4–10.6 × 10(9)/L) with neutrophilic predominance (absolute neutrophil count (ANC), 2.05 × 10(9)/L (reference range 1.40–6.60 × 10(9)/L)). Electrolyte panel showed hyponatremia 131 mmol/L (reference range 135–145 mmol/L) but was otherwise normal, including creatinine 0.9 mg/dL (reference range 0.6–1.1 mg/dL). LFTs were elevated with alkaline phosphatase 318 U/L (reference range 55–142 U/L), alanine aminotransferase (ALT) 145 U/L (reference range 7–45 U/L), and aspartate aminotransferase (AST) 252 U/L (reference range 9–43 U/L). Most notably, her ferritin was drastically elevated at 27,300 mcg/L (reference range 11–307 mcg/L). Additionally, triglycerides were elevated at 272 mg/dL (reference range < 150 mg/dL), and fibrinogen was reduced at 120 mg/dL (reference range 200–430 mg/dL). Chest X-ray showed trace bilateral pleural effusions and small calcified granulomata in the upper lungs bilaterally. Given her diffusely tender joints, X-ray of the hands were performed and revealed numerous subchondral cysts and erosion, as well as subluxation of the right index finger distal phalanx, with sparing of the metacarpophalangeal joints consistent with rheumatoid arthritis. Due to tachypnea, leukopenia, and hemodynamic instability, she was diagnosed with sepsis.
She initially received broad spectrum antibiotics and underwent paracentesis which was negative for peritonitis. Bacterial and fungal cultures of the ascitic fluid showed no growth. Her significantly elevated ferritin prompted a bone marrow biopsy (BMB), which showed features of hemophagocytic lymphohistiocytosis (Figure 1(a)). Given her findings of pancytopenia, elevated ferritin and triglycerides, reduced fibrinogen, and evidence of hemophagocytosis on BMB, she was treated with high-dose steroids and intravenous fluids. After initiation of steroids, her thrombocytopenia and joint pain improved. However, her WBC count continued to drop, and the patient continued to spike fevers; thus, antibiotics were adjusted to cover for neutropenic fever. Without an identified infectious source, a CT of the brain, chest, abdomen, and pelvis was performed which showed bilateral pulmonary infiltrates but was otherwise unremarkable. Liver biopsy was considered but was deemed unsafe due to coagulopathy. Her respiratory status declined eventually requiring high-flow oxygen due to acute respiratory distress syndrome (ARDS) (Figure 1(b)), and she was treated with aggressive diuresis. Initially, she had adequate response but ultimately developed oliguria and renal failure.
On hospital day four, the ferritin had improved to 609 mcg/L (reference range 11–307 mcg/L); however, LFTs continued to rise, and resultant coagulopathy required daily cryoprecipitate transfusion to maintain safe fibrinogen levels. Due to worsening clinical status with multiorgan failure including the liver, kidney, respiratory, and bone marrow, it was decided to add etoposide for more aggressive treatment of HLH. Despite these efforts, her ferritin rapidly climbed to over 80,000 mcg/L (reference range 11–307 mcg/L). Infectious workup to date was negative including blood bacterial and fungal cultures, ascites bacterial and fungal cultures, and blood tests for HIV, HHV-6, EBV DNA, hepatitis A and E IgM, parvovirus B19, adenovirus, and tuberculosis quantiferon.
Infectious etiology was identified when her urine histoplasmosis antigen returned positive above the upper detectable limit. The bone marrow biopsy was stained for histoplasmosis and confirmed disseminated infection (Figure 1(c)). Amphotericin therapy was initiated as the patient began CRRT for worsening kidney failure. Over the next eight days, however, she did not show any clinical improvement and was treated supportively for ICU delirium, respiratory failure, anuria requiring intermittent hemodialysis, worsening coagulopathy and rising ammonia, and malnutrition requiring tube feeds. On day twelve, voriconazole was added for additional antifungal coverage.
Unfortunately, despite these efforts, the patient's blood counts continued to decline, and she developed massive melena on hospital day 13 with a hemoglobin of 4 g/dL (reference range 12.0–15.5 g/dL), WBC 0.1/L (reference range 3.4–10.6 × 10(9)/L), ANC 0.11/L (reference range 1.40–6.60 × 10(9)/L), and platelets 41/L (reference range 149–375 × 10(9)/L). At this point, the patient and her power of attorney elected to withdraw aggressive treatments, and she was transferred to inpatient hospice.
3. Case Report #2
A 41-year-old woman residing in Arizona with a history of ulcerative colitis from who was on Remicade up until one month earlier was admitted three times over a course of a month with a variety of symptoms without identifying etiology. Initially, she had nonspecific fevers, headache, neck pain, fatigue, nausea, vomiting, and arthralgias. She was found to have an edematous gallbladder (Figure 2(a)) and mild splenomegaly, with a negative infectious workup. With symptomatic care, her fevers were controlled, and she was discharged with a diagnosis of presumed viral syndrome versus Remicade toxicity. However, symptoms worsened, and she represented with fever, sepsis, cholestatic jaundice, acute kidney injury, pancytopenia, and multiple metabolic abnormalities requiring admission to the intensive care unit. Initially, she underwent ERCP with sphincterotomy, and common bile duct stent was placed. On endoscopy, the duodenal mucosa was noted to be friable, biopsy revealed reactive gastropathy, and H. pylori testing was negative. She then underwent laparoscopic cholecystectomy for acalculous cholecystitis. Postoperatively, she developed bloody secretions from the endotracheal tube followed by ARDS; thus, she was unable to be extubated. She also had episodes of epistaxis and melena through this time. Her clinical status quickly deteriorated to multiorgan failure including renal failure requiring dialysis, cholestatic liver failure, respiratory failure requiring mechanical ventilation, and critical pancytopenia requiring high-volume transfusions including 17 units of packed red blood cells, 17 units of platelets, and 6 units of cryoprecipitate.
Workup through this point revealed a markedly elevated ferritin of 73,469 mcg/L (reference range 11–307 mcg/L), elevated lactate dehydrogenase of 2,375 U/L (reference range 122–222 U/L), hypofibrinogenemia of 135 mg/dL (reference range 200-430 mg/dL), and hypertriglyceridemia 2,259 mg/dL (reference range < 150 mg/dL), raising suspicion for HLH. Bone marrow biopsy confirmed the diagnosis (Figures 2(b)–2(d)), and she was initiated on high-dose steroids and etoposide. She developed a severe diffuse rash to etoposide necessitating its discontinuation. Investigation for an underlying trigger included bronchoalveolar lavage (BAL) culture which returned positive for Histoplasma capsulatum, in addition to positive histoplasma urinary antigen. During the same hospitalization, she additionally underwent cholecystectomy, and cultured gallbladder tissue ultimately grew H. capsulatum. Based on history, this was likely acquired in the setting of prior Remicade use while exploring bat caves in Cancun, Mexico, two weeks prior to admission. The patient was born and lived in Arizona until her presentation and denied travel to any endemic areas. Her Aspergillus antigen was also positive from BAL, but this was felt to be a false positive as Aspergillus antigen testing cross-reacts with Histoplasma.
For treatment of disseminated histoplasmosis, she received intravenous AmBisome starting on day 4 of hospitalization and later transitioned to oral itraconazole. With these treatments, she recovered well and was eventually transferred out of the intensive care unit on day 18. She required one dose of Neupogen for leukopenia, but her white blood cell count recovered thereafter, and platelet count returned to normal. Her ferritin had dramatically decreased to 1,568 mcg/L (reference range 11–307 mcg/L). Her kidney and liver function recovered to the point where she could be safely discharged to acute rehabilitation after an approximately four weeks stay in the hospital. She continued to improve during a two-week rehabilitation stay and was then discharged home with an oral steroid taper and oral itraconazole for one year following diagnosis.
4. Discussion
The diagnosis and treatment of acquired HLH in adults are serious and challenging, as the clinical presentation can be fairly nonspecific and diagnosis is based on a collection of both clinical and laboratory abnormalities. In pediatric patients with familial HLH, an elevated ferritin greater than 10,000 μg/L is highly sensitive and specific for diagnosis [19]. In adults, however, elevated ferritin has been linked to various conditions including malignancy, liver dysfunction, infection, anemia of chronic disease, or iron overload [20]. Markedly elevated ferritin, however, is thought to be more specific for adult onset stills disease, macrophage activation syndrome, and HLH. In a retrospective study [20] of patients with ferritin levels greater than 50,000 μg/L, 19% were found to have HLH. The most frequently seen diagnosis in these patients was renal failure (73%), liver injury (61%), infections (52%), and hematologic malignancies (36%). No ferritin cut off level was found to be specific for HLH in this study. Currently, ferritin > 500 μg/L is included in the diagnostic criteria for HLH, although many prefer to use >3000 μg/L. Given the lack of specific criteria for diagnosis of adult acquired HLH, a scoring system which includes the above mentioned diagnostic criteria for HLH was developed and has been shown to be 90% sensitive and 79% specific, although specificity decreases as patients become less stable [21]. Once the diagnosis is confirmed, treatment must be initiated immediately. Additionally, a search must be undertaken to find an underlying trigger for HLH; as without treating the source, there is little chance for clinical improvement.
Here, we present two cases of HLH secondary to disseminated histoplasmosis. Previously, published cases of histoplasmosis associated HLH were reported in HIV [22], hematologic malignancy [16], and transplant patients on immunosuppression [18, 22]. Disseminated histoplasmosis by itself is also quite serious but generally treatable with antifungal therapy. Current IDSA guidelines for moderate to severe disease include liposomal amphotericin B (3.0 mg/kg daily) for 1-2 weeks, followed with oral itraconazole for at least 12 months [9]. Patients who have both disseminated histoplasmosis and HLH portend a worse prognosis. In a retrospective review of eleven cases of histoplasmosis associated HLH, 45% died within 30 days, and 63% died within 90 days [22]. The main challenge of caring for patients with histoplasmosis associated HLH is management of the multiorgan failure that can result from this combination of diseases. Both HLH and histoplasmosis can cause hematologic abnormalities, namely, pancytopenia, and both patients presented here required large volume transfusions. In addition, both patients developed respiratory failure from ARDS, renal failure requiring renal replacement therapy, liver failure, and gastrointestinal bleeding. Disseminated histoplasmosis involving the gastrointestinal system can cause cholecystitis and appendicitis leading to surgery, as well as melena and gastritis, which were seen in these cases.
The main risk factors for disseminated histoplasmosis leading to HLH in these cases were immunosuppressive medication (methotrexate and infliximab) and environmental exposure (bird or bat droppings, especially in caves). Interestingly, in both cases, the offending medication had been discontinued due to laboratory abnormalities 1-2 months prior to any presenting symptoms. It is unclear whether this may have been a risk factor for disease. Nevertheless, with a presentation of diffuse infectious symptoms without an identified etiology in the context of recent immunosuppressive medication, an exhaustive history and laboratory inquiry should be pursued to avoid delayed diagnosis for serious conditions such as disseminated fungal infection and HLH.
Data Availability
No datasets were used.
Conflicts of Interest
No authors have conflict of interest to disclose.
Authors' Contributions
All authors included have made substantial contributions to conception, design, data acquisition, drafting, and/or revising of the manuscript. All authors have read and approved the submission of this manuscript.
Figure 1 (a) Bone marrow aspirate reveals evidence of hemophagocytosis. (b) Chest X-ray reveals evidence of bilateral infiltrates, and patient then diagnosed with ARDS. (c) Bone marrow core biopsy GMS stain reveals histoplasmosis.
Figure 2 (a) CT abdomen on admission reveals edematous gallbladder which was later found to have evidence of Histoplasma capsulatum. (b, c) Bone marrow aspirate reveals hemophagocytosis. (d) GMS stain of bone marrow core biopsy positive for histoplasmosis. | Not recovered | ReactionOutcome | CC BY | 33552603 | 19,036,089 | 2021 |
What was the outcome of reaction 'Pancytopenia'? | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis in Rheumatologic Disease.
Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections.
Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.
1. Background
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune overactivation that can lead to tissue destruction and organ failure. As a primary disorder, it is typically seen in pediatrics and has several associated genetic mutations [1]. In adults, it presents as a secondary phenomenon, seen in conjunction with infection, malignancy, immunodeficiency, or another immune dysregulating event. The diagnosis is established by meeting five of eight criteria, including fever greater than 38.5 degrees Celsius; splenomegaly; peripheral cytopenia (at least two of hemoglobin < 9 g/dL, platelets < 100, 000/microL, absolute neutrophil count < 1000/microL); hypertriglyceridemia (fasting > 265 mg/dL) or hypofibrinogenemia (<150 mg/dL); hemophagocytosis in the bone marrow, spleen, lymph node, or liver; decreased natural killer cell activity; ferritin > 500 ng/mL; and elevated soluble CD25 (IL-2 receptor α) two standard deviations above age-adjusted norms [2, 3]. Laboratory evaluation of soluble CD25 and natural killer cell activity require specialized testing and therefore do not result in real time. Without treatment, prognosis is limited to a few months, and the greatest barrier to survival is delay in diagnosis. Treatment entails identification and treatment of the underlying trigger. With proper treatment and identification of triggering event, survival increases to 54% at 6.2 years [4, 5]. Prognosis is worse with higher ferritin levels, underlying malignancy, older age, and low serum albumin levels [6, 7].
Although rheumatologic disease by itself can be a trigger for HLH, this is rare. Among adults on biological therapies for rheumatologic disease, infection is the most common trigger [8]. Histoplasmosis is a serious fungal infection that is endemic to the Ohio and Mississippi River valleys in the United States, as well as parts of Central and South America. The infective agent, Histoplasma capsulatum, is most likely to be found in soil containing bird or bat droppings. Inhalation of the spores allows them to transform into yeast and travel throughout the lymphatic and vascular system. Pulmonary histoplasmosis can cause pneumonia, mediastinal or hilar masses, pulmonary nodules, cavitary lung disease, and pericarditis. Risk factors for disseminated histoplasmosis include AIDS, immunodeficiency, immunosuppressive medications, and extremes of age. Untreated diffuse histoplasmosis is fatal within weeks, but proper antifungal treatment with amphotericin B or itraconazole increases survival rates dramatically [9].
Cases of HLH secondary to disseminated histoplasmosis are rare and extremely serious. Several case reports in the literature describe patients with AIDS [10–15], malignancy [16], or immunosuppression due to medications [17, 18]. Below we present two cases of patients with HLH secondary to disseminated histoplasmosis, both in the setting of recent immunosuppressive medication for underlying autoimmune disease.
2. Case Report #1
A 66-year-old woman presented to an emergency department near her home in Mexico with fever and abdominal pain of two weeks duration. She also described two months of increased fatigue and malaise, as well as increased swelling around her feet and ankles that had more recently developed. Although she was born in the United States in Oregon, she had been living in Mexico for several years. She denied travel to any other regions. A CT scan demonstrated appendicitis, and she was admitted to a hospital in Mexico for appendectomy. However, over the subsequent five days, she continued to have worsening fevers and abdominal pain. At this point, she flew to Mayo Clinic Arizona for further evaluation.
Her past medical history was significant for rheumatoid arthritis and chronic low back pain. Medications included gabapentin, daily prednisone (20 mg/day), spironolactone, and omeprazole. Following her appendix surgery, she had been placed on moxifloxacin for five days. She had been on methotrexate for several years, but this was discontinued a few months prior due to elevation of liver enzymes.
At the time of presentation, she appeared ill, and her vitals included fluid responsive hypotension, tachypnea with respiratory rate of 22, and mild hypoxia with oxygen saturation 88-95% on room air. Physical exam was significant for bibasilar crackles, abdominal distension, and diffuse tenderness to palpation without peritoneal signs, diffusely tender joints, and erythema over the left elbow and the right knee that was warm to touch. Initial laboratory evaluation demonstrated a hemoglobin of 12.5 g/dL (reference range 12.0–15.5 g/dL), platelet count of 8 × 10(9)/L (reference range 149–375 × 10(9)/L), and white blood cell count (WBC) 2.7 × 10(9)/L (reference range 3.4–10.6 × 10(9)/L) with neutrophilic predominance (absolute neutrophil count (ANC), 2.05 × 10(9)/L (reference range 1.40–6.60 × 10(9)/L)). Electrolyte panel showed hyponatremia 131 mmol/L (reference range 135–145 mmol/L) but was otherwise normal, including creatinine 0.9 mg/dL (reference range 0.6–1.1 mg/dL). LFTs were elevated with alkaline phosphatase 318 U/L (reference range 55–142 U/L), alanine aminotransferase (ALT) 145 U/L (reference range 7–45 U/L), and aspartate aminotransferase (AST) 252 U/L (reference range 9–43 U/L). Most notably, her ferritin was drastically elevated at 27,300 mcg/L (reference range 11–307 mcg/L). Additionally, triglycerides were elevated at 272 mg/dL (reference range < 150 mg/dL), and fibrinogen was reduced at 120 mg/dL (reference range 200–430 mg/dL). Chest X-ray showed trace bilateral pleural effusions and small calcified granulomata in the upper lungs bilaterally. Given her diffusely tender joints, X-ray of the hands were performed and revealed numerous subchondral cysts and erosion, as well as subluxation of the right index finger distal phalanx, with sparing of the metacarpophalangeal joints consistent with rheumatoid arthritis. Due to tachypnea, leukopenia, and hemodynamic instability, she was diagnosed with sepsis.
She initially received broad spectrum antibiotics and underwent paracentesis which was negative for peritonitis. Bacterial and fungal cultures of the ascitic fluid showed no growth. Her significantly elevated ferritin prompted a bone marrow biopsy (BMB), which showed features of hemophagocytic lymphohistiocytosis (Figure 1(a)). Given her findings of pancytopenia, elevated ferritin and triglycerides, reduced fibrinogen, and evidence of hemophagocytosis on BMB, she was treated with high-dose steroids and intravenous fluids. After initiation of steroids, her thrombocytopenia and joint pain improved. However, her WBC count continued to drop, and the patient continued to spike fevers; thus, antibiotics were adjusted to cover for neutropenic fever. Without an identified infectious source, a CT of the brain, chest, abdomen, and pelvis was performed which showed bilateral pulmonary infiltrates but was otherwise unremarkable. Liver biopsy was considered but was deemed unsafe due to coagulopathy. Her respiratory status declined eventually requiring high-flow oxygen due to acute respiratory distress syndrome (ARDS) (Figure 1(b)), and she was treated with aggressive diuresis. Initially, she had adequate response but ultimately developed oliguria and renal failure.
On hospital day four, the ferritin had improved to 609 mcg/L (reference range 11–307 mcg/L); however, LFTs continued to rise, and resultant coagulopathy required daily cryoprecipitate transfusion to maintain safe fibrinogen levels. Due to worsening clinical status with multiorgan failure including the liver, kidney, respiratory, and bone marrow, it was decided to add etoposide for more aggressive treatment of HLH. Despite these efforts, her ferritin rapidly climbed to over 80,000 mcg/L (reference range 11–307 mcg/L). Infectious workup to date was negative including blood bacterial and fungal cultures, ascites bacterial and fungal cultures, and blood tests for HIV, HHV-6, EBV DNA, hepatitis A and E IgM, parvovirus B19, adenovirus, and tuberculosis quantiferon.
Infectious etiology was identified when her urine histoplasmosis antigen returned positive above the upper detectable limit. The bone marrow biopsy was stained for histoplasmosis and confirmed disseminated infection (Figure 1(c)). Amphotericin therapy was initiated as the patient began CRRT for worsening kidney failure. Over the next eight days, however, she did not show any clinical improvement and was treated supportively for ICU delirium, respiratory failure, anuria requiring intermittent hemodialysis, worsening coagulopathy and rising ammonia, and malnutrition requiring tube feeds. On day twelve, voriconazole was added for additional antifungal coverage.
Unfortunately, despite these efforts, the patient's blood counts continued to decline, and she developed massive melena on hospital day 13 with a hemoglobin of 4 g/dL (reference range 12.0–15.5 g/dL), WBC 0.1/L (reference range 3.4–10.6 × 10(9)/L), ANC 0.11/L (reference range 1.40–6.60 × 10(9)/L), and platelets 41/L (reference range 149–375 × 10(9)/L). At this point, the patient and her power of attorney elected to withdraw aggressive treatments, and she was transferred to inpatient hospice.
3. Case Report #2
A 41-year-old woman residing in Arizona with a history of ulcerative colitis from who was on Remicade up until one month earlier was admitted three times over a course of a month with a variety of symptoms without identifying etiology. Initially, she had nonspecific fevers, headache, neck pain, fatigue, nausea, vomiting, and arthralgias. She was found to have an edematous gallbladder (Figure 2(a)) and mild splenomegaly, with a negative infectious workup. With symptomatic care, her fevers were controlled, and she was discharged with a diagnosis of presumed viral syndrome versus Remicade toxicity. However, symptoms worsened, and she represented with fever, sepsis, cholestatic jaundice, acute kidney injury, pancytopenia, and multiple metabolic abnormalities requiring admission to the intensive care unit. Initially, she underwent ERCP with sphincterotomy, and common bile duct stent was placed. On endoscopy, the duodenal mucosa was noted to be friable, biopsy revealed reactive gastropathy, and H. pylori testing was negative. She then underwent laparoscopic cholecystectomy for acalculous cholecystitis. Postoperatively, she developed bloody secretions from the endotracheal tube followed by ARDS; thus, she was unable to be extubated. She also had episodes of epistaxis and melena through this time. Her clinical status quickly deteriorated to multiorgan failure including renal failure requiring dialysis, cholestatic liver failure, respiratory failure requiring mechanical ventilation, and critical pancytopenia requiring high-volume transfusions including 17 units of packed red blood cells, 17 units of platelets, and 6 units of cryoprecipitate.
Workup through this point revealed a markedly elevated ferritin of 73,469 mcg/L (reference range 11–307 mcg/L), elevated lactate dehydrogenase of 2,375 U/L (reference range 122–222 U/L), hypofibrinogenemia of 135 mg/dL (reference range 200-430 mg/dL), and hypertriglyceridemia 2,259 mg/dL (reference range < 150 mg/dL), raising suspicion for HLH. Bone marrow biopsy confirmed the diagnosis (Figures 2(b)–2(d)), and she was initiated on high-dose steroids and etoposide. She developed a severe diffuse rash to etoposide necessitating its discontinuation. Investigation for an underlying trigger included bronchoalveolar lavage (BAL) culture which returned positive for Histoplasma capsulatum, in addition to positive histoplasma urinary antigen. During the same hospitalization, she additionally underwent cholecystectomy, and cultured gallbladder tissue ultimately grew H. capsulatum. Based on history, this was likely acquired in the setting of prior Remicade use while exploring bat caves in Cancun, Mexico, two weeks prior to admission. The patient was born and lived in Arizona until her presentation and denied travel to any endemic areas. Her Aspergillus antigen was also positive from BAL, but this was felt to be a false positive as Aspergillus antigen testing cross-reacts with Histoplasma.
For treatment of disseminated histoplasmosis, she received intravenous AmBisome starting on day 4 of hospitalization and later transitioned to oral itraconazole. With these treatments, she recovered well and was eventually transferred out of the intensive care unit on day 18. She required one dose of Neupogen for leukopenia, but her white blood cell count recovered thereafter, and platelet count returned to normal. Her ferritin had dramatically decreased to 1,568 mcg/L (reference range 11–307 mcg/L). Her kidney and liver function recovered to the point where she could be safely discharged to acute rehabilitation after an approximately four weeks stay in the hospital. She continued to improve during a two-week rehabilitation stay and was then discharged home with an oral steroid taper and oral itraconazole for one year following diagnosis.
4. Discussion
The diagnosis and treatment of acquired HLH in adults are serious and challenging, as the clinical presentation can be fairly nonspecific and diagnosis is based on a collection of both clinical and laboratory abnormalities. In pediatric patients with familial HLH, an elevated ferritin greater than 10,000 μg/L is highly sensitive and specific for diagnosis [19]. In adults, however, elevated ferritin has been linked to various conditions including malignancy, liver dysfunction, infection, anemia of chronic disease, or iron overload [20]. Markedly elevated ferritin, however, is thought to be more specific for adult onset stills disease, macrophage activation syndrome, and HLH. In a retrospective study [20] of patients with ferritin levels greater than 50,000 μg/L, 19% were found to have HLH. The most frequently seen diagnosis in these patients was renal failure (73%), liver injury (61%), infections (52%), and hematologic malignancies (36%). No ferritin cut off level was found to be specific for HLH in this study. Currently, ferritin > 500 μg/L is included in the diagnostic criteria for HLH, although many prefer to use >3000 μg/L. Given the lack of specific criteria for diagnosis of adult acquired HLH, a scoring system which includes the above mentioned diagnostic criteria for HLH was developed and has been shown to be 90% sensitive and 79% specific, although specificity decreases as patients become less stable [21]. Once the diagnosis is confirmed, treatment must be initiated immediately. Additionally, a search must be undertaken to find an underlying trigger for HLH; as without treating the source, there is little chance for clinical improvement.
Here, we present two cases of HLH secondary to disseminated histoplasmosis. Previously, published cases of histoplasmosis associated HLH were reported in HIV [22], hematologic malignancy [16], and transplant patients on immunosuppression [18, 22]. Disseminated histoplasmosis by itself is also quite serious but generally treatable with antifungal therapy. Current IDSA guidelines for moderate to severe disease include liposomal amphotericin B (3.0 mg/kg daily) for 1-2 weeks, followed with oral itraconazole for at least 12 months [9]. Patients who have both disseminated histoplasmosis and HLH portend a worse prognosis. In a retrospective review of eleven cases of histoplasmosis associated HLH, 45% died within 30 days, and 63% died within 90 days [22]. The main challenge of caring for patients with histoplasmosis associated HLH is management of the multiorgan failure that can result from this combination of diseases. Both HLH and histoplasmosis can cause hematologic abnormalities, namely, pancytopenia, and both patients presented here required large volume transfusions. In addition, both patients developed respiratory failure from ARDS, renal failure requiring renal replacement therapy, liver failure, and gastrointestinal bleeding. Disseminated histoplasmosis involving the gastrointestinal system can cause cholecystitis and appendicitis leading to surgery, as well as melena and gastritis, which were seen in these cases.
The main risk factors for disseminated histoplasmosis leading to HLH in these cases were immunosuppressive medication (methotrexate and infliximab) and environmental exposure (bird or bat droppings, especially in caves). Interestingly, in both cases, the offending medication had been discontinued due to laboratory abnormalities 1-2 months prior to any presenting symptoms. It is unclear whether this may have been a risk factor for disease. Nevertheless, with a presentation of diffuse infectious symptoms without an identified etiology in the context of recent immunosuppressive medication, an exhaustive history and laboratory inquiry should be pursued to avoid delayed diagnosis for serious conditions such as disseminated fungal infection and HLH.
Data Availability
No datasets were used.
Conflicts of Interest
No authors have conflict of interest to disclose.
Authors' Contributions
All authors included have made substantial contributions to conception, design, data acquisition, drafting, and/or revising of the manuscript. All authors have read and approved the submission of this manuscript.
Figure 1 (a) Bone marrow aspirate reveals evidence of hemophagocytosis. (b) Chest X-ray reveals evidence of bilateral infiltrates, and patient then diagnosed with ARDS. (c) Bone marrow core biopsy GMS stain reveals histoplasmosis.
Figure 2 (a) CT abdomen on admission reveals edematous gallbladder which was later found to have evidence of Histoplasma capsulatum. (b, c) Bone marrow aspirate reveals hemophagocytosis. (d) GMS stain of bone marrow core biopsy positive for histoplasmosis. | Not recovered | ReactionOutcome | CC BY | 33552603 | 19,036,089 | 2021 |
What was the outcome of reaction 'Rash'? | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis in Rheumatologic Disease.
Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections.
Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.
1. Background
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune overactivation that can lead to tissue destruction and organ failure. As a primary disorder, it is typically seen in pediatrics and has several associated genetic mutations [1]. In adults, it presents as a secondary phenomenon, seen in conjunction with infection, malignancy, immunodeficiency, or another immune dysregulating event. The diagnosis is established by meeting five of eight criteria, including fever greater than 38.5 degrees Celsius; splenomegaly; peripheral cytopenia (at least two of hemoglobin < 9 g/dL, platelets < 100, 000/microL, absolute neutrophil count < 1000/microL); hypertriglyceridemia (fasting > 265 mg/dL) or hypofibrinogenemia (<150 mg/dL); hemophagocytosis in the bone marrow, spleen, lymph node, or liver; decreased natural killer cell activity; ferritin > 500 ng/mL; and elevated soluble CD25 (IL-2 receptor α) two standard deviations above age-adjusted norms [2, 3]. Laboratory evaluation of soluble CD25 and natural killer cell activity require specialized testing and therefore do not result in real time. Without treatment, prognosis is limited to a few months, and the greatest barrier to survival is delay in diagnosis. Treatment entails identification and treatment of the underlying trigger. With proper treatment and identification of triggering event, survival increases to 54% at 6.2 years [4, 5]. Prognosis is worse with higher ferritin levels, underlying malignancy, older age, and low serum albumin levels [6, 7].
Although rheumatologic disease by itself can be a trigger for HLH, this is rare. Among adults on biological therapies for rheumatologic disease, infection is the most common trigger [8]. Histoplasmosis is a serious fungal infection that is endemic to the Ohio and Mississippi River valleys in the United States, as well as parts of Central and South America. The infective agent, Histoplasma capsulatum, is most likely to be found in soil containing bird or bat droppings. Inhalation of the spores allows them to transform into yeast and travel throughout the lymphatic and vascular system. Pulmonary histoplasmosis can cause pneumonia, mediastinal or hilar masses, pulmonary nodules, cavitary lung disease, and pericarditis. Risk factors for disseminated histoplasmosis include AIDS, immunodeficiency, immunosuppressive medications, and extremes of age. Untreated diffuse histoplasmosis is fatal within weeks, but proper antifungal treatment with amphotericin B or itraconazole increases survival rates dramatically [9].
Cases of HLH secondary to disseminated histoplasmosis are rare and extremely serious. Several case reports in the literature describe patients with AIDS [10–15], malignancy [16], or immunosuppression due to medications [17, 18]. Below we present two cases of patients with HLH secondary to disseminated histoplasmosis, both in the setting of recent immunosuppressive medication for underlying autoimmune disease.
2. Case Report #1
A 66-year-old woman presented to an emergency department near her home in Mexico with fever and abdominal pain of two weeks duration. She also described two months of increased fatigue and malaise, as well as increased swelling around her feet and ankles that had more recently developed. Although she was born in the United States in Oregon, she had been living in Mexico for several years. She denied travel to any other regions. A CT scan demonstrated appendicitis, and she was admitted to a hospital in Mexico for appendectomy. However, over the subsequent five days, she continued to have worsening fevers and abdominal pain. At this point, she flew to Mayo Clinic Arizona for further evaluation.
Her past medical history was significant for rheumatoid arthritis and chronic low back pain. Medications included gabapentin, daily prednisone (20 mg/day), spironolactone, and omeprazole. Following her appendix surgery, she had been placed on moxifloxacin for five days. She had been on methotrexate for several years, but this was discontinued a few months prior due to elevation of liver enzymes.
At the time of presentation, she appeared ill, and her vitals included fluid responsive hypotension, tachypnea with respiratory rate of 22, and mild hypoxia with oxygen saturation 88-95% on room air. Physical exam was significant for bibasilar crackles, abdominal distension, and diffuse tenderness to palpation without peritoneal signs, diffusely tender joints, and erythema over the left elbow and the right knee that was warm to touch. Initial laboratory evaluation demonstrated a hemoglobin of 12.5 g/dL (reference range 12.0–15.5 g/dL), platelet count of 8 × 10(9)/L (reference range 149–375 × 10(9)/L), and white blood cell count (WBC) 2.7 × 10(9)/L (reference range 3.4–10.6 × 10(9)/L) with neutrophilic predominance (absolute neutrophil count (ANC), 2.05 × 10(9)/L (reference range 1.40–6.60 × 10(9)/L)). Electrolyte panel showed hyponatremia 131 mmol/L (reference range 135–145 mmol/L) but was otherwise normal, including creatinine 0.9 mg/dL (reference range 0.6–1.1 mg/dL). LFTs were elevated with alkaline phosphatase 318 U/L (reference range 55–142 U/L), alanine aminotransferase (ALT) 145 U/L (reference range 7–45 U/L), and aspartate aminotransferase (AST) 252 U/L (reference range 9–43 U/L). Most notably, her ferritin was drastically elevated at 27,300 mcg/L (reference range 11–307 mcg/L). Additionally, triglycerides were elevated at 272 mg/dL (reference range < 150 mg/dL), and fibrinogen was reduced at 120 mg/dL (reference range 200–430 mg/dL). Chest X-ray showed trace bilateral pleural effusions and small calcified granulomata in the upper lungs bilaterally. Given her diffusely tender joints, X-ray of the hands were performed and revealed numerous subchondral cysts and erosion, as well as subluxation of the right index finger distal phalanx, with sparing of the metacarpophalangeal joints consistent with rheumatoid arthritis. Due to tachypnea, leukopenia, and hemodynamic instability, she was diagnosed with sepsis.
She initially received broad spectrum antibiotics and underwent paracentesis which was negative for peritonitis. Bacterial and fungal cultures of the ascitic fluid showed no growth. Her significantly elevated ferritin prompted a bone marrow biopsy (BMB), which showed features of hemophagocytic lymphohistiocytosis (Figure 1(a)). Given her findings of pancytopenia, elevated ferritin and triglycerides, reduced fibrinogen, and evidence of hemophagocytosis on BMB, she was treated with high-dose steroids and intravenous fluids. After initiation of steroids, her thrombocytopenia and joint pain improved. However, her WBC count continued to drop, and the patient continued to spike fevers; thus, antibiotics were adjusted to cover for neutropenic fever. Without an identified infectious source, a CT of the brain, chest, abdomen, and pelvis was performed which showed bilateral pulmonary infiltrates but was otherwise unremarkable. Liver biopsy was considered but was deemed unsafe due to coagulopathy. Her respiratory status declined eventually requiring high-flow oxygen due to acute respiratory distress syndrome (ARDS) (Figure 1(b)), and she was treated with aggressive diuresis. Initially, she had adequate response but ultimately developed oliguria and renal failure.
On hospital day four, the ferritin had improved to 609 mcg/L (reference range 11–307 mcg/L); however, LFTs continued to rise, and resultant coagulopathy required daily cryoprecipitate transfusion to maintain safe fibrinogen levels. Due to worsening clinical status with multiorgan failure including the liver, kidney, respiratory, and bone marrow, it was decided to add etoposide for more aggressive treatment of HLH. Despite these efforts, her ferritin rapidly climbed to over 80,000 mcg/L (reference range 11–307 mcg/L). Infectious workup to date was negative including blood bacterial and fungal cultures, ascites bacterial and fungal cultures, and blood tests for HIV, HHV-6, EBV DNA, hepatitis A and E IgM, parvovirus B19, adenovirus, and tuberculosis quantiferon.
Infectious etiology was identified when her urine histoplasmosis antigen returned positive above the upper detectable limit. The bone marrow biopsy was stained for histoplasmosis and confirmed disseminated infection (Figure 1(c)). Amphotericin therapy was initiated as the patient began CRRT for worsening kidney failure. Over the next eight days, however, she did not show any clinical improvement and was treated supportively for ICU delirium, respiratory failure, anuria requiring intermittent hemodialysis, worsening coagulopathy and rising ammonia, and malnutrition requiring tube feeds. On day twelve, voriconazole was added for additional antifungal coverage.
Unfortunately, despite these efforts, the patient's blood counts continued to decline, and she developed massive melena on hospital day 13 with a hemoglobin of 4 g/dL (reference range 12.0–15.5 g/dL), WBC 0.1/L (reference range 3.4–10.6 × 10(9)/L), ANC 0.11/L (reference range 1.40–6.60 × 10(9)/L), and platelets 41/L (reference range 149–375 × 10(9)/L). At this point, the patient and her power of attorney elected to withdraw aggressive treatments, and she was transferred to inpatient hospice.
3. Case Report #2
A 41-year-old woman residing in Arizona with a history of ulcerative colitis from who was on Remicade up until one month earlier was admitted three times over a course of a month with a variety of symptoms without identifying etiology. Initially, she had nonspecific fevers, headache, neck pain, fatigue, nausea, vomiting, and arthralgias. She was found to have an edematous gallbladder (Figure 2(a)) and mild splenomegaly, with a negative infectious workup. With symptomatic care, her fevers were controlled, and she was discharged with a diagnosis of presumed viral syndrome versus Remicade toxicity. However, symptoms worsened, and she represented with fever, sepsis, cholestatic jaundice, acute kidney injury, pancytopenia, and multiple metabolic abnormalities requiring admission to the intensive care unit. Initially, she underwent ERCP with sphincterotomy, and common bile duct stent was placed. On endoscopy, the duodenal mucosa was noted to be friable, biopsy revealed reactive gastropathy, and H. pylori testing was negative. She then underwent laparoscopic cholecystectomy for acalculous cholecystitis. Postoperatively, she developed bloody secretions from the endotracheal tube followed by ARDS; thus, she was unable to be extubated. She also had episodes of epistaxis and melena through this time. Her clinical status quickly deteriorated to multiorgan failure including renal failure requiring dialysis, cholestatic liver failure, respiratory failure requiring mechanical ventilation, and critical pancytopenia requiring high-volume transfusions including 17 units of packed red blood cells, 17 units of platelets, and 6 units of cryoprecipitate.
Workup through this point revealed a markedly elevated ferritin of 73,469 mcg/L (reference range 11–307 mcg/L), elevated lactate dehydrogenase of 2,375 U/L (reference range 122–222 U/L), hypofibrinogenemia of 135 mg/dL (reference range 200-430 mg/dL), and hypertriglyceridemia 2,259 mg/dL (reference range < 150 mg/dL), raising suspicion for HLH. Bone marrow biopsy confirmed the diagnosis (Figures 2(b)–2(d)), and she was initiated on high-dose steroids and etoposide. She developed a severe diffuse rash to etoposide necessitating its discontinuation. Investigation for an underlying trigger included bronchoalveolar lavage (BAL) culture which returned positive for Histoplasma capsulatum, in addition to positive histoplasma urinary antigen. During the same hospitalization, she additionally underwent cholecystectomy, and cultured gallbladder tissue ultimately grew H. capsulatum. Based on history, this was likely acquired in the setting of prior Remicade use while exploring bat caves in Cancun, Mexico, two weeks prior to admission. The patient was born and lived in Arizona until her presentation and denied travel to any endemic areas. Her Aspergillus antigen was also positive from BAL, but this was felt to be a false positive as Aspergillus antigen testing cross-reacts with Histoplasma.
For treatment of disseminated histoplasmosis, she received intravenous AmBisome starting on day 4 of hospitalization and later transitioned to oral itraconazole. With these treatments, she recovered well and was eventually transferred out of the intensive care unit on day 18. She required one dose of Neupogen for leukopenia, but her white blood cell count recovered thereafter, and platelet count returned to normal. Her ferritin had dramatically decreased to 1,568 mcg/L (reference range 11–307 mcg/L). Her kidney and liver function recovered to the point where she could be safely discharged to acute rehabilitation after an approximately four weeks stay in the hospital. She continued to improve during a two-week rehabilitation stay and was then discharged home with an oral steroid taper and oral itraconazole for one year following diagnosis.
4. Discussion
The diagnosis and treatment of acquired HLH in adults are serious and challenging, as the clinical presentation can be fairly nonspecific and diagnosis is based on a collection of both clinical and laboratory abnormalities. In pediatric patients with familial HLH, an elevated ferritin greater than 10,000 μg/L is highly sensitive and specific for diagnosis [19]. In adults, however, elevated ferritin has been linked to various conditions including malignancy, liver dysfunction, infection, anemia of chronic disease, or iron overload [20]. Markedly elevated ferritin, however, is thought to be more specific for adult onset stills disease, macrophage activation syndrome, and HLH. In a retrospective study [20] of patients with ferritin levels greater than 50,000 μg/L, 19% were found to have HLH. The most frequently seen diagnosis in these patients was renal failure (73%), liver injury (61%), infections (52%), and hematologic malignancies (36%). No ferritin cut off level was found to be specific for HLH in this study. Currently, ferritin > 500 μg/L is included in the diagnostic criteria for HLH, although many prefer to use >3000 μg/L. Given the lack of specific criteria for diagnosis of adult acquired HLH, a scoring system which includes the above mentioned diagnostic criteria for HLH was developed and has been shown to be 90% sensitive and 79% specific, although specificity decreases as patients become less stable [21]. Once the diagnosis is confirmed, treatment must be initiated immediately. Additionally, a search must be undertaken to find an underlying trigger for HLH; as without treating the source, there is little chance for clinical improvement.
Here, we present two cases of HLH secondary to disseminated histoplasmosis. Previously, published cases of histoplasmosis associated HLH were reported in HIV [22], hematologic malignancy [16], and transplant patients on immunosuppression [18, 22]. Disseminated histoplasmosis by itself is also quite serious but generally treatable with antifungal therapy. Current IDSA guidelines for moderate to severe disease include liposomal amphotericin B (3.0 mg/kg daily) for 1-2 weeks, followed with oral itraconazole for at least 12 months [9]. Patients who have both disseminated histoplasmosis and HLH portend a worse prognosis. In a retrospective review of eleven cases of histoplasmosis associated HLH, 45% died within 30 days, and 63% died within 90 days [22]. The main challenge of caring for patients with histoplasmosis associated HLH is management of the multiorgan failure that can result from this combination of diseases. Both HLH and histoplasmosis can cause hematologic abnormalities, namely, pancytopenia, and both patients presented here required large volume transfusions. In addition, both patients developed respiratory failure from ARDS, renal failure requiring renal replacement therapy, liver failure, and gastrointestinal bleeding. Disseminated histoplasmosis involving the gastrointestinal system can cause cholecystitis and appendicitis leading to surgery, as well as melena and gastritis, which were seen in these cases.
The main risk factors for disseminated histoplasmosis leading to HLH in these cases were immunosuppressive medication (methotrexate and infliximab) and environmental exposure (bird or bat droppings, especially in caves). Interestingly, in both cases, the offending medication had been discontinued due to laboratory abnormalities 1-2 months prior to any presenting symptoms. It is unclear whether this may have been a risk factor for disease. Nevertheless, with a presentation of diffuse infectious symptoms without an identified etiology in the context of recent immunosuppressive medication, an exhaustive history and laboratory inquiry should be pursued to avoid delayed diagnosis for serious conditions such as disseminated fungal infection and HLH.
Data Availability
No datasets were used.
Conflicts of Interest
No authors have conflict of interest to disclose.
Authors' Contributions
All authors included have made substantial contributions to conception, design, data acquisition, drafting, and/or revising of the manuscript. All authors have read and approved the submission of this manuscript.
Figure 1 (a) Bone marrow aspirate reveals evidence of hemophagocytosis. (b) Chest X-ray reveals evidence of bilateral infiltrates, and patient then diagnosed with ARDS. (c) Bone marrow core biopsy GMS stain reveals histoplasmosis.
Figure 2 (a) CT abdomen on admission reveals edematous gallbladder which was later found to have evidence of Histoplasma capsulatum. (b, c) Bone marrow aspirate reveals hemophagocytosis. (d) GMS stain of bone marrow core biopsy positive for histoplasmosis. | Recovered | ReactionOutcome | CC BY | 33552603 | 18,986,284 | 2021 |
What was the outcome of reaction 'Sepsis'? | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis in Rheumatologic Disease.
Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections.
Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.
1. Background
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune overactivation that can lead to tissue destruction and organ failure. As a primary disorder, it is typically seen in pediatrics and has several associated genetic mutations [1]. In adults, it presents as a secondary phenomenon, seen in conjunction with infection, malignancy, immunodeficiency, or another immune dysregulating event. The diagnosis is established by meeting five of eight criteria, including fever greater than 38.5 degrees Celsius; splenomegaly; peripheral cytopenia (at least two of hemoglobin < 9 g/dL, platelets < 100, 000/microL, absolute neutrophil count < 1000/microL); hypertriglyceridemia (fasting > 265 mg/dL) or hypofibrinogenemia (<150 mg/dL); hemophagocytosis in the bone marrow, spleen, lymph node, or liver; decreased natural killer cell activity; ferritin > 500 ng/mL; and elevated soluble CD25 (IL-2 receptor α) two standard deviations above age-adjusted norms [2, 3]. Laboratory evaluation of soluble CD25 and natural killer cell activity require specialized testing and therefore do not result in real time. Without treatment, prognosis is limited to a few months, and the greatest barrier to survival is delay in diagnosis. Treatment entails identification and treatment of the underlying trigger. With proper treatment and identification of triggering event, survival increases to 54% at 6.2 years [4, 5]. Prognosis is worse with higher ferritin levels, underlying malignancy, older age, and low serum albumin levels [6, 7].
Although rheumatologic disease by itself can be a trigger for HLH, this is rare. Among adults on biological therapies for rheumatologic disease, infection is the most common trigger [8]. Histoplasmosis is a serious fungal infection that is endemic to the Ohio and Mississippi River valleys in the United States, as well as parts of Central and South America. The infective agent, Histoplasma capsulatum, is most likely to be found in soil containing bird or bat droppings. Inhalation of the spores allows them to transform into yeast and travel throughout the lymphatic and vascular system. Pulmonary histoplasmosis can cause pneumonia, mediastinal or hilar masses, pulmonary nodules, cavitary lung disease, and pericarditis. Risk factors for disseminated histoplasmosis include AIDS, immunodeficiency, immunosuppressive medications, and extremes of age. Untreated diffuse histoplasmosis is fatal within weeks, but proper antifungal treatment with amphotericin B or itraconazole increases survival rates dramatically [9].
Cases of HLH secondary to disseminated histoplasmosis are rare and extremely serious. Several case reports in the literature describe patients with AIDS [10–15], malignancy [16], or immunosuppression due to medications [17, 18]. Below we present two cases of patients with HLH secondary to disseminated histoplasmosis, both in the setting of recent immunosuppressive medication for underlying autoimmune disease.
2. Case Report #1
A 66-year-old woman presented to an emergency department near her home in Mexico with fever and abdominal pain of two weeks duration. She also described two months of increased fatigue and malaise, as well as increased swelling around her feet and ankles that had more recently developed. Although she was born in the United States in Oregon, she had been living in Mexico for several years. She denied travel to any other regions. A CT scan demonstrated appendicitis, and she was admitted to a hospital in Mexico for appendectomy. However, over the subsequent five days, she continued to have worsening fevers and abdominal pain. At this point, she flew to Mayo Clinic Arizona for further evaluation.
Her past medical history was significant for rheumatoid arthritis and chronic low back pain. Medications included gabapentin, daily prednisone (20 mg/day), spironolactone, and omeprazole. Following her appendix surgery, she had been placed on moxifloxacin for five days. She had been on methotrexate for several years, but this was discontinued a few months prior due to elevation of liver enzymes.
At the time of presentation, she appeared ill, and her vitals included fluid responsive hypotension, tachypnea with respiratory rate of 22, and mild hypoxia with oxygen saturation 88-95% on room air. Physical exam was significant for bibasilar crackles, abdominal distension, and diffuse tenderness to palpation without peritoneal signs, diffusely tender joints, and erythema over the left elbow and the right knee that was warm to touch. Initial laboratory evaluation demonstrated a hemoglobin of 12.5 g/dL (reference range 12.0–15.5 g/dL), platelet count of 8 × 10(9)/L (reference range 149–375 × 10(9)/L), and white blood cell count (WBC) 2.7 × 10(9)/L (reference range 3.4–10.6 × 10(9)/L) with neutrophilic predominance (absolute neutrophil count (ANC), 2.05 × 10(9)/L (reference range 1.40–6.60 × 10(9)/L)). Electrolyte panel showed hyponatremia 131 mmol/L (reference range 135–145 mmol/L) but was otherwise normal, including creatinine 0.9 mg/dL (reference range 0.6–1.1 mg/dL). LFTs were elevated with alkaline phosphatase 318 U/L (reference range 55–142 U/L), alanine aminotransferase (ALT) 145 U/L (reference range 7–45 U/L), and aspartate aminotransferase (AST) 252 U/L (reference range 9–43 U/L). Most notably, her ferritin was drastically elevated at 27,300 mcg/L (reference range 11–307 mcg/L). Additionally, triglycerides were elevated at 272 mg/dL (reference range < 150 mg/dL), and fibrinogen was reduced at 120 mg/dL (reference range 200–430 mg/dL). Chest X-ray showed trace bilateral pleural effusions and small calcified granulomata in the upper lungs bilaterally. Given her diffusely tender joints, X-ray of the hands were performed and revealed numerous subchondral cysts and erosion, as well as subluxation of the right index finger distal phalanx, with sparing of the metacarpophalangeal joints consistent with rheumatoid arthritis. Due to tachypnea, leukopenia, and hemodynamic instability, she was diagnosed with sepsis.
She initially received broad spectrum antibiotics and underwent paracentesis which was negative for peritonitis. Bacterial and fungal cultures of the ascitic fluid showed no growth. Her significantly elevated ferritin prompted a bone marrow biopsy (BMB), which showed features of hemophagocytic lymphohistiocytosis (Figure 1(a)). Given her findings of pancytopenia, elevated ferritin and triglycerides, reduced fibrinogen, and evidence of hemophagocytosis on BMB, she was treated with high-dose steroids and intravenous fluids. After initiation of steroids, her thrombocytopenia and joint pain improved. However, her WBC count continued to drop, and the patient continued to spike fevers; thus, antibiotics were adjusted to cover for neutropenic fever. Without an identified infectious source, a CT of the brain, chest, abdomen, and pelvis was performed which showed bilateral pulmonary infiltrates but was otherwise unremarkable. Liver biopsy was considered but was deemed unsafe due to coagulopathy. Her respiratory status declined eventually requiring high-flow oxygen due to acute respiratory distress syndrome (ARDS) (Figure 1(b)), and she was treated with aggressive diuresis. Initially, she had adequate response but ultimately developed oliguria and renal failure.
On hospital day four, the ferritin had improved to 609 mcg/L (reference range 11–307 mcg/L); however, LFTs continued to rise, and resultant coagulopathy required daily cryoprecipitate transfusion to maintain safe fibrinogen levels. Due to worsening clinical status with multiorgan failure including the liver, kidney, respiratory, and bone marrow, it was decided to add etoposide for more aggressive treatment of HLH. Despite these efforts, her ferritin rapidly climbed to over 80,000 mcg/L (reference range 11–307 mcg/L). Infectious workup to date was negative including blood bacterial and fungal cultures, ascites bacterial and fungal cultures, and blood tests for HIV, HHV-6, EBV DNA, hepatitis A and E IgM, parvovirus B19, adenovirus, and tuberculosis quantiferon.
Infectious etiology was identified when her urine histoplasmosis antigen returned positive above the upper detectable limit. The bone marrow biopsy was stained for histoplasmosis and confirmed disseminated infection (Figure 1(c)). Amphotericin therapy was initiated as the patient began CRRT for worsening kidney failure. Over the next eight days, however, she did not show any clinical improvement and was treated supportively for ICU delirium, respiratory failure, anuria requiring intermittent hemodialysis, worsening coagulopathy and rising ammonia, and malnutrition requiring tube feeds. On day twelve, voriconazole was added for additional antifungal coverage.
Unfortunately, despite these efforts, the patient's blood counts continued to decline, and she developed massive melena on hospital day 13 with a hemoglobin of 4 g/dL (reference range 12.0–15.5 g/dL), WBC 0.1/L (reference range 3.4–10.6 × 10(9)/L), ANC 0.11/L (reference range 1.40–6.60 × 10(9)/L), and platelets 41/L (reference range 149–375 × 10(9)/L). At this point, the patient and her power of attorney elected to withdraw aggressive treatments, and she was transferred to inpatient hospice.
3. Case Report #2
A 41-year-old woman residing in Arizona with a history of ulcerative colitis from who was on Remicade up until one month earlier was admitted three times over a course of a month with a variety of symptoms without identifying etiology. Initially, she had nonspecific fevers, headache, neck pain, fatigue, nausea, vomiting, and arthralgias. She was found to have an edematous gallbladder (Figure 2(a)) and mild splenomegaly, with a negative infectious workup. With symptomatic care, her fevers were controlled, and she was discharged with a diagnosis of presumed viral syndrome versus Remicade toxicity. However, symptoms worsened, and she represented with fever, sepsis, cholestatic jaundice, acute kidney injury, pancytopenia, and multiple metabolic abnormalities requiring admission to the intensive care unit. Initially, she underwent ERCP with sphincterotomy, and common bile duct stent was placed. On endoscopy, the duodenal mucosa was noted to be friable, biopsy revealed reactive gastropathy, and H. pylori testing was negative. She then underwent laparoscopic cholecystectomy for acalculous cholecystitis. Postoperatively, she developed bloody secretions from the endotracheal tube followed by ARDS; thus, she was unable to be extubated. She also had episodes of epistaxis and melena through this time. Her clinical status quickly deteriorated to multiorgan failure including renal failure requiring dialysis, cholestatic liver failure, respiratory failure requiring mechanical ventilation, and critical pancytopenia requiring high-volume transfusions including 17 units of packed red blood cells, 17 units of platelets, and 6 units of cryoprecipitate.
Workup through this point revealed a markedly elevated ferritin of 73,469 mcg/L (reference range 11–307 mcg/L), elevated lactate dehydrogenase of 2,375 U/L (reference range 122–222 U/L), hypofibrinogenemia of 135 mg/dL (reference range 200-430 mg/dL), and hypertriglyceridemia 2,259 mg/dL (reference range < 150 mg/dL), raising suspicion for HLH. Bone marrow biopsy confirmed the diagnosis (Figures 2(b)–2(d)), and she was initiated on high-dose steroids and etoposide. She developed a severe diffuse rash to etoposide necessitating its discontinuation. Investigation for an underlying trigger included bronchoalveolar lavage (BAL) culture which returned positive for Histoplasma capsulatum, in addition to positive histoplasma urinary antigen. During the same hospitalization, she additionally underwent cholecystectomy, and cultured gallbladder tissue ultimately grew H. capsulatum. Based on history, this was likely acquired in the setting of prior Remicade use while exploring bat caves in Cancun, Mexico, two weeks prior to admission. The patient was born and lived in Arizona until her presentation and denied travel to any endemic areas. Her Aspergillus antigen was also positive from BAL, but this was felt to be a false positive as Aspergillus antigen testing cross-reacts with Histoplasma.
For treatment of disseminated histoplasmosis, she received intravenous AmBisome starting on day 4 of hospitalization and later transitioned to oral itraconazole. With these treatments, she recovered well and was eventually transferred out of the intensive care unit on day 18. She required one dose of Neupogen for leukopenia, but her white blood cell count recovered thereafter, and platelet count returned to normal. Her ferritin had dramatically decreased to 1,568 mcg/L (reference range 11–307 mcg/L). Her kidney and liver function recovered to the point where she could be safely discharged to acute rehabilitation after an approximately four weeks stay in the hospital. She continued to improve during a two-week rehabilitation stay and was then discharged home with an oral steroid taper and oral itraconazole for one year following diagnosis.
4. Discussion
The diagnosis and treatment of acquired HLH in adults are serious and challenging, as the clinical presentation can be fairly nonspecific and diagnosis is based on a collection of both clinical and laboratory abnormalities. In pediatric patients with familial HLH, an elevated ferritin greater than 10,000 μg/L is highly sensitive and specific for diagnosis [19]. In adults, however, elevated ferritin has been linked to various conditions including malignancy, liver dysfunction, infection, anemia of chronic disease, or iron overload [20]. Markedly elevated ferritin, however, is thought to be more specific for adult onset stills disease, macrophage activation syndrome, and HLH. In a retrospective study [20] of patients with ferritin levels greater than 50,000 μg/L, 19% were found to have HLH. The most frequently seen diagnosis in these patients was renal failure (73%), liver injury (61%), infections (52%), and hematologic malignancies (36%). No ferritin cut off level was found to be specific for HLH in this study. Currently, ferritin > 500 μg/L is included in the diagnostic criteria for HLH, although many prefer to use >3000 μg/L. Given the lack of specific criteria for diagnosis of adult acquired HLH, a scoring system which includes the above mentioned diagnostic criteria for HLH was developed and has been shown to be 90% sensitive and 79% specific, although specificity decreases as patients become less stable [21]. Once the diagnosis is confirmed, treatment must be initiated immediately. Additionally, a search must be undertaken to find an underlying trigger for HLH; as without treating the source, there is little chance for clinical improvement.
Here, we present two cases of HLH secondary to disseminated histoplasmosis. Previously, published cases of histoplasmosis associated HLH were reported in HIV [22], hematologic malignancy [16], and transplant patients on immunosuppression [18, 22]. Disseminated histoplasmosis by itself is also quite serious but generally treatable with antifungal therapy. Current IDSA guidelines for moderate to severe disease include liposomal amphotericin B (3.0 mg/kg daily) for 1-2 weeks, followed with oral itraconazole for at least 12 months [9]. Patients who have both disseminated histoplasmosis and HLH portend a worse prognosis. In a retrospective review of eleven cases of histoplasmosis associated HLH, 45% died within 30 days, and 63% died within 90 days [22]. The main challenge of caring for patients with histoplasmosis associated HLH is management of the multiorgan failure that can result from this combination of diseases. Both HLH and histoplasmosis can cause hematologic abnormalities, namely, pancytopenia, and both patients presented here required large volume transfusions. In addition, both patients developed respiratory failure from ARDS, renal failure requiring renal replacement therapy, liver failure, and gastrointestinal bleeding. Disseminated histoplasmosis involving the gastrointestinal system can cause cholecystitis and appendicitis leading to surgery, as well as melena and gastritis, which were seen in these cases.
The main risk factors for disseminated histoplasmosis leading to HLH in these cases were immunosuppressive medication (methotrexate and infliximab) and environmental exposure (bird or bat droppings, especially in caves). Interestingly, in both cases, the offending medication had been discontinued due to laboratory abnormalities 1-2 months prior to any presenting symptoms. It is unclear whether this may have been a risk factor for disease. Nevertheless, with a presentation of diffuse infectious symptoms without an identified etiology in the context of recent immunosuppressive medication, an exhaustive history and laboratory inquiry should be pursued to avoid delayed diagnosis for serious conditions such as disseminated fungal infection and HLH.
Data Availability
No datasets were used.
Conflicts of Interest
No authors have conflict of interest to disclose.
Authors' Contributions
All authors included have made substantial contributions to conception, design, data acquisition, drafting, and/or revising of the manuscript. All authors have read and approved the submission of this manuscript.
Figure 1 (a) Bone marrow aspirate reveals evidence of hemophagocytosis. (b) Chest X-ray reveals evidence of bilateral infiltrates, and patient then diagnosed with ARDS. (c) Bone marrow core biopsy GMS stain reveals histoplasmosis.
Figure 2 (a) CT abdomen on admission reveals edematous gallbladder which was later found to have evidence of Histoplasma capsulatum. (b, c) Bone marrow aspirate reveals hemophagocytosis. (d) GMS stain of bone marrow core biopsy positive for histoplasmosis. | Not recovered | ReactionOutcome | CC BY | 33552603 | 19,036,089 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Cotard and Capgras Syndrome in a Patient with Treatment-Resistant Schizophrenia.
The presentation of both Cotard and Capgras syndromes is uncommon in schizophrenia. We present a case of a 23-year-old male with the diagnosis of schizophrenia with Cotard syndrome who later developed Capgras syndrome. By persisting significant symptoms despite the use of two antipsychotics, he was given the diagnosis of treatment-resistant schizophrenia, and his symptoms improved with clozapine. This is one of the few cases of Cotard and Capgras syndromes in a patient with schizophrenia.
1. Introduction
The presentation of both Cotard and Capgras syndromes is uncommon in schizophrenia, and a few cases have been reported. Cotard syndrome was first described by Jules Cotard in 1880, and one of the characteristics is the nihilistic delusions that are related to denying the existence of oneself or the world. Capgras syndrome was described in 1923 by Capgras and Reboul-Lachaux and is characterized by the delusion that the individual or family members have been replaced by substitutes [1]. We report the case of a patient with treatment-resistant schizophrenia who had symptoms of both syndromes.
2. Case Presentation
R. is a 23-year-old, male, with a family psychiatric history of psychotic disorder and whose symptoms started at 13 with social isolation and poor hygiene. At 15, he became aggressive and suspicious, and risperidone 3 mg was prescribed daily; then, auditory hallucinations developed, so the antipsychotic was increased to 4 mg daily. However, he subsequently presented on numerous occasions to the emergency room (ER) with aggressive behavior and persecutory delusions. When he was 18, disorganized behavior and delusions of prejudice were added; for this reason, sulpiride 400 mg and olanzapine 10 mg daily were prescribed but without good response. Then, he presented with nihilistic delusions concerning his existence “I am dead, I died in 2012,” nihilistic delusions related to his body “I do not have a heart,” hypochondriacal delusions “my organs are not working,” delusions of guilt “I am taking the blame,” and suicidal ideation. For these reasons, he was again taken for his dad to the ER. In the mental examination, he was agitated, asking people to kill him. The PANSS upon admission of the patient was 125. During the hospitalization, he continued with the suicidal ideation, and the initiation of electroconvulsive therapy was recommended. The patient received 25 sessions of electroconvulsive therapy with partial improvement in the psychotic symptoms. His previous medication was changed to quetiapine 900 mg daily, without improvement. He was given a diagnosis of treatment-resistant schizophrenia, and clozapine was started. During hospitalization, the patient started refusing food, and a nasogastric tube was inserted. On one occasion, he became unwell, developing aspiration pneumonia (Figure 1) and spent 15 days in intensive care. As his medical condition subsequently improved, he said “I don't have parents, the people who raised me are impostors, they look like my parents, they will be angels, my parents buried me and I never knew about them.” In the neurological physical exam, the patient was alert, oriented to person and time. He mentioned he was in purgatory. The speech was normal. The muscle strength was 5/5 bilaterally, with no motor deficits. The sensation was intact bilaterally. Reflexes are 2+ bilaterally. Brain computerized tomography scan showed no intra- or extra-axial fluid, hemorrhage, or mass; the ventricular size was normal, and the grey-white differentiation was preserved (Figure 2). The complete blood count, liver function test, creatinine, and glucose levels were within normal values. He later transferred back to the mental health hospital. The clozapine dose was gradually increased to 650 mg daily with an improvement of the auditory hallucinations, the suicidal ideation, and the symptoms of Cotard and Capgras syndrome. PANSS at the discharge was 51. A weekly normal absolute neutrophil count was obtained. The last WBC was 6500 cells/mcL and the ANC 4290 cells/mcL.
3. Discussion
In this case report, we present a patient with schizophrenia with Cotard syndrome who later developed Capgras syndrome. The association of Cotard and Capgras delusions in the same patient is extremely rare [2].
Cotard and Capgras delusions can also be understood as the one-stage or the two-stage model [3]. In the first one, the experiential, delusions are elucidated as a normal rationalization of the unusual perceptual experience. In the second one, the inferential, delusions are considered as an abnormal rationalization of the unusual perceptual experience. In this case, they may represent the way a person tries to attribute negative events to external causes (as in the case of Capgras that is accompanied by delusions of persecution) or internal causes (as in the case of Cotard in the setting of a depressive disorder) [4].
In our case, the Cotard syndrome did not improve with the electroconvulsive therapy (ECT), successful treatment in cases of melancholia, or psychotic depression [5]. The reasons for this could include that the Cotard syndrome appeared in the psychotic setting, the early onset of the disorder alongside his strong genetic load (both parents having features of schizophrenia). Our patient had persisting significant symptoms despite the use of two antipsychotics suggesting treatment-resistant schizophrenia, so the treatment was progressively changed to clozapine.
Through the observation of this case, we conclude that the recognition of symptoms of Cotard and Capgras syndrome in schizophrenia is important for the assessment of appropriate treatment.
Conflicts of Interest
None of the authors have any conflicts of interest to declare.
Figure 1 Frontal chest radiograph showing consolidation of both lungs with increasing density towards the lung bases, predominantly the left lung base.
Figure 2 Noncontrast computed tomography of the head. | OLANZAPINE, QUETIAPINE, RISPERIDONE, SULPIRIDE | DrugsGivenReaction | CC BY | 33552609 | 19,088,735 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hallucination, auditory'. | Cotard and Capgras Syndrome in a Patient with Treatment-Resistant Schizophrenia.
The presentation of both Cotard and Capgras syndromes is uncommon in schizophrenia. We present a case of a 23-year-old male with the diagnosis of schizophrenia with Cotard syndrome who later developed Capgras syndrome. By persisting significant symptoms despite the use of two antipsychotics, he was given the diagnosis of treatment-resistant schizophrenia, and his symptoms improved with clozapine. This is one of the few cases of Cotard and Capgras syndromes in a patient with schizophrenia.
1. Introduction
The presentation of both Cotard and Capgras syndromes is uncommon in schizophrenia, and a few cases have been reported. Cotard syndrome was first described by Jules Cotard in 1880, and one of the characteristics is the nihilistic delusions that are related to denying the existence of oneself or the world. Capgras syndrome was described in 1923 by Capgras and Reboul-Lachaux and is characterized by the delusion that the individual or family members have been replaced by substitutes [1]. We report the case of a patient with treatment-resistant schizophrenia who had symptoms of both syndromes.
2. Case Presentation
R. is a 23-year-old, male, with a family psychiatric history of psychotic disorder and whose symptoms started at 13 with social isolation and poor hygiene. At 15, he became aggressive and suspicious, and risperidone 3 mg was prescribed daily; then, auditory hallucinations developed, so the antipsychotic was increased to 4 mg daily. However, he subsequently presented on numerous occasions to the emergency room (ER) with aggressive behavior and persecutory delusions. When he was 18, disorganized behavior and delusions of prejudice were added; for this reason, sulpiride 400 mg and olanzapine 10 mg daily were prescribed but without good response. Then, he presented with nihilistic delusions concerning his existence “I am dead, I died in 2012,” nihilistic delusions related to his body “I do not have a heart,” hypochondriacal delusions “my organs are not working,” delusions of guilt “I am taking the blame,” and suicidal ideation. For these reasons, he was again taken for his dad to the ER. In the mental examination, he was agitated, asking people to kill him. The PANSS upon admission of the patient was 125. During the hospitalization, he continued with the suicidal ideation, and the initiation of electroconvulsive therapy was recommended. The patient received 25 sessions of electroconvulsive therapy with partial improvement in the psychotic symptoms. His previous medication was changed to quetiapine 900 mg daily, without improvement. He was given a diagnosis of treatment-resistant schizophrenia, and clozapine was started. During hospitalization, the patient started refusing food, and a nasogastric tube was inserted. On one occasion, he became unwell, developing aspiration pneumonia (Figure 1) and spent 15 days in intensive care. As his medical condition subsequently improved, he said “I don't have parents, the people who raised me are impostors, they look like my parents, they will be angels, my parents buried me and I never knew about them.” In the neurological physical exam, the patient was alert, oriented to person and time. He mentioned he was in purgatory. The speech was normal. The muscle strength was 5/5 bilaterally, with no motor deficits. The sensation was intact bilaterally. Reflexes are 2+ bilaterally. Brain computerized tomography scan showed no intra- or extra-axial fluid, hemorrhage, or mass; the ventricular size was normal, and the grey-white differentiation was preserved (Figure 2). The complete blood count, liver function test, creatinine, and glucose levels were within normal values. He later transferred back to the mental health hospital. The clozapine dose was gradually increased to 650 mg daily with an improvement of the auditory hallucinations, the suicidal ideation, and the symptoms of Cotard and Capgras syndrome. PANSS at the discharge was 51. A weekly normal absolute neutrophil count was obtained. The last WBC was 6500 cells/mcL and the ANC 4290 cells/mcL.
3. Discussion
In this case report, we present a patient with schizophrenia with Cotard syndrome who later developed Capgras syndrome. The association of Cotard and Capgras delusions in the same patient is extremely rare [2].
Cotard and Capgras delusions can also be understood as the one-stage or the two-stage model [3]. In the first one, the experiential, delusions are elucidated as a normal rationalization of the unusual perceptual experience. In the second one, the inferential, delusions are considered as an abnormal rationalization of the unusual perceptual experience. In this case, they may represent the way a person tries to attribute negative events to external causes (as in the case of Capgras that is accompanied by delusions of persecution) or internal causes (as in the case of Cotard in the setting of a depressive disorder) [4].
In our case, the Cotard syndrome did not improve with the electroconvulsive therapy (ECT), successful treatment in cases of melancholia, or psychotic depression [5]. The reasons for this could include that the Cotard syndrome appeared in the psychotic setting, the early onset of the disorder alongside his strong genetic load (both parents having features of schizophrenia). Our patient had persisting significant symptoms despite the use of two antipsychotics suggesting treatment-resistant schizophrenia, so the treatment was progressively changed to clozapine.
Through the observation of this case, we conclude that the recognition of symptoms of Cotard and Capgras syndrome in schizophrenia is important for the assessment of appropriate treatment.
Conflicts of Interest
None of the authors have any conflicts of interest to declare.
Figure 1 Frontal chest radiograph showing consolidation of both lungs with increasing density towards the lung bases, predominantly the left lung base.
Figure 2 Noncontrast computed tomography of the head. | OLANZAPINE, QUETIAPINE, RISPERIDONE, SULPIRIDE | DrugsGivenReaction | CC BY | 33552609 | 19,088,735 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Schizophrenia'. | Cotard and Capgras Syndrome in a Patient with Treatment-Resistant Schizophrenia.
The presentation of both Cotard and Capgras syndromes is uncommon in schizophrenia. We present a case of a 23-year-old male with the diagnosis of schizophrenia with Cotard syndrome who later developed Capgras syndrome. By persisting significant symptoms despite the use of two antipsychotics, he was given the diagnosis of treatment-resistant schizophrenia, and his symptoms improved with clozapine. This is one of the few cases of Cotard and Capgras syndromes in a patient with schizophrenia.
1. Introduction
The presentation of both Cotard and Capgras syndromes is uncommon in schizophrenia, and a few cases have been reported. Cotard syndrome was first described by Jules Cotard in 1880, and one of the characteristics is the nihilistic delusions that are related to denying the existence of oneself or the world. Capgras syndrome was described in 1923 by Capgras and Reboul-Lachaux and is characterized by the delusion that the individual or family members have been replaced by substitutes [1]. We report the case of a patient with treatment-resistant schizophrenia who had symptoms of both syndromes.
2. Case Presentation
R. is a 23-year-old, male, with a family psychiatric history of psychotic disorder and whose symptoms started at 13 with social isolation and poor hygiene. At 15, he became aggressive and suspicious, and risperidone 3 mg was prescribed daily; then, auditory hallucinations developed, so the antipsychotic was increased to 4 mg daily. However, he subsequently presented on numerous occasions to the emergency room (ER) with aggressive behavior and persecutory delusions. When he was 18, disorganized behavior and delusions of prejudice were added; for this reason, sulpiride 400 mg and olanzapine 10 mg daily were prescribed but without good response. Then, he presented with nihilistic delusions concerning his existence “I am dead, I died in 2012,” nihilistic delusions related to his body “I do not have a heart,” hypochondriacal delusions “my organs are not working,” delusions of guilt “I am taking the blame,” and suicidal ideation. For these reasons, he was again taken for his dad to the ER. In the mental examination, he was agitated, asking people to kill him. The PANSS upon admission of the patient was 125. During the hospitalization, he continued with the suicidal ideation, and the initiation of electroconvulsive therapy was recommended. The patient received 25 sessions of electroconvulsive therapy with partial improvement in the psychotic symptoms. His previous medication was changed to quetiapine 900 mg daily, without improvement. He was given a diagnosis of treatment-resistant schizophrenia, and clozapine was started. During hospitalization, the patient started refusing food, and a nasogastric tube was inserted. On one occasion, he became unwell, developing aspiration pneumonia (Figure 1) and spent 15 days in intensive care. As his medical condition subsequently improved, he said “I don't have parents, the people who raised me are impostors, they look like my parents, they will be angels, my parents buried me and I never knew about them.” In the neurological physical exam, the patient was alert, oriented to person and time. He mentioned he was in purgatory. The speech was normal. The muscle strength was 5/5 bilaterally, with no motor deficits. The sensation was intact bilaterally. Reflexes are 2+ bilaterally. Brain computerized tomography scan showed no intra- or extra-axial fluid, hemorrhage, or mass; the ventricular size was normal, and the grey-white differentiation was preserved (Figure 2). The complete blood count, liver function test, creatinine, and glucose levels were within normal values. He later transferred back to the mental health hospital. The clozapine dose was gradually increased to 650 mg daily with an improvement of the auditory hallucinations, the suicidal ideation, and the symptoms of Cotard and Capgras syndrome. PANSS at the discharge was 51. A weekly normal absolute neutrophil count was obtained. The last WBC was 6500 cells/mcL and the ANC 4290 cells/mcL.
3. Discussion
In this case report, we present a patient with schizophrenia with Cotard syndrome who later developed Capgras syndrome. The association of Cotard and Capgras delusions in the same patient is extremely rare [2].
Cotard and Capgras delusions can also be understood as the one-stage or the two-stage model [3]. In the first one, the experiential, delusions are elucidated as a normal rationalization of the unusual perceptual experience. In the second one, the inferential, delusions are considered as an abnormal rationalization of the unusual perceptual experience. In this case, they may represent the way a person tries to attribute negative events to external causes (as in the case of Capgras that is accompanied by delusions of persecution) or internal causes (as in the case of Cotard in the setting of a depressive disorder) [4].
In our case, the Cotard syndrome did not improve with the electroconvulsive therapy (ECT), successful treatment in cases of melancholia, or psychotic depression [5]. The reasons for this could include that the Cotard syndrome appeared in the psychotic setting, the early onset of the disorder alongside his strong genetic load (both parents having features of schizophrenia). Our patient had persisting significant symptoms despite the use of two antipsychotics suggesting treatment-resistant schizophrenia, so the treatment was progressively changed to clozapine.
Through the observation of this case, we conclude that the recognition of symptoms of Cotard and Capgras syndrome in schizophrenia is important for the assessment of appropriate treatment.
Conflicts of Interest
None of the authors have any conflicts of interest to declare.
Figure 1 Frontal chest radiograph showing consolidation of both lungs with increasing density towards the lung bases, predominantly the left lung base.
Figure 2 Noncontrast computed tomography of the head. | OLANZAPINE, QUETIAPINE, RISPERIDONE, SULPIRIDE | DrugsGivenReaction | CC BY | 33552609 | 19,088,735 | 2021 |
What was the outcome of reaction 'Drug ineffective'? | Cotard and Capgras Syndrome in a Patient with Treatment-Resistant Schizophrenia.
The presentation of both Cotard and Capgras syndromes is uncommon in schizophrenia. We present a case of a 23-year-old male with the diagnosis of schizophrenia with Cotard syndrome who later developed Capgras syndrome. By persisting significant symptoms despite the use of two antipsychotics, he was given the diagnosis of treatment-resistant schizophrenia, and his symptoms improved with clozapine. This is one of the few cases of Cotard and Capgras syndromes in a patient with schizophrenia.
1. Introduction
The presentation of both Cotard and Capgras syndromes is uncommon in schizophrenia, and a few cases have been reported. Cotard syndrome was first described by Jules Cotard in 1880, and one of the characteristics is the nihilistic delusions that are related to denying the existence of oneself or the world. Capgras syndrome was described in 1923 by Capgras and Reboul-Lachaux and is characterized by the delusion that the individual or family members have been replaced by substitutes [1]. We report the case of a patient with treatment-resistant schizophrenia who had symptoms of both syndromes.
2. Case Presentation
R. is a 23-year-old, male, with a family psychiatric history of psychotic disorder and whose symptoms started at 13 with social isolation and poor hygiene. At 15, he became aggressive and suspicious, and risperidone 3 mg was prescribed daily; then, auditory hallucinations developed, so the antipsychotic was increased to 4 mg daily. However, he subsequently presented on numerous occasions to the emergency room (ER) with aggressive behavior and persecutory delusions. When he was 18, disorganized behavior and delusions of prejudice were added; for this reason, sulpiride 400 mg and olanzapine 10 mg daily were prescribed but without good response. Then, he presented with nihilistic delusions concerning his existence “I am dead, I died in 2012,” nihilistic delusions related to his body “I do not have a heart,” hypochondriacal delusions “my organs are not working,” delusions of guilt “I am taking the blame,” and suicidal ideation. For these reasons, he was again taken for his dad to the ER. In the mental examination, he was agitated, asking people to kill him. The PANSS upon admission of the patient was 125. During the hospitalization, he continued with the suicidal ideation, and the initiation of electroconvulsive therapy was recommended. The patient received 25 sessions of electroconvulsive therapy with partial improvement in the psychotic symptoms. His previous medication was changed to quetiapine 900 mg daily, without improvement. He was given a diagnosis of treatment-resistant schizophrenia, and clozapine was started. During hospitalization, the patient started refusing food, and a nasogastric tube was inserted. On one occasion, he became unwell, developing aspiration pneumonia (Figure 1) and spent 15 days in intensive care. As his medical condition subsequently improved, he said “I don't have parents, the people who raised me are impostors, they look like my parents, they will be angels, my parents buried me and I never knew about them.” In the neurological physical exam, the patient was alert, oriented to person and time. He mentioned he was in purgatory. The speech was normal. The muscle strength was 5/5 bilaterally, with no motor deficits. The sensation was intact bilaterally. Reflexes are 2+ bilaterally. Brain computerized tomography scan showed no intra- or extra-axial fluid, hemorrhage, or mass; the ventricular size was normal, and the grey-white differentiation was preserved (Figure 2). The complete blood count, liver function test, creatinine, and glucose levels were within normal values. He later transferred back to the mental health hospital. The clozapine dose was gradually increased to 650 mg daily with an improvement of the auditory hallucinations, the suicidal ideation, and the symptoms of Cotard and Capgras syndrome. PANSS at the discharge was 51. A weekly normal absolute neutrophil count was obtained. The last WBC was 6500 cells/mcL and the ANC 4290 cells/mcL.
3. Discussion
In this case report, we present a patient with schizophrenia with Cotard syndrome who later developed Capgras syndrome. The association of Cotard and Capgras delusions in the same patient is extremely rare [2].
Cotard and Capgras delusions can also be understood as the one-stage or the two-stage model [3]. In the first one, the experiential, delusions are elucidated as a normal rationalization of the unusual perceptual experience. In the second one, the inferential, delusions are considered as an abnormal rationalization of the unusual perceptual experience. In this case, they may represent the way a person tries to attribute negative events to external causes (as in the case of Capgras that is accompanied by delusions of persecution) or internal causes (as in the case of Cotard in the setting of a depressive disorder) [4].
In our case, the Cotard syndrome did not improve with the electroconvulsive therapy (ECT), successful treatment in cases of melancholia, or psychotic depression [5]. The reasons for this could include that the Cotard syndrome appeared in the psychotic setting, the early onset of the disorder alongside his strong genetic load (both parents having features of schizophrenia). Our patient had persisting significant symptoms despite the use of two antipsychotics suggesting treatment-resistant schizophrenia, so the treatment was progressively changed to clozapine.
Through the observation of this case, we conclude that the recognition of symptoms of Cotard and Capgras syndrome in schizophrenia is important for the assessment of appropriate treatment.
Conflicts of Interest
None of the authors have any conflicts of interest to declare.
Figure 1 Frontal chest radiograph showing consolidation of both lungs with increasing density towards the lung bases, predominantly the left lung base.
Figure 2 Noncontrast computed tomography of the head. | Recovering | ReactionOutcome | CC BY | 33552609 | 19,088,735 | 2021 |
What was the outcome of reaction 'Hallucination, auditory'? | Cotard and Capgras Syndrome in a Patient with Treatment-Resistant Schizophrenia.
The presentation of both Cotard and Capgras syndromes is uncommon in schizophrenia. We present a case of a 23-year-old male with the diagnosis of schizophrenia with Cotard syndrome who later developed Capgras syndrome. By persisting significant symptoms despite the use of two antipsychotics, he was given the diagnosis of treatment-resistant schizophrenia, and his symptoms improved with clozapine. This is one of the few cases of Cotard and Capgras syndromes in a patient with schizophrenia.
1. Introduction
The presentation of both Cotard and Capgras syndromes is uncommon in schizophrenia, and a few cases have been reported. Cotard syndrome was first described by Jules Cotard in 1880, and one of the characteristics is the nihilistic delusions that are related to denying the existence of oneself or the world. Capgras syndrome was described in 1923 by Capgras and Reboul-Lachaux and is characterized by the delusion that the individual or family members have been replaced by substitutes [1]. We report the case of a patient with treatment-resistant schizophrenia who had symptoms of both syndromes.
2. Case Presentation
R. is a 23-year-old, male, with a family psychiatric history of psychotic disorder and whose symptoms started at 13 with social isolation and poor hygiene. At 15, he became aggressive and suspicious, and risperidone 3 mg was prescribed daily; then, auditory hallucinations developed, so the antipsychotic was increased to 4 mg daily. However, he subsequently presented on numerous occasions to the emergency room (ER) with aggressive behavior and persecutory delusions. When he was 18, disorganized behavior and delusions of prejudice were added; for this reason, sulpiride 400 mg and olanzapine 10 mg daily were prescribed but without good response. Then, he presented with nihilistic delusions concerning his existence “I am dead, I died in 2012,” nihilistic delusions related to his body “I do not have a heart,” hypochondriacal delusions “my organs are not working,” delusions of guilt “I am taking the blame,” and suicidal ideation. For these reasons, he was again taken for his dad to the ER. In the mental examination, he was agitated, asking people to kill him. The PANSS upon admission of the patient was 125. During the hospitalization, he continued with the suicidal ideation, and the initiation of electroconvulsive therapy was recommended. The patient received 25 sessions of electroconvulsive therapy with partial improvement in the psychotic symptoms. His previous medication was changed to quetiapine 900 mg daily, without improvement. He was given a diagnosis of treatment-resistant schizophrenia, and clozapine was started. During hospitalization, the patient started refusing food, and a nasogastric tube was inserted. On one occasion, he became unwell, developing aspiration pneumonia (Figure 1) and spent 15 days in intensive care. As his medical condition subsequently improved, he said “I don't have parents, the people who raised me are impostors, they look like my parents, they will be angels, my parents buried me and I never knew about them.” In the neurological physical exam, the patient was alert, oriented to person and time. He mentioned he was in purgatory. The speech was normal. The muscle strength was 5/5 bilaterally, with no motor deficits. The sensation was intact bilaterally. Reflexes are 2+ bilaterally. Brain computerized tomography scan showed no intra- or extra-axial fluid, hemorrhage, or mass; the ventricular size was normal, and the grey-white differentiation was preserved (Figure 2). The complete blood count, liver function test, creatinine, and glucose levels were within normal values. He later transferred back to the mental health hospital. The clozapine dose was gradually increased to 650 mg daily with an improvement of the auditory hallucinations, the suicidal ideation, and the symptoms of Cotard and Capgras syndrome. PANSS at the discharge was 51. A weekly normal absolute neutrophil count was obtained. The last WBC was 6500 cells/mcL and the ANC 4290 cells/mcL.
3. Discussion
In this case report, we present a patient with schizophrenia with Cotard syndrome who later developed Capgras syndrome. The association of Cotard and Capgras delusions in the same patient is extremely rare [2].
Cotard and Capgras delusions can also be understood as the one-stage or the two-stage model [3]. In the first one, the experiential, delusions are elucidated as a normal rationalization of the unusual perceptual experience. In the second one, the inferential, delusions are considered as an abnormal rationalization of the unusual perceptual experience. In this case, they may represent the way a person tries to attribute negative events to external causes (as in the case of Capgras that is accompanied by delusions of persecution) or internal causes (as in the case of Cotard in the setting of a depressive disorder) [4].
In our case, the Cotard syndrome did not improve with the electroconvulsive therapy (ECT), successful treatment in cases of melancholia, or psychotic depression [5]. The reasons for this could include that the Cotard syndrome appeared in the psychotic setting, the early onset of the disorder alongside his strong genetic load (both parents having features of schizophrenia). Our patient had persisting significant symptoms despite the use of two antipsychotics suggesting treatment-resistant schizophrenia, so the treatment was progressively changed to clozapine.
Through the observation of this case, we conclude that the recognition of symptoms of Cotard and Capgras syndrome in schizophrenia is important for the assessment of appropriate treatment.
Conflicts of Interest
None of the authors have any conflicts of interest to declare.
Figure 1 Frontal chest radiograph showing consolidation of both lungs with increasing density towards the lung bases, predominantly the left lung base.
Figure 2 Noncontrast computed tomography of the head. | Recovering | ReactionOutcome | CC BY | 33552609 | 19,088,735 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Successful Treatment of Auricular Dystonia by Unilateral Pallidothalamic Tractotomy.
Ear movement disorders are rarely reported. Although some patients may respond to botulinum toxin injections, reports on surgical treatment options remain limited.
A 57-year-old woman was diagnosed with auricular dystonia, which was refractory to botulinum toxin injections. Since involuntary movement and pain were predominantly present on the right side and the patient rejected the implantation of a mechanical device, we decided to perform left pallidothalamic tractotomy. Immediately following lesioning, bilateral ear movements and right auricular pain ceased with no complications.
Stereotactic neurosurgical treatment can be an alternative for auricular dystonia.
Ear movement disorders, such as auricular myoclonus or dystonia, are rarely reported.The present case was refractory to repetitive botulinum toxin injections and oral medications.To the best of our knowledge, this is the first case of auricular dystonia that successfully improved with stereotactic neurosurgical treatment (pallidothalamic tractotomy).
INTRODUCTION
Moving ears syndrome (ear movement disorders), including auricular myoclonus, dystonia or focal motor seizure, are rarely reported [123456]. Three major muscles located around the auricle, namely the anterior, superior, and posterior auricular muscles, are functionally vestigial in humans. Previous studies have shown that ear movement disorders can successfully be treated with botulinum toxin injections [257]; however, to date, there have been no reports on surgical treatment. Herein, we report a patient with auricular dystonia, which was refractory to botulinum toxin injections, who was successfully treated with unilateral pallidothalamic tractotomy.
CASE DESCRIPTION
The patient, a 57-year-old woman, had no significant history of traumatic injuries or psychiatric or movement disorders. Involuntary movement of the right ear had gradually developed at 53 years of age, and involuntary movement of the left ear had developed two months later. Initially, the movements were intermittent; bilateral ear movements had developed gradually, and became continuous with significant pain in the right auricle and posterior neck. She was diagnosed with focal auricular dystonia and received oral medicines including clonazepam (3 mg), pain medications (NSAID and tramadol hydrochloride), repetitive botulinum toxin injections (5–10 IU) into the right posterior auricular muscles, and occipital nerve blockers (lidocaine). However, these treatments were not effective in reducing pain and involuntary movements of the ear. She discontinued anticholinergic drugs due to side effects including dry mouth, sleepiness, and dizziness. Although botulinum toxin injections into the anterior auricular and/or superior muscle were partially effective for involuntary movement of the right auricle, she discontinued botulinum toxin injections due to high associated costs and unpredictable effects. She was ultimately referred to our hospital for surgical treatment evaluation. Her ear movements were predominantly on the right side. Involuntary muscle contractions were confirmed in the right anterior and superior auricular muscles of the right auricle (Video 1). In the left auricle, the main involuntary muscle contraction was confirmed to be in the superior auricular muscle (Video 1). She exhibited no voluntary control over these ear movements, and could not suppress them; significant pain was only present in the right auricle. There were no synchronous and rhythmic movements between the two ears. Involuntary movements were not confirmed during sleep and were mild in the morning. Her brain MRI showed no abnormalities; electromyography was not performed. Before the onset of the auricular movements, she had not taken any oral medications. We diagnosed her with focal auricular dystonia. Although we suggested deep brain stimulation, the patient rejected the implantation of a mechanical device. Since involuntary movements and pain were predominantly present on the right side, we decided to perform left pallidothalamic tractotomy after the patient provided written informed consent for the surgery.
Video 1 Preoperative condition.
T2-weighted brain MRI was used to identify a potential surgical target, while brain lab elements were used for stereotactic planning. The target was 9 mm lateral, 0.5 mm posterior, and 3.5 mm inferior to the midpoint of the anterior and posterior commissures. The surgery was performed under local anesthesia. A Leksell neurogenerator and monopolar radiofrequency electrode (1 mm diameter, 4 mm insulated tip) were used to perform macrostimulation and lesioning. Macrostimulation at the target (100 µs, 133 Hz, and 1–3.5 mA) induced no abnormal sensory or motor responses. We made two contiguous lesions and a 3 mm withdrawn point at 70ºC/40 seconds. Immediately following lesioning (on the day of the surgery), bilateral ear movements had ceased (Video 2). The right auricular pain was completely resolved, while that in the posterior neck was not. Post-operative brain MRI showed a coagulated lesion located on the intended target (Figure 1). There were no significant complications, although the patient continued to complain of discomfort in the left auricle despite no visual observations of involuntary movements 3-months postoperatively.
Video 2 Postoperative condition.
Figure 1 Postoperative MRI.
T1-axial (A) and T2-coronal (B) MRI showing a lesion on the left pallidothalamic tract. Black arrow showing the mammillothalamic tract and white arrow showing the subthalamic nucleus.
DISCUSSION
To the best of our knowledge, this is the first reported case of auricular dystonia (moving ears syndrome) successfully improved with stereotactic neurosurgical intervention. The present case was refractory to repetitive botulinum toxin injections and oral medications, including clonazepam. The significant pain in the right auricle and the involuntary movements were disabling; therefore, we decided to perform stereotactic neurosurgical intervention.
Moving ears syndrome has rarely been reported; it is associated with involuntary muscle contractions in the superior, anterior, and posterior auricular muscles. Caviness et al. reported four cases of ear dyskinesia following carbamazepine treatment [1]. Chaudhuri also reported on two cases of focal ear dystonia treated by clonazepam and botulinum toxin injections into the superior and posterior auricular muscles [2]. Carluer et al. reported a single case of ear dyskinesia treated by botulinum toxin injections into the superior auricular muscles [5]. Alonso-Navarro et al. reported on a case of ear dystonia where they confirmed right posterior auricular irregular activity on a needle electromyogram with muscle activity lasting a few seconds; this was successfully treated with botulinum toxin injections [3]. However, the present case was refractory to repetitive botulinum toxin injections. For patients who show no response to botulinum toxin injections during focal dystonia treatment, stereotactic neurosurgical treatment can be an alternative option. The most widely available surgical treatment is deep brain stimulation (DBS) of the globus pallidus internus (GPi) [8]. Previous studies have reported significant efficacy of GPi-DBS for dystonia in the craniocervical region [910]. However, there have been no reports on surgical treatment for focal auricular dystonia. The primary complaints in the present case included involuntary movement and pain in the right auricle. Therefore, we believed that surgery on the left side was sufficient for treating the right auricular involuntary movement and pain. Our patient rejected DBS since it involves implantation of a mechanical device in the body; thus, we suggested unilateral lesioning surgery as a viable alternative treatment option.
Comorbid pain associated with moving ears syndrome has not yet been reported. In this case, the patient complained of right whole auricular pain, which developed after the onset of the right auricular involuntary movement. Pain reduction was achieved in concurrence with the improvement of right auricular involuntary movement after surgery. Sensory innervations of the auricle include the great auricular nerve for the postero-inferior region, lesser occipital nerve for the supero-posterior region, auricular branch of the vagus nerve for the anterior region, and the auricular temporal nerve (branch of the mandibular nerve) for the antero-superior region [11]. Involuntary auricular muscle movements may compress or entrap those nerves, probably resulting in comorbid auricular pain.
Pallidotomy is the most widely available lesioning surgery for dystonia [1213], and we recently reported on the efficacy of lesioning on the pallidothalamic tract for dystonia [14]. In our experience, the effects of pallidothalamic tractotomy on dystonia are similar to those of pallidotomy (more than 150 cases). The GPi has several adjacent vital structures, including the internal capsule, optic tract, and the globus pallidus externus. Unexpected hemorrhage or lesioning dislocation on adjacent structures can induce hemiparesis, visual field disturbance, or parkinsonism. The pallidothalamic tract is located lateral to the mammillothalamic tract and above the subthalamic nucleus. Possible off-target complications include dyskinesia with ablation of the subthalamic nucleus and amnesia with ablation of the mammillothalamic tract. The subthalamic nucleus and mammillothalamic tract are clearly visualized as low-intensity areas on T2-MRI; both can be avoided by stereotactic planning. Therefore, we preferred the pallidothalamic tract over the GPi in the treatment of dystonia due to the relative ease of access.
Other than pallidothalamic tractotomy, available surgical treatments for the present case included DBS, focus ultrasound ablation, and peripheral denervation. DBS can provide significant improvement in craniocervical dystonia without irreversible lesions [910]. Dystonia in the craniocervical region including blepharospasm, tongue protrusion dystonia, or cervical dystonia usually require bilateral surgical interventions. However, previous studies reported on some patients with craniocervical dystonia who responded successfully to unilateral surgical intervention [1516171819]. Bilateral ablative procedures are associated with risks of possible complications including dysarthria, dysphagia, and dysphonia. In our previous study, unilateral pallidotomy combined with contralateral pallidothalamic tractotomy for dystonia induced mild hypophonia in 6 of 11 patients [14]. Recurrence or deterioration of dystonia may develop in the present case at a later stage. Considering the possible complications and long-term effects, DBS is a safer surgical treatment compared to ablative treatments. Focused ultrasound pallidothalamic tractotomy, which allows for ablative lesions without an incision, is a safe and effective procedure for Parkinson’s disease [20]. However, bilateral pallidothalamic tractotomy using focused ultrasound also induced hypophonia [20]. The possible risks of bilateral focused ultrasound ablations may be same as those of bilateral radiofrequency ablations. Auricular muscles are innervated by the branches of the facial nerve [21]. Peripheral denervation of those branches can improve moving ears syndrome, which has not yet been reported.
ETHICS AND CONSENT
This study was performed in accordance with the ethical standards detailed in the Declaration of Helsinki.
FUNDING INFORMATION
This work received funding from Takeda Science Foundation.
COMPETING INTERESTS
The authors have no competing interests to declare. | BOTULINUM TOXIN NOS, CLONAZEPAM, DEXTROSE\LIDOCAINE HYDROCHLORIDE, TRAMADOL HYDROCHLORIDE, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33552671 | 19,130,541 | 2021-01-22 |
What was the administration route of drug 'BOTULINUM TOXIN NOS'? | Successful Treatment of Auricular Dystonia by Unilateral Pallidothalamic Tractotomy.
Ear movement disorders are rarely reported. Although some patients may respond to botulinum toxin injections, reports on surgical treatment options remain limited.
A 57-year-old woman was diagnosed with auricular dystonia, which was refractory to botulinum toxin injections. Since involuntary movement and pain were predominantly present on the right side and the patient rejected the implantation of a mechanical device, we decided to perform left pallidothalamic tractotomy. Immediately following lesioning, bilateral ear movements and right auricular pain ceased with no complications.
Stereotactic neurosurgical treatment can be an alternative for auricular dystonia.
Ear movement disorders, such as auricular myoclonus or dystonia, are rarely reported.The present case was refractory to repetitive botulinum toxin injections and oral medications.To the best of our knowledge, this is the first case of auricular dystonia that successfully improved with stereotactic neurosurgical treatment (pallidothalamic tractotomy).
INTRODUCTION
Moving ears syndrome (ear movement disorders), including auricular myoclonus, dystonia or focal motor seizure, are rarely reported [123456]. Three major muscles located around the auricle, namely the anterior, superior, and posterior auricular muscles, are functionally vestigial in humans. Previous studies have shown that ear movement disorders can successfully be treated with botulinum toxin injections [257]; however, to date, there have been no reports on surgical treatment. Herein, we report a patient with auricular dystonia, which was refractory to botulinum toxin injections, who was successfully treated with unilateral pallidothalamic tractotomy.
CASE DESCRIPTION
The patient, a 57-year-old woman, had no significant history of traumatic injuries or psychiatric or movement disorders. Involuntary movement of the right ear had gradually developed at 53 years of age, and involuntary movement of the left ear had developed two months later. Initially, the movements were intermittent; bilateral ear movements had developed gradually, and became continuous with significant pain in the right auricle and posterior neck. She was diagnosed with focal auricular dystonia and received oral medicines including clonazepam (3 mg), pain medications (NSAID and tramadol hydrochloride), repetitive botulinum toxin injections (5–10 IU) into the right posterior auricular muscles, and occipital nerve blockers (lidocaine). However, these treatments were not effective in reducing pain and involuntary movements of the ear. She discontinued anticholinergic drugs due to side effects including dry mouth, sleepiness, and dizziness. Although botulinum toxin injections into the anterior auricular and/or superior muscle were partially effective for involuntary movement of the right auricle, she discontinued botulinum toxin injections due to high associated costs and unpredictable effects. She was ultimately referred to our hospital for surgical treatment evaluation. Her ear movements were predominantly on the right side. Involuntary muscle contractions were confirmed in the right anterior and superior auricular muscles of the right auricle (Video 1). In the left auricle, the main involuntary muscle contraction was confirmed to be in the superior auricular muscle (Video 1). She exhibited no voluntary control over these ear movements, and could not suppress them; significant pain was only present in the right auricle. There were no synchronous and rhythmic movements between the two ears. Involuntary movements were not confirmed during sleep and were mild in the morning. Her brain MRI showed no abnormalities; electromyography was not performed. Before the onset of the auricular movements, she had not taken any oral medications. We diagnosed her with focal auricular dystonia. Although we suggested deep brain stimulation, the patient rejected the implantation of a mechanical device. Since involuntary movements and pain were predominantly present on the right side, we decided to perform left pallidothalamic tractotomy after the patient provided written informed consent for the surgery.
Video 1 Preoperative condition.
T2-weighted brain MRI was used to identify a potential surgical target, while brain lab elements were used for stereotactic planning. The target was 9 mm lateral, 0.5 mm posterior, and 3.5 mm inferior to the midpoint of the anterior and posterior commissures. The surgery was performed under local anesthesia. A Leksell neurogenerator and monopolar radiofrequency electrode (1 mm diameter, 4 mm insulated tip) were used to perform macrostimulation and lesioning. Macrostimulation at the target (100 µs, 133 Hz, and 1–3.5 mA) induced no abnormal sensory or motor responses. We made two contiguous lesions and a 3 mm withdrawn point at 70ºC/40 seconds. Immediately following lesioning (on the day of the surgery), bilateral ear movements had ceased (Video 2). The right auricular pain was completely resolved, while that in the posterior neck was not. Post-operative brain MRI showed a coagulated lesion located on the intended target (Figure 1). There were no significant complications, although the patient continued to complain of discomfort in the left auricle despite no visual observations of involuntary movements 3-months postoperatively.
Video 2 Postoperative condition.
Figure 1 Postoperative MRI.
T1-axial (A) and T2-coronal (B) MRI showing a lesion on the left pallidothalamic tract. Black arrow showing the mammillothalamic tract and white arrow showing the subthalamic nucleus.
DISCUSSION
To the best of our knowledge, this is the first reported case of auricular dystonia (moving ears syndrome) successfully improved with stereotactic neurosurgical intervention. The present case was refractory to repetitive botulinum toxin injections and oral medications, including clonazepam. The significant pain in the right auricle and the involuntary movements were disabling; therefore, we decided to perform stereotactic neurosurgical intervention.
Moving ears syndrome has rarely been reported; it is associated with involuntary muscle contractions in the superior, anterior, and posterior auricular muscles. Caviness et al. reported four cases of ear dyskinesia following carbamazepine treatment [1]. Chaudhuri also reported on two cases of focal ear dystonia treated by clonazepam and botulinum toxin injections into the superior and posterior auricular muscles [2]. Carluer et al. reported a single case of ear dyskinesia treated by botulinum toxin injections into the superior auricular muscles [5]. Alonso-Navarro et al. reported on a case of ear dystonia where they confirmed right posterior auricular irregular activity on a needle electromyogram with muscle activity lasting a few seconds; this was successfully treated with botulinum toxin injections [3]. However, the present case was refractory to repetitive botulinum toxin injections. For patients who show no response to botulinum toxin injections during focal dystonia treatment, stereotactic neurosurgical treatment can be an alternative option. The most widely available surgical treatment is deep brain stimulation (DBS) of the globus pallidus internus (GPi) [8]. Previous studies have reported significant efficacy of GPi-DBS for dystonia in the craniocervical region [910]. However, there have been no reports on surgical treatment for focal auricular dystonia. The primary complaints in the present case included involuntary movement and pain in the right auricle. Therefore, we believed that surgery on the left side was sufficient for treating the right auricular involuntary movement and pain. Our patient rejected DBS since it involves implantation of a mechanical device in the body; thus, we suggested unilateral lesioning surgery as a viable alternative treatment option.
Comorbid pain associated with moving ears syndrome has not yet been reported. In this case, the patient complained of right whole auricular pain, which developed after the onset of the right auricular involuntary movement. Pain reduction was achieved in concurrence with the improvement of right auricular involuntary movement after surgery. Sensory innervations of the auricle include the great auricular nerve for the postero-inferior region, lesser occipital nerve for the supero-posterior region, auricular branch of the vagus nerve for the anterior region, and the auricular temporal nerve (branch of the mandibular nerve) for the antero-superior region [11]. Involuntary auricular muscle movements may compress or entrap those nerves, probably resulting in comorbid auricular pain.
Pallidotomy is the most widely available lesioning surgery for dystonia [1213], and we recently reported on the efficacy of lesioning on the pallidothalamic tract for dystonia [14]. In our experience, the effects of pallidothalamic tractotomy on dystonia are similar to those of pallidotomy (more than 150 cases). The GPi has several adjacent vital structures, including the internal capsule, optic tract, and the globus pallidus externus. Unexpected hemorrhage or lesioning dislocation on adjacent structures can induce hemiparesis, visual field disturbance, or parkinsonism. The pallidothalamic tract is located lateral to the mammillothalamic tract and above the subthalamic nucleus. Possible off-target complications include dyskinesia with ablation of the subthalamic nucleus and amnesia with ablation of the mammillothalamic tract. The subthalamic nucleus and mammillothalamic tract are clearly visualized as low-intensity areas on T2-MRI; both can be avoided by stereotactic planning. Therefore, we preferred the pallidothalamic tract over the GPi in the treatment of dystonia due to the relative ease of access.
Other than pallidothalamic tractotomy, available surgical treatments for the present case included DBS, focus ultrasound ablation, and peripheral denervation. DBS can provide significant improvement in craniocervical dystonia without irreversible lesions [910]. Dystonia in the craniocervical region including blepharospasm, tongue protrusion dystonia, or cervical dystonia usually require bilateral surgical interventions. However, previous studies reported on some patients with craniocervical dystonia who responded successfully to unilateral surgical intervention [1516171819]. Bilateral ablative procedures are associated with risks of possible complications including dysarthria, dysphagia, and dysphonia. In our previous study, unilateral pallidotomy combined with contralateral pallidothalamic tractotomy for dystonia induced mild hypophonia in 6 of 11 patients [14]. Recurrence or deterioration of dystonia may develop in the present case at a later stage. Considering the possible complications and long-term effects, DBS is a safer surgical treatment compared to ablative treatments. Focused ultrasound pallidothalamic tractotomy, which allows for ablative lesions without an incision, is a safe and effective procedure for Parkinson’s disease [20]. However, bilateral pallidothalamic tractotomy using focused ultrasound also induced hypophonia [20]. The possible risks of bilateral focused ultrasound ablations may be same as those of bilateral radiofrequency ablations. Auricular muscles are innervated by the branches of the facial nerve [21]. Peripheral denervation of those branches can improve moving ears syndrome, which has not yet been reported.
ETHICS AND CONSENT
This study was performed in accordance with the ethical standards detailed in the Declaration of Helsinki.
FUNDING INFORMATION
This work received funding from Takeda Science Foundation.
COMPETING INTERESTS
The authors have no competing interests to declare. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33552671 | 19,130,541 | 2021-01-22 |
What was the dosage of drug 'CLONAZEPAM'? | Successful Treatment of Auricular Dystonia by Unilateral Pallidothalamic Tractotomy.
Ear movement disorders are rarely reported. Although some patients may respond to botulinum toxin injections, reports on surgical treatment options remain limited.
A 57-year-old woman was diagnosed with auricular dystonia, which was refractory to botulinum toxin injections. Since involuntary movement and pain were predominantly present on the right side and the patient rejected the implantation of a mechanical device, we decided to perform left pallidothalamic tractotomy. Immediately following lesioning, bilateral ear movements and right auricular pain ceased with no complications.
Stereotactic neurosurgical treatment can be an alternative for auricular dystonia.
Ear movement disorders, such as auricular myoclonus or dystonia, are rarely reported.The present case was refractory to repetitive botulinum toxin injections and oral medications.To the best of our knowledge, this is the first case of auricular dystonia that successfully improved with stereotactic neurosurgical treatment (pallidothalamic tractotomy).
INTRODUCTION
Moving ears syndrome (ear movement disorders), including auricular myoclonus, dystonia or focal motor seizure, are rarely reported [123456]. Three major muscles located around the auricle, namely the anterior, superior, and posterior auricular muscles, are functionally vestigial in humans. Previous studies have shown that ear movement disorders can successfully be treated with botulinum toxin injections [257]; however, to date, there have been no reports on surgical treatment. Herein, we report a patient with auricular dystonia, which was refractory to botulinum toxin injections, who was successfully treated with unilateral pallidothalamic tractotomy.
CASE DESCRIPTION
The patient, a 57-year-old woman, had no significant history of traumatic injuries or psychiatric or movement disorders. Involuntary movement of the right ear had gradually developed at 53 years of age, and involuntary movement of the left ear had developed two months later. Initially, the movements were intermittent; bilateral ear movements had developed gradually, and became continuous with significant pain in the right auricle and posterior neck. She was diagnosed with focal auricular dystonia and received oral medicines including clonazepam (3 mg), pain medications (NSAID and tramadol hydrochloride), repetitive botulinum toxin injections (5–10 IU) into the right posterior auricular muscles, and occipital nerve blockers (lidocaine). However, these treatments were not effective in reducing pain and involuntary movements of the ear. She discontinued anticholinergic drugs due to side effects including dry mouth, sleepiness, and dizziness. Although botulinum toxin injections into the anterior auricular and/or superior muscle were partially effective for involuntary movement of the right auricle, she discontinued botulinum toxin injections due to high associated costs and unpredictable effects. She was ultimately referred to our hospital for surgical treatment evaluation. Her ear movements were predominantly on the right side. Involuntary muscle contractions were confirmed in the right anterior and superior auricular muscles of the right auricle (Video 1). In the left auricle, the main involuntary muscle contraction was confirmed to be in the superior auricular muscle (Video 1). She exhibited no voluntary control over these ear movements, and could not suppress them; significant pain was only present in the right auricle. There were no synchronous and rhythmic movements between the two ears. Involuntary movements were not confirmed during sleep and were mild in the morning. Her brain MRI showed no abnormalities; electromyography was not performed. Before the onset of the auricular movements, she had not taken any oral medications. We diagnosed her with focal auricular dystonia. Although we suggested deep brain stimulation, the patient rejected the implantation of a mechanical device. Since involuntary movements and pain were predominantly present on the right side, we decided to perform left pallidothalamic tractotomy after the patient provided written informed consent for the surgery.
Video 1 Preoperative condition.
T2-weighted brain MRI was used to identify a potential surgical target, while brain lab elements were used for stereotactic planning. The target was 9 mm lateral, 0.5 mm posterior, and 3.5 mm inferior to the midpoint of the anterior and posterior commissures. The surgery was performed under local anesthesia. A Leksell neurogenerator and monopolar radiofrequency electrode (1 mm diameter, 4 mm insulated tip) were used to perform macrostimulation and lesioning. Macrostimulation at the target (100 µs, 133 Hz, and 1–3.5 mA) induced no abnormal sensory or motor responses. We made two contiguous lesions and a 3 mm withdrawn point at 70ºC/40 seconds. Immediately following lesioning (on the day of the surgery), bilateral ear movements had ceased (Video 2). The right auricular pain was completely resolved, while that in the posterior neck was not. Post-operative brain MRI showed a coagulated lesion located on the intended target (Figure 1). There were no significant complications, although the patient continued to complain of discomfort in the left auricle despite no visual observations of involuntary movements 3-months postoperatively.
Video 2 Postoperative condition.
Figure 1 Postoperative MRI.
T1-axial (A) and T2-coronal (B) MRI showing a lesion on the left pallidothalamic tract. Black arrow showing the mammillothalamic tract and white arrow showing the subthalamic nucleus.
DISCUSSION
To the best of our knowledge, this is the first reported case of auricular dystonia (moving ears syndrome) successfully improved with stereotactic neurosurgical intervention. The present case was refractory to repetitive botulinum toxin injections and oral medications, including clonazepam. The significant pain in the right auricle and the involuntary movements were disabling; therefore, we decided to perform stereotactic neurosurgical intervention.
Moving ears syndrome has rarely been reported; it is associated with involuntary muscle contractions in the superior, anterior, and posterior auricular muscles. Caviness et al. reported four cases of ear dyskinesia following carbamazepine treatment [1]. Chaudhuri also reported on two cases of focal ear dystonia treated by clonazepam and botulinum toxin injections into the superior and posterior auricular muscles [2]. Carluer et al. reported a single case of ear dyskinesia treated by botulinum toxin injections into the superior auricular muscles [5]. Alonso-Navarro et al. reported on a case of ear dystonia where they confirmed right posterior auricular irregular activity on a needle electromyogram with muscle activity lasting a few seconds; this was successfully treated with botulinum toxin injections [3]. However, the present case was refractory to repetitive botulinum toxin injections. For patients who show no response to botulinum toxin injections during focal dystonia treatment, stereotactic neurosurgical treatment can be an alternative option. The most widely available surgical treatment is deep brain stimulation (DBS) of the globus pallidus internus (GPi) [8]. Previous studies have reported significant efficacy of GPi-DBS for dystonia in the craniocervical region [910]. However, there have been no reports on surgical treatment for focal auricular dystonia. The primary complaints in the present case included involuntary movement and pain in the right auricle. Therefore, we believed that surgery on the left side was sufficient for treating the right auricular involuntary movement and pain. Our patient rejected DBS since it involves implantation of a mechanical device in the body; thus, we suggested unilateral lesioning surgery as a viable alternative treatment option.
Comorbid pain associated with moving ears syndrome has not yet been reported. In this case, the patient complained of right whole auricular pain, which developed after the onset of the right auricular involuntary movement. Pain reduction was achieved in concurrence with the improvement of right auricular involuntary movement after surgery. Sensory innervations of the auricle include the great auricular nerve for the postero-inferior region, lesser occipital nerve for the supero-posterior region, auricular branch of the vagus nerve for the anterior region, and the auricular temporal nerve (branch of the mandibular nerve) for the antero-superior region [11]. Involuntary auricular muscle movements may compress or entrap those nerves, probably resulting in comorbid auricular pain.
Pallidotomy is the most widely available lesioning surgery for dystonia [1213], and we recently reported on the efficacy of lesioning on the pallidothalamic tract for dystonia [14]. In our experience, the effects of pallidothalamic tractotomy on dystonia are similar to those of pallidotomy (more than 150 cases). The GPi has several adjacent vital structures, including the internal capsule, optic tract, and the globus pallidus externus. Unexpected hemorrhage or lesioning dislocation on adjacent structures can induce hemiparesis, visual field disturbance, or parkinsonism. The pallidothalamic tract is located lateral to the mammillothalamic tract and above the subthalamic nucleus. Possible off-target complications include dyskinesia with ablation of the subthalamic nucleus and amnesia with ablation of the mammillothalamic tract. The subthalamic nucleus and mammillothalamic tract are clearly visualized as low-intensity areas on T2-MRI; both can be avoided by stereotactic planning. Therefore, we preferred the pallidothalamic tract over the GPi in the treatment of dystonia due to the relative ease of access.
Other than pallidothalamic tractotomy, available surgical treatments for the present case included DBS, focus ultrasound ablation, and peripheral denervation. DBS can provide significant improvement in craniocervical dystonia without irreversible lesions [910]. Dystonia in the craniocervical region including blepharospasm, tongue protrusion dystonia, or cervical dystonia usually require bilateral surgical interventions. However, previous studies reported on some patients with craniocervical dystonia who responded successfully to unilateral surgical intervention [1516171819]. Bilateral ablative procedures are associated with risks of possible complications including dysarthria, dysphagia, and dysphonia. In our previous study, unilateral pallidotomy combined with contralateral pallidothalamic tractotomy for dystonia induced mild hypophonia in 6 of 11 patients [14]. Recurrence or deterioration of dystonia may develop in the present case at a later stage. Considering the possible complications and long-term effects, DBS is a safer surgical treatment compared to ablative treatments. Focused ultrasound pallidothalamic tractotomy, which allows for ablative lesions without an incision, is a safe and effective procedure for Parkinson’s disease [20]. However, bilateral pallidothalamic tractotomy using focused ultrasound also induced hypophonia [20]. The possible risks of bilateral focused ultrasound ablations may be same as those of bilateral radiofrequency ablations. Auricular muscles are innervated by the branches of the facial nerve [21]. Peripheral denervation of those branches can improve moving ears syndrome, which has not yet been reported.
ETHICS AND CONSENT
This study was performed in accordance with the ethical standards detailed in the Declaration of Helsinki.
FUNDING INFORMATION
This work received funding from Takeda Science Foundation.
COMPETING INTERESTS
The authors have no competing interests to declare. | 3 mg (milligrams). | DrugDosage | CC BY | 33552671 | 19,130,541 | 2021-01-22 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Jaundice'. | Severe and Late Acute Liver Injury Induced by Capecitabine.
Capecitabine (CAP) is an antineoplastic agent that is known to cause mild hepatotoxicity. However, severe and late acute liver injury was not reported previously as an adverse reaction of CAP. This report discusses the case of a 63-year-old man with colon cancer who was receiving the fifth cycle of CAP as a monotherapy and presented with fatigue and jaundice during the fifth cycle of CAP. Laboratory tests showed markedly elevated transaminases (aspartate transaminase: 2,448 U/L; alanine transaminase: 1,984 U/L). Eventually, discontinuation of CAP was enough to reverse the delayed CAP-induced acute hepatic injury in clinical and laboratory terms.
Introduction
Drug-induced liver injuries can be categorized into five patterns: cholestatic hepatitis, acute hepatitis, chronic hepatitis, chronic cholestasis, and acute cholestasis [1]. The American DILI Network reported that antibiotics, herbal agents, cardiovascular agents, anti-neoplastic agents, analgesics, and many other classes are implicated in drug-induced liver injury [2]. Colorectal cancer is one of the most common and fatal malignancies worldwide [3]. Capecitabine (CAP), an oral prodrug of 5-fluorouracil, is a pyrimidine analogue that has been used since 1998 to treat advanced colon cancer [4]. The recommended regimen of CAP is 850-1,250 mg/m2 orally twice daily for 14 days. The cycle needs to be repeated every three weeks for total eight cycles [5]. The most common adverse reactions are diarrhea, nausea, vomiting, abdominal pain, fatigue/weakness, and hyperbilirubinemia [6]. Drug-induced liver injury is a known side effect of CAP therapy, which usually manifests with a high bilirubin level. The suggested mechanism is thought to be direct hepatotoxicity. CAP is mainly metabolized in the liver through the microsomal enzyme system, and production of toxic substances may induce liver injury [4]. Serum aminotransaminase rarely may increase in some patients receiving CAP; however, it is unusual to result in high levels more than five times of upper limit of the reference range [4].
In this case report, we present the case of an elderly man who was treated with CAP for colon cancer and presented to our center in the fifth cycle of CAP because of acute liver injury with elevated transaminase in thousands.
Case presentation
A 63-year-old male patient was diagnosed with colorectal cancer accidentally after urgent surgery for bowel obstruction. He was referred to the oncology center and received four cycles of adjuvant chemotherapy with a conventional dose of CAP at 1,250 mg/m2. He was on the 10th day of the fifth cycle when he presented to our hospital complaining of fatigue and yellowish color of his eyes for one week. The patient denied any fever or abdominal pain but mentioned clay-colored stool and dark-colored urine without any changes in defecation or urination habits. Except for the mentioned cancer, his medical history was unremarkable. He also denied any recent intake of alcohol or regular medications or herbals.
On admission, he was afebrile, with a blood pressure of 135/84 mmHg, heart rate of 76 beats per minute, respiratory rate of 17 breaths per minute, and BMI of 26. Physical examination was positive for jaundice noted in sclera and skin. Abdominal examination was unremarkable with no organomegaly. Laboratory findings were significant for markedly elevated serum transaminases and bilirubin (Table 1). Viral hepatitis was ruled out by negative serology for hepatitis A, B, C, and E, Epstein-Barr virus, cytomegalovirus, and herpes simplex virus. Autoimmune panel including ANA, ANCA, and AMA was negative. Ultrasound of the abdomen was unremarkable. CT of the abdomen revealed no hepatic metastases. One month before the presentation, the patient’s baseline liver enzymes and bilirubin were normal (Table 1). The multidisciplinary team decided to discontinue CAP as it was the likely implicated reason behind this severe hepatotoxicity. Two weeks later, the patient’s transaminase level went down with clinical improvement as well. Therefore, the diagnosis of CAP-induced acute liver injury was established. Laboratory tests after six-month follow-up revealed normal serum transaminase and bilirubin levels. At that point, the patient was not taking any chemotherapy and he refused to resume chemotherapy afterward.
Table 1 Blood tests
ALT, alanine transaminase; AST, aspartate transaminase; INR, international normalized ratio
Detail
One month before the presentation
On admission
Two weeks after hospitalization
Normal range
ALT
16
1,984
110
1-43 U/L
AST
21
2,448
68
1-43 U/L
Total bilirubin
0.97
23.03
3.96
0.5-1.2 mg/dL
Direct bilirubin
NA
20.8
2.10
0.00-0.30 mg/dL
Alkaline phosphatase
523
90-290 U/L
INR
1.25
0.9-1.2
Urea
34
10-40 mg/dL
Creatinine
1.09
0.5-1.4 mg/dL
Sodium
141
136-145 mmol/L
Potassium
4.1
3.5-5.1 mmol/L
Discussion
Severe hepatotoxicity (high alanine transaminase [ALT] and aspartate transaminase [AST] > 1,000 U/L) is usually related to a few etiologies including viral hepatitis, ischemic liver injury, and toxin- or drug-induced liver injury [7]. Drug-induced liver injury is a common cause of acute liver injury in general population. A detailed history taking should focus on the possible hepatotoxic medications along with other potential etiologies [8]. Although CAP is mainly metabolized by the liver, hepatopathy due to CAP is not a frequent manifestation due to its rapid metabolism and short half-life [9]. Mild hyperbilirubinemia is a well-known side effect of CAP. However, it is often reversible and isolated without other abnormal liver tests [4]. In addition, one article reported a mild serum enzyme elevation that was accompanied by steatosis and inflammation in a patient treated with CAP. This pathology resolved after holding the chemotherapy [10]. Hence, even though several hepatic adverse effects were reported, the severely elevated transaminase was not noticed.
In our case, the patient developed a late elevation of AST and ALT (while he was receiving the fifth course of CAP), which was not noticed in the previous cycles. Furthermore, it was a very severe increment in transaminase (in thousands), which was not reported previously in association with CAP as the patient was vitally stable and the viral hepatitis and autoimmune panels were negative; ischemic and viral etiologies of severe transaminitis were excluded. Therefore, drug-induced hepatotoxicity emerged as the principal diagnosis. A liver biopsy for histological confirmation was not performed in our patient due to the complete recovery of liver enzyme abnormalities after discontinuation of CAP. These unique associated findings were not reported previously as an adverse reaction of CAP.
Conclusions
CAP-induced acute liver injury with very high transaminase can be a serious and late side effect, and it should be considered anytime during the course of treatment. Monitoring liver enzymes for possible hepatotoxicity of CAP and the immediate cessation of treatment might be advisable to mitigate the toxic effects and possible complications.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained by all participants in this study
Authors acknowledge the esteemed contributions of Mohamed Alkayyal, MD, Asaad Alkoht, MD, Dana Abo Samra, MD, and Mohammad Sakkal, MD. | CAPECITABINE | DrugsGivenReaction | CC BY | 33552791 | 18,932,836 | 2021-01-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Liver injury'. | Severe and Late Acute Liver Injury Induced by Capecitabine.
Capecitabine (CAP) is an antineoplastic agent that is known to cause mild hepatotoxicity. However, severe and late acute liver injury was not reported previously as an adverse reaction of CAP. This report discusses the case of a 63-year-old man with colon cancer who was receiving the fifth cycle of CAP as a monotherapy and presented with fatigue and jaundice during the fifth cycle of CAP. Laboratory tests showed markedly elevated transaminases (aspartate transaminase: 2,448 U/L; alanine transaminase: 1,984 U/L). Eventually, discontinuation of CAP was enough to reverse the delayed CAP-induced acute hepatic injury in clinical and laboratory terms.
Introduction
Drug-induced liver injuries can be categorized into five patterns: cholestatic hepatitis, acute hepatitis, chronic hepatitis, chronic cholestasis, and acute cholestasis [1]. The American DILI Network reported that antibiotics, herbal agents, cardiovascular agents, anti-neoplastic agents, analgesics, and many other classes are implicated in drug-induced liver injury [2]. Colorectal cancer is one of the most common and fatal malignancies worldwide [3]. Capecitabine (CAP), an oral prodrug of 5-fluorouracil, is a pyrimidine analogue that has been used since 1998 to treat advanced colon cancer [4]. The recommended regimen of CAP is 850-1,250 mg/m2 orally twice daily for 14 days. The cycle needs to be repeated every three weeks for total eight cycles [5]. The most common adverse reactions are diarrhea, nausea, vomiting, abdominal pain, fatigue/weakness, and hyperbilirubinemia [6]. Drug-induced liver injury is a known side effect of CAP therapy, which usually manifests with a high bilirubin level. The suggested mechanism is thought to be direct hepatotoxicity. CAP is mainly metabolized in the liver through the microsomal enzyme system, and production of toxic substances may induce liver injury [4]. Serum aminotransaminase rarely may increase in some patients receiving CAP; however, it is unusual to result in high levels more than five times of upper limit of the reference range [4].
In this case report, we present the case of an elderly man who was treated with CAP for colon cancer and presented to our center in the fifth cycle of CAP because of acute liver injury with elevated transaminase in thousands.
Case presentation
A 63-year-old male patient was diagnosed with colorectal cancer accidentally after urgent surgery for bowel obstruction. He was referred to the oncology center and received four cycles of adjuvant chemotherapy with a conventional dose of CAP at 1,250 mg/m2. He was on the 10th day of the fifth cycle when he presented to our hospital complaining of fatigue and yellowish color of his eyes for one week. The patient denied any fever or abdominal pain but mentioned clay-colored stool and dark-colored urine without any changes in defecation or urination habits. Except for the mentioned cancer, his medical history was unremarkable. He also denied any recent intake of alcohol or regular medications or herbals.
On admission, he was afebrile, with a blood pressure of 135/84 mmHg, heart rate of 76 beats per minute, respiratory rate of 17 breaths per minute, and BMI of 26. Physical examination was positive for jaundice noted in sclera and skin. Abdominal examination was unremarkable with no organomegaly. Laboratory findings were significant for markedly elevated serum transaminases and bilirubin (Table 1). Viral hepatitis was ruled out by negative serology for hepatitis A, B, C, and E, Epstein-Barr virus, cytomegalovirus, and herpes simplex virus. Autoimmune panel including ANA, ANCA, and AMA was negative. Ultrasound of the abdomen was unremarkable. CT of the abdomen revealed no hepatic metastases. One month before the presentation, the patient’s baseline liver enzymes and bilirubin were normal (Table 1). The multidisciplinary team decided to discontinue CAP as it was the likely implicated reason behind this severe hepatotoxicity. Two weeks later, the patient’s transaminase level went down with clinical improvement as well. Therefore, the diagnosis of CAP-induced acute liver injury was established. Laboratory tests after six-month follow-up revealed normal serum transaminase and bilirubin levels. At that point, the patient was not taking any chemotherapy and he refused to resume chemotherapy afterward.
Table 1 Blood tests
ALT, alanine transaminase; AST, aspartate transaminase; INR, international normalized ratio
Detail
One month before the presentation
On admission
Two weeks after hospitalization
Normal range
ALT
16
1,984
110
1-43 U/L
AST
21
2,448
68
1-43 U/L
Total bilirubin
0.97
23.03
3.96
0.5-1.2 mg/dL
Direct bilirubin
NA
20.8
2.10
0.00-0.30 mg/dL
Alkaline phosphatase
523
90-290 U/L
INR
1.25
0.9-1.2
Urea
34
10-40 mg/dL
Creatinine
1.09
0.5-1.4 mg/dL
Sodium
141
136-145 mmol/L
Potassium
4.1
3.5-5.1 mmol/L
Discussion
Severe hepatotoxicity (high alanine transaminase [ALT] and aspartate transaminase [AST] > 1,000 U/L) is usually related to a few etiologies including viral hepatitis, ischemic liver injury, and toxin- or drug-induced liver injury [7]. Drug-induced liver injury is a common cause of acute liver injury in general population. A detailed history taking should focus on the possible hepatotoxic medications along with other potential etiologies [8]. Although CAP is mainly metabolized by the liver, hepatopathy due to CAP is not a frequent manifestation due to its rapid metabolism and short half-life [9]. Mild hyperbilirubinemia is a well-known side effect of CAP. However, it is often reversible and isolated without other abnormal liver tests [4]. In addition, one article reported a mild serum enzyme elevation that was accompanied by steatosis and inflammation in a patient treated with CAP. This pathology resolved after holding the chemotherapy [10]. Hence, even though several hepatic adverse effects were reported, the severely elevated transaminase was not noticed.
In our case, the patient developed a late elevation of AST and ALT (while he was receiving the fifth course of CAP), which was not noticed in the previous cycles. Furthermore, it was a very severe increment in transaminase (in thousands), which was not reported previously in association with CAP as the patient was vitally stable and the viral hepatitis and autoimmune panels were negative; ischemic and viral etiologies of severe transaminitis were excluded. Therefore, drug-induced hepatotoxicity emerged as the principal diagnosis. A liver biopsy for histological confirmation was not performed in our patient due to the complete recovery of liver enzyme abnormalities after discontinuation of CAP. These unique associated findings were not reported previously as an adverse reaction of CAP.
Conclusions
CAP-induced acute liver injury with very high transaminase can be a serious and late side effect, and it should be considered anytime during the course of treatment. Monitoring liver enzymes for possible hepatotoxicity of CAP and the immediate cessation of treatment might be advisable to mitigate the toxic effects and possible complications.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained by all participants in this study
Authors acknowledge the esteemed contributions of Mohamed Alkayyal, MD, Asaad Alkoht, MD, Dana Abo Samra, MD, and Mohammad Sakkal, MD. | CAPECITABINE | DrugsGivenReaction | CC BY | 33552791 | 18,932,836 | 2021-01-04 |
What was the administration route of drug 'CAPECITABINE'? | Severe and Late Acute Liver Injury Induced by Capecitabine.
Capecitabine (CAP) is an antineoplastic agent that is known to cause mild hepatotoxicity. However, severe and late acute liver injury was not reported previously as an adverse reaction of CAP. This report discusses the case of a 63-year-old man with colon cancer who was receiving the fifth cycle of CAP as a monotherapy and presented with fatigue and jaundice during the fifth cycle of CAP. Laboratory tests showed markedly elevated transaminases (aspartate transaminase: 2,448 U/L; alanine transaminase: 1,984 U/L). Eventually, discontinuation of CAP was enough to reverse the delayed CAP-induced acute hepatic injury in clinical and laboratory terms.
Introduction
Drug-induced liver injuries can be categorized into five patterns: cholestatic hepatitis, acute hepatitis, chronic hepatitis, chronic cholestasis, and acute cholestasis [1]. The American DILI Network reported that antibiotics, herbal agents, cardiovascular agents, anti-neoplastic agents, analgesics, and many other classes are implicated in drug-induced liver injury [2]. Colorectal cancer is one of the most common and fatal malignancies worldwide [3]. Capecitabine (CAP), an oral prodrug of 5-fluorouracil, is a pyrimidine analogue that has been used since 1998 to treat advanced colon cancer [4]. The recommended regimen of CAP is 850-1,250 mg/m2 orally twice daily for 14 days. The cycle needs to be repeated every three weeks for total eight cycles [5]. The most common adverse reactions are diarrhea, nausea, vomiting, abdominal pain, fatigue/weakness, and hyperbilirubinemia [6]. Drug-induced liver injury is a known side effect of CAP therapy, which usually manifests with a high bilirubin level. The suggested mechanism is thought to be direct hepatotoxicity. CAP is mainly metabolized in the liver through the microsomal enzyme system, and production of toxic substances may induce liver injury [4]. Serum aminotransaminase rarely may increase in some patients receiving CAP; however, it is unusual to result in high levels more than five times of upper limit of the reference range [4].
In this case report, we present the case of an elderly man who was treated with CAP for colon cancer and presented to our center in the fifth cycle of CAP because of acute liver injury with elevated transaminase in thousands.
Case presentation
A 63-year-old male patient was diagnosed with colorectal cancer accidentally after urgent surgery for bowel obstruction. He was referred to the oncology center and received four cycles of adjuvant chemotherapy with a conventional dose of CAP at 1,250 mg/m2. He was on the 10th day of the fifth cycle when he presented to our hospital complaining of fatigue and yellowish color of his eyes for one week. The patient denied any fever or abdominal pain but mentioned clay-colored stool and dark-colored urine without any changes in defecation or urination habits. Except for the mentioned cancer, his medical history was unremarkable. He also denied any recent intake of alcohol or regular medications or herbals.
On admission, he was afebrile, with a blood pressure of 135/84 mmHg, heart rate of 76 beats per minute, respiratory rate of 17 breaths per minute, and BMI of 26. Physical examination was positive for jaundice noted in sclera and skin. Abdominal examination was unremarkable with no organomegaly. Laboratory findings were significant for markedly elevated serum transaminases and bilirubin (Table 1). Viral hepatitis was ruled out by negative serology for hepatitis A, B, C, and E, Epstein-Barr virus, cytomegalovirus, and herpes simplex virus. Autoimmune panel including ANA, ANCA, and AMA was negative. Ultrasound of the abdomen was unremarkable. CT of the abdomen revealed no hepatic metastases. One month before the presentation, the patient’s baseline liver enzymes and bilirubin were normal (Table 1). The multidisciplinary team decided to discontinue CAP as it was the likely implicated reason behind this severe hepatotoxicity. Two weeks later, the patient’s transaminase level went down with clinical improvement as well. Therefore, the diagnosis of CAP-induced acute liver injury was established. Laboratory tests after six-month follow-up revealed normal serum transaminase and bilirubin levels. At that point, the patient was not taking any chemotherapy and he refused to resume chemotherapy afterward.
Table 1 Blood tests
ALT, alanine transaminase; AST, aspartate transaminase; INR, international normalized ratio
Detail
One month before the presentation
On admission
Two weeks after hospitalization
Normal range
ALT
16
1,984
110
1-43 U/L
AST
21
2,448
68
1-43 U/L
Total bilirubin
0.97
23.03
3.96
0.5-1.2 mg/dL
Direct bilirubin
NA
20.8
2.10
0.00-0.30 mg/dL
Alkaline phosphatase
523
90-290 U/L
INR
1.25
0.9-1.2
Urea
34
10-40 mg/dL
Creatinine
1.09
0.5-1.4 mg/dL
Sodium
141
136-145 mmol/L
Potassium
4.1
3.5-5.1 mmol/L
Discussion
Severe hepatotoxicity (high alanine transaminase [ALT] and aspartate transaminase [AST] > 1,000 U/L) is usually related to a few etiologies including viral hepatitis, ischemic liver injury, and toxin- or drug-induced liver injury [7]. Drug-induced liver injury is a common cause of acute liver injury in general population. A detailed history taking should focus on the possible hepatotoxic medications along with other potential etiologies [8]. Although CAP is mainly metabolized by the liver, hepatopathy due to CAP is not a frequent manifestation due to its rapid metabolism and short half-life [9]. Mild hyperbilirubinemia is a well-known side effect of CAP. However, it is often reversible and isolated without other abnormal liver tests [4]. In addition, one article reported a mild serum enzyme elevation that was accompanied by steatosis and inflammation in a patient treated with CAP. This pathology resolved after holding the chemotherapy [10]. Hence, even though several hepatic adverse effects were reported, the severely elevated transaminase was not noticed.
In our case, the patient developed a late elevation of AST and ALT (while he was receiving the fifth course of CAP), which was not noticed in the previous cycles. Furthermore, it was a very severe increment in transaminase (in thousands), which was not reported previously in association with CAP as the patient was vitally stable and the viral hepatitis and autoimmune panels were negative; ischemic and viral etiologies of severe transaminitis were excluded. Therefore, drug-induced hepatotoxicity emerged as the principal diagnosis. A liver biopsy for histological confirmation was not performed in our patient due to the complete recovery of liver enzyme abnormalities after discontinuation of CAP. These unique associated findings were not reported previously as an adverse reaction of CAP.
Conclusions
CAP-induced acute liver injury with very high transaminase can be a serious and late side effect, and it should be considered anytime during the course of treatment. Monitoring liver enzymes for possible hepatotoxicity of CAP and the immediate cessation of treatment might be advisable to mitigate the toxic effects and possible complications.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained by all participants in this study
Authors acknowledge the esteemed contributions of Mohamed Alkayyal, MD, Asaad Alkoht, MD, Dana Abo Samra, MD, and Mohammad Sakkal, MD. | Oral | DrugAdministrationRoute | CC BY | 33552791 | 18,953,001 | 2021-01-04 |
What was the outcome of reaction 'Jaundice'? | Severe and Late Acute Liver Injury Induced by Capecitabine.
Capecitabine (CAP) is an antineoplastic agent that is known to cause mild hepatotoxicity. However, severe and late acute liver injury was not reported previously as an adverse reaction of CAP. This report discusses the case of a 63-year-old man with colon cancer who was receiving the fifth cycle of CAP as a monotherapy and presented with fatigue and jaundice during the fifth cycle of CAP. Laboratory tests showed markedly elevated transaminases (aspartate transaminase: 2,448 U/L; alanine transaminase: 1,984 U/L). Eventually, discontinuation of CAP was enough to reverse the delayed CAP-induced acute hepatic injury in clinical and laboratory terms.
Introduction
Drug-induced liver injuries can be categorized into five patterns: cholestatic hepatitis, acute hepatitis, chronic hepatitis, chronic cholestasis, and acute cholestasis [1]. The American DILI Network reported that antibiotics, herbal agents, cardiovascular agents, anti-neoplastic agents, analgesics, and many other classes are implicated in drug-induced liver injury [2]. Colorectal cancer is one of the most common and fatal malignancies worldwide [3]. Capecitabine (CAP), an oral prodrug of 5-fluorouracil, is a pyrimidine analogue that has been used since 1998 to treat advanced colon cancer [4]. The recommended regimen of CAP is 850-1,250 mg/m2 orally twice daily for 14 days. The cycle needs to be repeated every three weeks for total eight cycles [5]. The most common adverse reactions are diarrhea, nausea, vomiting, abdominal pain, fatigue/weakness, and hyperbilirubinemia [6]. Drug-induced liver injury is a known side effect of CAP therapy, which usually manifests with a high bilirubin level. The suggested mechanism is thought to be direct hepatotoxicity. CAP is mainly metabolized in the liver through the microsomal enzyme system, and production of toxic substances may induce liver injury [4]. Serum aminotransaminase rarely may increase in some patients receiving CAP; however, it is unusual to result in high levels more than five times of upper limit of the reference range [4].
In this case report, we present the case of an elderly man who was treated with CAP for colon cancer and presented to our center in the fifth cycle of CAP because of acute liver injury with elevated transaminase in thousands.
Case presentation
A 63-year-old male patient was diagnosed with colorectal cancer accidentally after urgent surgery for bowel obstruction. He was referred to the oncology center and received four cycles of adjuvant chemotherapy with a conventional dose of CAP at 1,250 mg/m2. He was on the 10th day of the fifth cycle when he presented to our hospital complaining of fatigue and yellowish color of his eyes for one week. The patient denied any fever or abdominal pain but mentioned clay-colored stool and dark-colored urine without any changes in defecation or urination habits. Except for the mentioned cancer, his medical history was unremarkable. He also denied any recent intake of alcohol or regular medications or herbals.
On admission, he was afebrile, with a blood pressure of 135/84 mmHg, heart rate of 76 beats per minute, respiratory rate of 17 breaths per minute, and BMI of 26. Physical examination was positive for jaundice noted in sclera and skin. Abdominal examination was unremarkable with no organomegaly. Laboratory findings were significant for markedly elevated serum transaminases and bilirubin (Table 1). Viral hepatitis was ruled out by negative serology for hepatitis A, B, C, and E, Epstein-Barr virus, cytomegalovirus, and herpes simplex virus. Autoimmune panel including ANA, ANCA, and AMA was negative. Ultrasound of the abdomen was unremarkable. CT of the abdomen revealed no hepatic metastases. One month before the presentation, the patient’s baseline liver enzymes and bilirubin were normal (Table 1). The multidisciplinary team decided to discontinue CAP as it was the likely implicated reason behind this severe hepatotoxicity. Two weeks later, the patient’s transaminase level went down with clinical improvement as well. Therefore, the diagnosis of CAP-induced acute liver injury was established. Laboratory tests after six-month follow-up revealed normal serum transaminase and bilirubin levels. At that point, the patient was not taking any chemotherapy and he refused to resume chemotherapy afterward.
Table 1 Blood tests
ALT, alanine transaminase; AST, aspartate transaminase; INR, international normalized ratio
Detail
One month before the presentation
On admission
Two weeks after hospitalization
Normal range
ALT
16
1,984
110
1-43 U/L
AST
21
2,448
68
1-43 U/L
Total bilirubin
0.97
23.03
3.96
0.5-1.2 mg/dL
Direct bilirubin
NA
20.8
2.10
0.00-0.30 mg/dL
Alkaline phosphatase
523
90-290 U/L
INR
1.25
0.9-1.2
Urea
34
10-40 mg/dL
Creatinine
1.09
0.5-1.4 mg/dL
Sodium
141
136-145 mmol/L
Potassium
4.1
3.5-5.1 mmol/L
Discussion
Severe hepatotoxicity (high alanine transaminase [ALT] and aspartate transaminase [AST] > 1,000 U/L) is usually related to a few etiologies including viral hepatitis, ischemic liver injury, and toxin- or drug-induced liver injury [7]. Drug-induced liver injury is a common cause of acute liver injury in general population. A detailed history taking should focus on the possible hepatotoxic medications along with other potential etiologies [8]. Although CAP is mainly metabolized by the liver, hepatopathy due to CAP is not a frequent manifestation due to its rapid metabolism and short half-life [9]. Mild hyperbilirubinemia is a well-known side effect of CAP. However, it is often reversible and isolated without other abnormal liver tests [4]. In addition, one article reported a mild serum enzyme elevation that was accompanied by steatosis and inflammation in a patient treated with CAP. This pathology resolved after holding the chemotherapy [10]. Hence, even though several hepatic adverse effects were reported, the severely elevated transaminase was not noticed.
In our case, the patient developed a late elevation of AST and ALT (while he was receiving the fifth course of CAP), which was not noticed in the previous cycles. Furthermore, it was a very severe increment in transaminase (in thousands), which was not reported previously in association with CAP as the patient was vitally stable and the viral hepatitis and autoimmune panels were negative; ischemic and viral etiologies of severe transaminitis were excluded. Therefore, drug-induced hepatotoxicity emerged as the principal diagnosis. A liver biopsy for histological confirmation was not performed in our patient due to the complete recovery of liver enzyme abnormalities after discontinuation of CAP. These unique associated findings were not reported previously as an adverse reaction of CAP.
Conclusions
CAP-induced acute liver injury with very high transaminase can be a serious and late side effect, and it should be considered anytime during the course of treatment. Monitoring liver enzymes for possible hepatotoxicity of CAP and the immediate cessation of treatment might be advisable to mitigate the toxic effects and possible complications.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained by all participants in this study
Authors acknowledge the esteemed contributions of Mohamed Alkayyal, MD, Asaad Alkoht, MD, Dana Abo Samra, MD, and Mohammad Sakkal, MD. | Recovered | ReactionOutcome | CC BY | 33552791 | 18,932,836 | 2021-01-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Escherichia infection'. | Rare presentation of isolated bilateral testicular myeloid sarcoma: A case report.
Myeloid sarcoma (MS) of the testis is a rare soft tissue tumour which can herald the development of acute myeloid leukaemia (AML). The diagnosis of MS requires a high degree of suspicion as appropriate immunohistochemical staining must be performed to yield an early diagnosis. Whilst there is no consensus on treatment on MS involving the testis, most patients undergo orchidectomy and systemic chemotherapy, with or without radiation therapy. Early and aggressive treatment is key to achieving remission. This case report describes a patient with bilateral testicular MS which heralded the development of AML, who underwent induction chemotherapy and achieved remission.
Introduction
Primary testicular malignancy makes up approximately 1% of male cancers in Western society, and 1–2% of cases have bilateral testicular involvement.1 Testicular myeloid sarcoma (MS) is a highly aggressive extramedullary presentation of acute myeloid leukaemia (AML), secondary to rapid, uncontrolled expansion of immature blast cell populations beyond the bone marrow.2 Extramedullary deposits are more commonly found elsewhere in the body such as the lymph nodes, skin, eye orbits and connective tissue of the neck. MS involvement of the testicles has only been recorded in 68 cases and in only four of those cases was it defined as the presenting symptom, where bilateral testicles were involved.2 This case reviews the presentation and management of a rare case of bilateral testicular MS, preceding any diagnosis of AML or other blood dyscrasia.
Case presentation
A 67 year old male presented with a one week history of tender testicles bilaterally with newly palpable growing masses. The patient's medical history included hypertension and type 2 diabetes mellitus. He denied fevers, weight loss and had no history of undescended testicles or previous scrotal surgery. Examination demonstrated bilaterally tender testicles with firm central masses.
Ultrasound demonstrated hypervascular solid infiltrative masses within both testes (Fig. 1). Baseline bloods were all within normal limits as were alpha foetal protein (AFP) and human chorionic gonadotropin (hCG). Lactate dehydronegase was mildly elevated at 272 U/L (Table 1).Fig. 1 Ultrasound imaging of the testes demonstrating bilateral hypervascular solid infiltrative masses. The right testis in longitudinal (A) and transverse view (B), and the left testis in longitudinal (C) and transverse views (D).
Fig. 1Table 1 Laboratory investigations.
Table 1 Marker Result (reference range)
Blood Beta-HCG <1 IU/L (0–5 IU/L)
AFP 2 μg/L (<11 μg/L)
LDH 272 U/L (120–250 U/L)
Left testis immunohistochemistry MPO Negative
Ly Positive
CD43 Positive
A left inguinal orchidectomy was undertaken where histology was provisionally reported as non-Hodgkin lymphoma, and further immunohistochemistry (IHC) stains were required. Following review by a genitourinary pathologist, the diagnosis of MS of the testis was made (Table 1; Fig. 2). The case was reviewed at a multi-disciplinary meeting and the patient was subsequently transferred under the care of haematology at a tertiary hospital.Fig. 2 Histology of specimen. Haematoxylin and eosin stain at low (20x) (A) and high (100x) (B) power show the infiltrative growth of haemopoetic lesions without the destruction otherwise seen in most other malignant neoplasms. High power (400x) view (C) shows the cytological features of the myeloid sarcoma and an adjacent benign residual tubule (bottom left of image). (D) Cell membrane staining of CD43 and cytoplasmic staining of lysozyme, diagnostic for myeloid sarcoma (400x).
Fig. 2
A fluorodeoxyglucose (FDG)-positron emission tomography (PET) demonstrated multiple sub-centimetre, subcutaneous nodules over the anterior chest wall which were not FDG-tracer-avid and no other lesions were defined. Notably the residual right testicular mass was also not FDG-tracer avid. An MRI brain was ordered due the patient's complaint of right jaw numbness, which demonstrated leukaemic invasion at the base of skull. A lumbar puncture was performed which demonstrated an expanded populations of monocytic cells which was suspicious for leukaemic involvement of the central nervous system.
He received induction chemotherapy of intrathecal 7 + 3 (cytarabine, methotrexate and dexamethasone). This was complicated by neutropenic colitis, an Escherichia coli and Staphylococcus haemolyticus bacteraemia, drug-induced hypersensitivity syndrome and severe delirium requiring intubation and ionotropic support for one week.
The patient improved clinically and returned home. Repeated FDG PET scan at did not demonstrate any avid lesions and the patient's right testis returned to pre-morbid size where previously it had a palpable mass centrally.
Discussion
In an audit of the National Cancer Centre Database from 2004 to 2013, only 746 patients out of all patients with diagnosed with AML presented with MS of any site, accounting for 0.8% of all AML cases.3 A systematic review of 68 cases of testicular MS diagnosed over 30 years identified that unilateral and bilateral testicular involvement was equivalent, but only four cases had bilateral testicular involvement at presentation without any prior diagnosis of blood dyscrasia.2
Testicular masses are deemed malignant until histologically disproven, although some features of the presenting symptoms of testicular MS may be unique. Mass growth is often rapid (appearing over one week in the case of our patient), and may be more associated with pain, nausea and extreme tenderness on examination. Ultrasound is useful in defining mass size and excluding epididymoorchitis as a differential, but lacks specificity and sensitivity to diagnose the type of malignancy.
The morphological appearance of MS is highly variable and is often similar to other lymphoid malignancies. IHC staining for chloroacetate esterase (CAE), CD43, myeloperoxidase (MPO) and lysozyme (Ly) characterises myeloid lineage and may reveal the correct diagnosis.2
Misdiagnosis continues to be of significant concern with these cancers, as noted by McIlwain et al., where six of eight cases of reviewed testicular MS were intially misdiagnosed.4 The most common misdiagnoses are lymphoma, infection, spermatocele and plasmacytoma. Flow cytometry's increasing availability has made it easier to distinguish between morphological variants and further emergence of the use of cytogenetics as a diagnostic tool for haematological malignancies can have important prognostic and treatment indications.2
There is no consensus on the best course of treatment for testicular MS. Management is often multimodal utilising orchidectomy as a diagnostic and therapeutic tool, followed by a chemotherapeutic regimen and, in some cases, radiation therapy. Due to the highly aggressive nature of MS, an early diagnosis of testicular MS is associated with better survival outcomes for patients.5 The mean time to develop AML from the diagnosis of isolated MS may be five months, and as such it is typically recommended that extramedullary lesions are treated with upfront chemotherapy following an AML regimen immediately post diagnosis.3
There is an added layer of complexity for the treatment of cancer in reproductive organs due the effect of treatment on fertility. Whilst this was not a concern for the patient presented above, fertility counselling should be a consideration for patients with family planning in mind.
Conclusion
This is a rare presentation of bilateral testicular MS presenting prior to any diagnosis of AML or blood dyscrasia. This patient's early review by a genitourinary pathologist who had knowledge of the appropriate IHC stains led to rapid diagnosis, upfront treatment and early remission. This highlights the utility of being aware of testicular MS and appropriate IHC stain choice to ensure a correct and prompt diagnosis to allow for treatment, resulting in a positive treatment outcome.
Consent
Informed consent was obtained from the patient on which this case report was written.
Declaration of competing interest
The authors declare they have no conflict of interest. | CYTARABINE, DEXAMETHASONE, METHOTREXATE | DrugsGivenReaction | CC BY-NC-ND | 33552919 | 18,999,117 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Rare presentation of isolated bilateral testicular myeloid sarcoma: A case report.
Myeloid sarcoma (MS) of the testis is a rare soft tissue tumour which can herald the development of acute myeloid leukaemia (AML). The diagnosis of MS requires a high degree of suspicion as appropriate immunohistochemical staining must be performed to yield an early diagnosis. Whilst there is no consensus on treatment on MS involving the testis, most patients undergo orchidectomy and systemic chemotherapy, with or without radiation therapy. Early and aggressive treatment is key to achieving remission. This case report describes a patient with bilateral testicular MS which heralded the development of AML, who underwent induction chemotherapy and achieved remission.
Introduction
Primary testicular malignancy makes up approximately 1% of male cancers in Western society, and 1–2% of cases have bilateral testicular involvement.1 Testicular myeloid sarcoma (MS) is a highly aggressive extramedullary presentation of acute myeloid leukaemia (AML), secondary to rapid, uncontrolled expansion of immature blast cell populations beyond the bone marrow.2 Extramedullary deposits are more commonly found elsewhere in the body such as the lymph nodes, skin, eye orbits and connective tissue of the neck. MS involvement of the testicles has only been recorded in 68 cases and in only four of those cases was it defined as the presenting symptom, where bilateral testicles were involved.2 This case reviews the presentation and management of a rare case of bilateral testicular MS, preceding any diagnosis of AML or other blood dyscrasia.
Case presentation
A 67 year old male presented with a one week history of tender testicles bilaterally with newly palpable growing masses. The patient's medical history included hypertension and type 2 diabetes mellitus. He denied fevers, weight loss and had no history of undescended testicles or previous scrotal surgery. Examination demonstrated bilaterally tender testicles with firm central masses.
Ultrasound demonstrated hypervascular solid infiltrative masses within both testes (Fig. 1). Baseline bloods were all within normal limits as were alpha foetal protein (AFP) and human chorionic gonadotropin (hCG). Lactate dehydronegase was mildly elevated at 272 U/L (Table 1).Fig. 1 Ultrasound imaging of the testes demonstrating bilateral hypervascular solid infiltrative masses. The right testis in longitudinal (A) and transverse view (B), and the left testis in longitudinal (C) and transverse views (D).
Fig. 1Table 1 Laboratory investigations.
Table 1 Marker Result (reference range)
Blood Beta-HCG <1 IU/L (0–5 IU/L)
AFP 2 μg/L (<11 μg/L)
LDH 272 U/L (120–250 U/L)
Left testis immunohistochemistry MPO Negative
Ly Positive
CD43 Positive
A left inguinal orchidectomy was undertaken where histology was provisionally reported as non-Hodgkin lymphoma, and further immunohistochemistry (IHC) stains were required. Following review by a genitourinary pathologist, the diagnosis of MS of the testis was made (Table 1; Fig. 2). The case was reviewed at a multi-disciplinary meeting and the patient was subsequently transferred under the care of haematology at a tertiary hospital.Fig. 2 Histology of specimen. Haematoxylin and eosin stain at low (20x) (A) and high (100x) (B) power show the infiltrative growth of haemopoetic lesions without the destruction otherwise seen in most other malignant neoplasms. High power (400x) view (C) shows the cytological features of the myeloid sarcoma and an adjacent benign residual tubule (bottom left of image). (D) Cell membrane staining of CD43 and cytoplasmic staining of lysozyme, diagnostic for myeloid sarcoma (400x).
Fig. 2
A fluorodeoxyglucose (FDG)-positron emission tomography (PET) demonstrated multiple sub-centimetre, subcutaneous nodules over the anterior chest wall which were not FDG-tracer-avid and no other lesions were defined. Notably the residual right testicular mass was also not FDG-tracer avid. An MRI brain was ordered due the patient's complaint of right jaw numbness, which demonstrated leukaemic invasion at the base of skull. A lumbar puncture was performed which demonstrated an expanded populations of monocytic cells which was suspicious for leukaemic involvement of the central nervous system.
He received induction chemotherapy of intrathecal 7 + 3 (cytarabine, methotrexate and dexamethasone). This was complicated by neutropenic colitis, an Escherichia coli and Staphylococcus haemolyticus bacteraemia, drug-induced hypersensitivity syndrome and severe delirium requiring intubation and ionotropic support for one week.
The patient improved clinically and returned home. Repeated FDG PET scan at did not demonstrate any avid lesions and the patient's right testis returned to pre-morbid size where previously it had a palpable mass centrally.
Discussion
In an audit of the National Cancer Centre Database from 2004 to 2013, only 746 patients out of all patients with diagnosed with AML presented with MS of any site, accounting for 0.8% of all AML cases.3 A systematic review of 68 cases of testicular MS diagnosed over 30 years identified that unilateral and bilateral testicular involvement was equivalent, but only four cases had bilateral testicular involvement at presentation without any prior diagnosis of blood dyscrasia.2
Testicular masses are deemed malignant until histologically disproven, although some features of the presenting symptoms of testicular MS may be unique. Mass growth is often rapid (appearing over one week in the case of our patient), and may be more associated with pain, nausea and extreme tenderness on examination. Ultrasound is useful in defining mass size and excluding epididymoorchitis as a differential, but lacks specificity and sensitivity to diagnose the type of malignancy.
The morphological appearance of MS is highly variable and is often similar to other lymphoid malignancies. IHC staining for chloroacetate esterase (CAE), CD43, myeloperoxidase (MPO) and lysozyme (Ly) characterises myeloid lineage and may reveal the correct diagnosis.2
Misdiagnosis continues to be of significant concern with these cancers, as noted by McIlwain et al., where six of eight cases of reviewed testicular MS were intially misdiagnosed.4 The most common misdiagnoses are lymphoma, infection, spermatocele and plasmacytoma. Flow cytometry's increasing availability has made it easier to distinguish between morphological variants and further emergence of the use of cytogenetics as a diagnostic tool for haematological malignancies can have important prognostic and treatment indications.2
There is no consensus on the best course of treatment for testicular MS. Management is often multimodal utilising orchidectomy as a diagnostic and therapeutic tool, followed by a chemotherapeutic regimen and, in some cases, radiation therapy. Due to the highly aggressive nature of MS, an early diagnosis of testicular MS is associated with better survival outcomes for patients.5 The mean time to develop AML from the diagnosis of isolated MS may be five months, and as such it is typically recommended that extramedullary lesions are treated with upfront chemotherapy following an AML regimen immediately post diagnosis.3
There is an added layer of complexity for the treatment of cancer in reproductive organs due the effect of treatment on fertility. Whilst this was not a concern for the patient presented above, fertility counselling should be a consideration for patients with family planning in mind.
Conclusion
This is a rare presentation of bilateral testicular MS presenting prior to any diagnosis of AML or blood dyscrasia. This patient's early review by a genitourinary pathologist who had knowledge of the appropriate IHC stains led to rapid diagnosis, upfront treatment and early remission. This highlights the utility of being aware of testicular MS and appropriate IHC stain choice to ensure a correct and prompt diagnosis to allow for treatment, resulting in a positive treatment outcome.
Consent
Informed consent was obtained from the patient on which this case report was written.
Declaration of competing interest
The authors declare they have no conflict of interest. | CYTARABINE, DEXAMETHASONE, METHOTREXATE | DrugsGivenReaction | CC BY-NC-ND | 33552919 | 19,009,026 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Rare presentation of isolated bilateral testicular myeloid sarcoma: A case report.
Myeloid sarcoma (MS) of the testis is a rare soft tissue tumour which can herald the development of acute myeloid leukaemia (AML). The diagnosis of MS requires a high degree of suspicion as appropriate immunohistochemical staining must be performed to yield an early diagnosis. Whilst there is no consensus on treatment on MS involving the testis, most patients undergo orchidectomy and systemic chemotherapy, with or without radiation therapy. Early and aggressive treatment is key to achieving remission. This case report describes a patient with bilateral testicular MS which heralded the development of AML, who underwent induction chemotherapy and achieved remission.
Introduction
Primary testicular malignancy makes up approximately 1% of male cancers in Western society, and 1–2% of cases have bilateral testicular involvement.1 Testicular myeloid sarcoma (MS) is a highly aggressive extramedullary presentation of acute myeloid leukaemia (AML), secondary to rapid, uncontrolled expansion of immature blast cell populations beyond the bone marrow.2 Extramedullary deposits are more commonly found elsewhere in the body such as the lymph nodes, skin, eye orbits and connective tissue of the neck. MS involvement of the testicles has only been recorded in 68 cases and in only four of those cases was it defined as the presenting symptom, where bilateral testicles were involved.2 This case reviews the presentation and management of a rare case of bilateral testicular MS, preceding any diagnosis of AML or other blood dyscrasia.
Case presentation
A 67 year old male presented with a one week history of tender testicles bilaterally with newly palpable growing masses. The patient's medical history included hypertension and type 2 diabetes mellitus. He denied fevers, weight loss and had no history of undescended testicles or previous scrotal surgery. Examination demonstrated bilaterally tender testicles with firm central masses.
Ultrasound demonstrated hypervascular solid infiltrative masses within both testes (Fig. 1). Baseline bloods were all within normal limits as were alpha foetal protein (AFP) and human chorionic gonadotropin (hCG). Lactate dehydronegase was mildly elevated at 272 U/L (Table 1).Fig. 1 Ultrasound imaging of the testes demonstrating bilateral hypervascular solid infiltrative masses. The right testis in longitudinal (A) and transverse view (B), and the left testis in longitudinal (C) and transverse views (D).
Fig. 1Table 1 Laboratory investigations.
Table 1 Marker Result (reference range)
Blood Beta-HCG <1 IU/L (0–5 IU/L)
AFP 2 μg/L (<11 μg/L)
LDH 272 U/L (120–250 U/L)
Left testis immunohistochemistry MPO Negative
Ly Positive
CD43 Positive
A left inguinal orchidectomy was undertaken where histology was provisionally reported as non-Hodgkin lymphoma, and further immunohistochemistry (IHC) stains were required. Following review by a genitourinary pathologist, the diagnosis of MS of the testis was made (Table 1; Fig. 2). The case was reviewed at a multi-disciplinary meeting and the patient was subsequently transferred under the care of haematology at a tertiary hospital.Fig. 2 Histology of specimen. Haematoxylin and eosin stain at low (20x) (A) and high (100x) (B) power show the infiltrative growth of haemopoetic lesions without the destruction otherwise seen in most other malignant neoplasms. High power (400x) view (C) shows the cytological features of the myeloid sarcoma and an adjacent benign residual tubule (bottom left of image). (D) Cell membrane staining of CD43 and cytoplasmic staining of lysozyme, diagnostic for myeloid sarcoma (400x).
Fig. 2
A fluorodeoxyglucose (FDG)-positron emission tomography (PET) demonstrated multiple sub-centimetre, subcutaneous nodules over the anterior chest wall which were not FDG-tracer-avid and no other lesions were defined. Notably the residual right testicular mass was also not FDG-tracer avid. An MRI brain was ordered due the patient's complaint of right jaw numbness, which demonstrated leukaemic invasion at the base of skull. A lumbar puncture was performed which demonstrated an expanded populations of monocytic cells which was suspicious for leukaemic involvement of the central nervous system.
He received induction chemotherapy of intrathecal 7 + 3 (cytarabine, methotrexate and dexamethasone). This was complicated by neutropenic colitis, an Escherichia coli and Staphylococcus haemolyticus bacteraemia, drug-induced hypersensitivity syndrome and severe delirium requiring intubation and ionotropic support for one week.
The patient improved clinically and returned home. Repeated FDG PET scan at did not demonstrate any avid lesions and the patient's right testis returned to pre-morbid size where previously it had a palpable mass centrally.
Discussion
In an audit of the National Cancer Centre Database from 2004 to 2013, only 746 patients out of all patients with diagnosed with AML presented with MS of any site, accounting for 0.8% of all AML cases.3 A systematic review of 68 cases of testicular MS diagnosed over 30 years identified that unilateral and bilateral testicular involvement was equivalent, but only four cases had bilateral testicular involvement at presentation without any prior diagnosis of blood dyscrasia.2
Testicular masses are deemed malignant until histologically disproven, although some features of the presenting symptoms of testicular MS may be unique. Mass growth is often rapid (appearing over one week in the case of our patient), and may be more associated with pain, nausea and extreme tenderness on examination. Ultrasound is useful in defining mass size and excluding epididymoorchitis as a differential, but lacks specificity and sensitivity to diagnose the type of malignancy.
The morphological appearance of MS is highly variable and is often similar to other lymphoid malignancies. IHC staining for chloroacetate esterase (CAE), CD43, myeloperoxidase (MPO) and lysozyme (Ly) characterises myeloid lineage and may reveal the correct diagnosis.2
Misdiagnosis continues to be of significant concern with these cancers, as noted by McIlwain et al., where six of eight cases of reviewed testicular MS were intially misdiagnosed.4 The most common misdiagnoses are lymphoma, infection, spermatocele and plasmacytoma. Flow cytometry's increasing availability has made it easier to distinguish between morphological variants and further emergence of the use of cytogenetics as a diagnostic tool for haematological malignancies can have important prognostic and treatment indications.2
There is no consensus on the best course of treatment for testicular MS. Management is often multimodal utilising orchidectomy as a diagnostic and therapeutic tool, followed by a chemotherapeutic regimen and, in some cases, radiation therapy. Due to the highly aggressive nature of MS, an early diagnosis of testicular MS is associated with better survival outcomes for patients.5 The mean time to develop AML from the diagnosis of isolated MS may be five months, and as such it is typically recommended that extramedullary lesions are treated with upfront chemotherapy following an AML regimen immediately post diagnosis.3
There is an added layer of complexity for the treatment of cancer in reproductive organs due the effect of treatment on fertility. Whilst this was not a concern for the patient presented above, fertility counselling should be a consideration for patients with family planning in mind.
Conclusion
This is a rare presentation of bilateral testicular MS presenting prior to any diagnosis of AML or blood dyscrasia. This patient's early review by a genitourinary pathologist who had knowledge of the appropriate IHC stains led to rapid diagnosis, upfront treatment and early remission. This highlights the utility of being aware of testicular MS and appropriate IHC stain choice to ensure a correct and prompt diagnosis to allow for treatment, resulting in a positive treatment outcome.
Consent
Informed consent was obtained from the patient on which this case report was written.
Declaration of competing interest
The authors declare they have no conflict of interest. | CYTARABINE, DEXAMETHASONE, METHOTREXATE | DrugsGivenReaction | CC BY-NC-ND | 33552919 | 19,048,668 | 2021-05 |
What was the administration route of drug 'CYTARABINE'? | Rare presentation of isolated bilateral testicular myeloid sarcoma: A case report.
Myeloid sarcoma (MS) of the testis is a rare soft tissue tumour which can herald the development of acute myeloid leukaemia (AML). The diagnosis of MS requires a high degree of suspicion as appropriate immunohistochemical staining must be performed to yield an early diagnosis. Whilst there is no consensus on treatment on MS involving the testis, most patients undergo orchidectomy and systemic chemotherapy, with or without radiation therapy. Early and aggressive treatment is key to achieving remission. This case report describes a patient with bilateral testicular MS which heralded the development of AML, who underwent induction chemotherapy and achieved remission.
Introduction
Primary testicular malignancy makes up approximately 1% of male cancers in Western society, and 1–2% of cases have bilateral testicular involvement.1 Testicular myeloid sarcoma (MS) is a highly aggressive extramedullary presentation of acute myeloid leukaemia (AML), secondary to rapid, uncontrolled expansion of immature blast cell populations beyond the bone marrow.2 Extramedullary deposits are more commonly found elsewhere in the body such as the lymph nodes, skin, eye orbits and connective tissue of the neck. MS involvement of the testicles has only been recorded in 68 cases and in only four of those cases was it defined as the presenting symptom, where bilateral testicles were involved.2 This case reviews the presentation and management of a rare case of bilateral testicular MS, preceding any diagnosis of AML or other blood dyscrasia.
Case presentation
A 67 year old male presented with a one week history of tender testicles bilaterally with newly palpable growing masses. The patient's medical history included hypertension and type 2 diabetes mellitus. He denied fevers, weight loss and had no history of undescended testicles or previous scrotal surgery. Examination demonstrated bilaterally tender testicles with firm central masses.
Ultrasound demonstrated hypervascular solid infiltrative masses within both testes (Fig. 1). Baseline bloods were all within normal limits as were alpha foetal protein (AFP) and human chorionic gonadotropin (hCG). Lactate dehydronegase was mildly elevated at 272 U/L (Table 1).Fig. 1 Ultrasound imaging of the testes demonstrating bilateral hypervascular solid infiltrative masses. The right testis in longitudinal (A) and transverse view (B), and the left testis in longitudinal (C) and transverse views (D).
Fig. 1Table 1 Laboratory investigations.
Table 1 Marker Result (reference range)
Blood Beta-HCG <1 IU/L (0–5 IU/L)
AFP 2 μg/L (<11 μg/L)
LDH 272 U/L (120–250 U/L)
Left testis immunohistochemistry MPO Negative
Ly Positive
CD43 Positive
A left inguinal orchidectomy was undertaken where histology was provisionally reported as non-Hodgkin lymphoma, and further immunohistochemistry (IHC) stains were required. Following review by a genitourinary pathologist, the diagnosis of MS of the testis was made (Table 1; Fig. 2). The case was reviewed at a multi-disciplinary meeting and the patient was subsequently transferred under the care of haematology at a tertiary hospital.Fig. 2 Histology of specimen. Haematoxylin and eosin stain at low (20x) (A) and high (100x) (B) power show the infiltrative growth of haemopoetic lesions without the destruction otherwise seen in most other malignant neoplasms. High power (400x) view (C) shows the cytological features of the myeloid sarcoma and an adjacent benign residual tubule (bottom left of image). (D) Cell membrane staining of CD43 and cytoplasmic staining of lysozyme, diagnostic for myeloid sarcoma (400x).
Fig. 2
A fluorodeoxyglucose (FDG)-positron emission tomography (PET) demonstrated multiple sub-centimetre, subcutaneous nodules over the anterior chest wall which were not FDG-tracer-avid and no other lesions were defined. Notably the residual right testicular mass was also not FDG-tracer avid. An MRI brain was ordered due the patient's complaint of right jaw numbness, which demonstrated leukaemic invasion at the base of skull. A lumbar puncture was performed which demonstrated an expanded populations of monocytic cells which was suspicious for leukaemic involvement of the central nervous system.
He received induction chemotherapy of intrathecal 7 + 3 (cytarabine, methotrexate and dexamethasone). This was complicated by neutropenic colitis, an Escherichia coli and Staphylococcus haemolyticus bacteraemia, drug-induced hypersensitivity syndrome and severe delirium requiring intubation and ionotropic support for one week.
The patient improved clinically and returned home. Repeated FDG PET scan at did not demonstrate any avid lesions and the patient's right testis returned to pre-morbid size where previously it had a palpable mass centrally.
Discussion
In an audit of the National Cancer Centre Database from 2004 to 2013, only 746 patients out of all patients with diagnosed with AML presented with MS of any site, accounting for 0.8% of all AML cases.3 A systematic review of 68 cases of testicular MS diagnosed over 30 years identified that unilateral and bilateral testicular involvement was equivalent, but only four cases had bilateral testicular involvement at presentation without any prior diagnosis of blood dyscrasia.2
Testicular masses are deemed malignant until histologically disproven, although some features of the presenting symptoms of testicular MS may be unique. Mass growth is often rapid (appearing over one week in the case of our patient), and may be more associated with pain, nausea and extreme tenderness on examination. Ultrasound is useful in defining mass size and excluding epididymoorchitis as a differential, but lacks specificity and sensitivity to diagnose the type of malignancy.
The morphological appearance of MS is highly variable and is often similar to other lymphoid malignancies. IHC staining for chloroacetate esterase (CAE), CD43, myeloperoxidase (MPO) and lysozyme (Ly) characterises myeloid lineage and may reveal the correct diagnosis.2
Misdiagnosis continues to be of significant concern with these cancers, as noted by McIlwain et al., where six of eight cases of reviewed testicular MS were intially misdiagnosed.4 The most common misdiagnoses are lymphoma, infection, spermatocele and plasmacytoma. Flow cytometry's increasing availability has made it easier to distinguish between morphological variants and further emergence of the use of cytogenetics as a diagnostic tool for haematological malignancies can have important prognostic and treatment indications.2
There is no consensus on the best course of treatment for testicular MS. Management is often multimodal utilising orchidectomy as a diagnostic and therapeutic tool, followed by a chemotherapeutic regimen and, in some cases, radiation therapy. Due to the highly aggressive nature of MS, an early diagnosis of testicular MS is associated with better survival outcomes for patients.5 The mean time to develop AML from the diagnosis of isolated MS may be five months, and as such it is typically recommended that extramedullary lesions are treated with upfront chemotherapy following an AML regimen immediately post diagnosis.3
There is an added layer of complexity for the treatment of cancer in reproductive organs due the effect of treatment on fertility. Whilst this was not a concern for the patient presented above, fertility counselling should be a consideration for patients with family planning in mind.
Conclusion
This is a rare presentation of bilateral testicular MS presenting prior to any diagnosis of AML or blood dyscrasia. This patient's early review by a genitourinary pathologist who had knowledge of the appropriate IHC stains led to rapid diagnosis, upfront treatment and early remission. This highlights the utility of being aware of testicular MS and appropriate IHC stain choice to ensure a correct and prompt diagnosis to allow for treatment, resulting in a positive treatment outcome.
Consent
Informed consent was obtained from the patient on which this case report was written.
Declaration of competing interest
The authors declare they have no conflict of interest. | Intrathecal | DrugAdministrationRoute | CC BY-NC-ND | 33552919 | 18,999,117 | 2021-05 |
What was the administration route of drug 'DEXAMETHASONE SODIUM PHOSPHATE'? | Rare presentation of isolated bilateral testicular myeloid sarcoma: A case report.
Myeloid sarcoma (MS) of the testis is a rare soft tissue tumour which can herald the development of acute myeloid leukaemia (AML). The diagnosis of MS requires a high degree of suspicion as appropriate immunohistochemical staining must be performed to yield an early diagnosis. Whilst there is no consensus on treatment on MS involving the testis, most patients undergo orchidectomy and systemic chemotherapy, with or without radiation therapy. Early and aggressive treatment is key to achieving remission. This case report describes a patient with bilateral testicular MS which heralded the development of AML, who underwent induction chemotherapy and achieved remission.
Introduction
Primary testicular malignancy makes up approximately 1% of male cancers in Western society, and 1–2% of cases have bilateral testicular involvement.1 Testicular myeloid sarcoma (MS) is a highly aggressive extramedullary presentation of acute myeloid leukaemia (AML), secondary to rapid, uncontrolled expansion of immature blast cell populations beyond the bone marrow.2 Extramedullary deposits are more commonly found elsewhere in the body such as the lymph nodes, skin, eye orbits and connective tissue of the neck. MS involvement of the testicles has only been recorded in 68 cases and in only four of those cases was it defined as the presenting symptom, where bilateral testicles were involved.2 This case reviews the presentation and management of a rare case of bilateral testicular MS, preceding any diagnosis of AML or other blood dyscrasia.
Case presentation
A 67 year old male presented with a one week history of tender testicles bilaterally with newly palpable growing masses. The patient's medical history included hypertension and type 2 diabetes mellitus. He denied fevers, weight loss and had no history of undescended testicles or previous scrotal surgery. Examination demonstrated bilaterally tender testicles with firm central masses.
Ultrasound demonstrated hypervascular solid infiltrative masses within both testes (Fig. 1). Baseline bloods were all within normal limits as were alpha foetal protein (AFP) and human chorionic gonadotropin (hCG). Lactate dehydronegase was mildly elevated at 272 U/L (Table 1).Fig. 1 Ultrasound imaging of the testes demonstrating bilateral hypervascular solid infiltrative masses. The right testis in longitudinal (A) and transverse view (B), and the left testis in longitudinal (C) and transverse views (D).
Fig. 1Table 1 Laboratory investigations.
Table 1 Marker Result (reference range)
Blood Beta-HCG <1 IU/L (0–5 IU/L)
AFP 2 μg/L (<11 μg/L)
LDH 272 U/L (120–250 U/L)
Left testis immunohistochemistry MPO Negative
Ly Positive
CD43 Positive
A left inguinal orchidectomy was undertaken where histology was provisionally reported as non-Hodgkin lymphoma, and further immunohistochemistry (IHC) stains were required. Following review by a genitourinary pathologist, the diagnosis of MS of the testis was made (Table 1; Fig. 2). The case was reviewed at a multi-disciplinary meeting and the patient was subsequently transferred under the care of haematology at a tertiary hospital.Fig. 2 Histology of specimen. Haematoxylin and eosin stain at low (20x) (A) and high (100x) (B) power show the infiltrative growth of haemopoetic lesions without the destruction otherwise seen in most other malignant neoplasms. High power (400x) view (C) shows the cytological features of the myeloid sarcoma and an adjacent benign residual tubule (bottom left of image). (D) Cell membrane staining of CD43 and cytoplasmic staining of lysozyme, diagnostic for myeloid sarcoma (400x).
Fig. 2
A fluorodeoxyglucose (FDG)-positron emission tomography (PET) demonstrated multiple sub-centimetre, subcutaneous nodules over the anterior chest wall which were not FDG-tracer-avid and no other lesions were defined. Notably the residual right testicular mass was also not FDG-tracer avid. An MRI brain was ordered due the patient's complaint of right jaw numbness, which demonstrated leukaemic invasion at the base of skull. A lumbar puncture was performed which demonstrated an expanded populations of monocytic cells which was suspicious for leukaemic involvement of the central nervous system.
He received induction chemotherapy of intrathecal 7 + 3 (cytarabine, methotrexate and dexamethasone). This was complicated by neutropenic colitis, an Escherichia coli and Staphylococcus haemolyticus bacteraemia, drug-induced hypersensitivity syndrome and severe delirium requiring intubation and ionotropic support for one week.
The patient improved clinically and returned home. Repeated FDG PET scan at did not demonstrate any avid lesions and the patient's right testis returned to pre-morbid size where previously it had a palpable mass centrally.
Discussion
In an audit of the National Cancer Centre Database from 2004 to 2013, only 746 patients out of all patients with diagnosed with AML presented with MS of any site, accounting for 0.8% of all AML cases.3 A systematic review of 68 cases of testicular MS diagnosed over 30 years identified that unilateral and bilateral testicular involvement was equivalent, but only four cases had bilateral testicular involvement at presentation without any prior diagnosis of blood dyscrasia.2
Testicular masses are deemed malignant until histologically disproven, although some features of the presenting symptoms of testicular MS may be unique. Mass growth is often rapid (appearing over one week in the case of our patient), and may be more associated with pain, nausea and extreme tenderness on examination. Ultrasound is useful in defining mass size and excluding epididymoorchitis as a differential, but lacks specificity and sensitivity to diagnose the type of malignancy.
The morphological appearance of MS is highly variable and is often similar to other lymphoid malignancies. IHC staining for chloroacetate esterase (CAE), CD43, myeloperoxidase (MPO) and lysozyme (Ly) characterises myeloid lineage and may reveal the correct diagnosis.2
Misdiagnosis continues to be of significant concern with these cancers, as noted by McIlwain et al., where six of eight cases of reviewed testicular MS were intially misdiagnosed.4 The most common misdiagnoses are lymphoma, infection, spermatocele and plasmacytoma. Flow cytometry's increasing availability has made it easier to distinguish between morphological variants and further emergence of the use of cytogenetics as a diagnostic tool for haematological malignancies can have important prognostic and treatment indications.2
There is no consensus on the best course of treatment for testicular MS. Management is often multimodal utilising orchidectomy as a diagnostic and therapeutic tool, followed by a chemotherapeutic regimen and, in some cases, radiation therapy. Due to the highly aggressive nature of MS, an early diagnosis of testicular MS is associated with better survival outcomes for patients.5 The mean time to develop AML from the diagnosis of isolated MS may be five months, and as such it is typically recommended that extramedullary lesions are treated with upfront chemotherapy following an AML regimen immediately post diagnosis.3
There is an added layer of complexity for the treatment of cancer in reproductive organs due the effect of treatment on fertility. Whilst this was not a concern for the patient presented above, fertility counselling should be a consideration for patients with family planning in mind.
Conclusion
This is a rare presentation of bilateral testicular MS presenting prior to any diagnosis of AML or blood dyscrasia. This patient's early review by a genitourinary pathologist who had knowledge of the appropriate IHC stains led to rapid diagnosis, upfront treatment and early remission. This highlights the utility of being aware of testicular MS and appropriate IHC stain choice to ensure a correct and prompt diagnosis to allow for treatment, resulting in a positive treatment outcome.
Consent
Informed consent was obtained from the patient on which this case report was written.
Declaration of competing interest
The authors declare they have no conflict of interest. | Intrathecal | DrugAdministrationRoute | CC BY-NC-ND | 33552919 | 18,991,002 | 2021-05 |
What was the administration route of drug 'DEXAMETHASONE'? | Rare presentation of isolated bilateral testicular myeloid sarcoma: A case report.
Myeloid sarcoma (MS) of the testis is a rare soft tissue tumour which can herald the development of acute myeloid leukaemia (AML). The diagnosis of MS requires a high degree of suspicion as appropriate immunohistochemical staining must be performed to yield an early diagnosis. Whilst there is no consensus on treatment on MS involving the testis, most patients undergo orchidectomy and systemic chemotherapy, with or without radiation therapy. Early and aggressive treatment is key to achieving remission. This case report describes a patient with bilateral testicular MS which heralded the development of AML, who underwent induction chemotherapy and achieved remission.
Introduction
Primary testicular malignancy makes up approximately 1% of male cancers in Western society, and 1–2% of cases have bilateral testicular involvement.1 Testicular myeloid sarcoma (MS) is a highly aggressive extramedullary presentation of acute myeloid leukaemia (AML), secondary to rapid, uncontrolled expansion of immature blast cell populations beyond the bone marrow.2 Extramedullary deposits are more commonly found elsewhere in the body such as the lymph nodes, skin, eye orbits and connective tissue of the neck. MS involvement of the testicles has only been recorded in 68 cases and in only four of those cases was it defined as the presenting symptom, where bilateral testicles were involved.2 This case reviews the presentation and management of a rare case of bilateral testicular MS, preceding any diagnosis of AML or other blood dyscrasia.
Case presentation
A 67 year old male presented with a one week history of tender testicles bilaterally with newly palpable growing masses. The patient's medical history included hypertension and type 2 diabetes mellitus. He denied fevers, weight loss and had no history of undescended testicles or previous scrotal surgery. Examination demonstrated bilaterally tender testicles with firm central masses.
Ultrasound demonstrated hypervascular solid infiltrative masses within both testes (Fig. 1). Baseline bloods were all within normal limits as were alpha foetal protein (AFP) and human chorionic gonadotropin (hCG). Lactate dehydronegase was mildly elevated at 272 U/L (Table 1).Fig. 1 Ultrasound imaging of the testes demonstrating bilateral hypervascular solid infiltrative masses. The right testis in longitudinal (A) and transverse view (B), and the left testis in longitudinal (C) and transverse views (D).
Fig. 1Table 1 Laboratory investigations.
Table 1 Marker Result (reference range)
Blood Beta-HCG <1 IU/L (0–5 IU/L)
AFP 2 μg/L (<11 μg/L)
LDH 272 U/L (120–250 U/L)
Left testis immunohistochemistry MPO Negative
Ly Positive
CD43 Positive
A left inguinal orchidectomy was undertaken where histology was provisionally reported as non-Hodgkin lymphoma, and further immunohistochemistry (IHC) stains were required. Following review by a genitourinary pathologist, the diagnosis of MS of the testis was made (Table 1; Fig. 2). The case was reviewed at a multi-disciplinary meeting and the patient was subsequently transferred under the care of haematology at a tertiary hospital.Fig. 2 Histology of specimen. Haematoxylin and eosin stain at low (20x) (A) and high (100x) (B) power show the infiltrative growth of haemopoetic lesions without the destruction otherwise seen in most other malignant neoplasms. High power (400x) view (C) shows the cytological features of the myeloid sarcoma and an adjacent benign residual tubule (bottom left of image). (D) Cell membrane staining of CD43 and cytoplasmic staining of lysozyme, diagnostic for myeloid sarcoma (400x).
Fig. 2
A fluorodeoxyglucose (FDG)-positron emission tomography (PET) demonstrated multiple sub-centimetre, subcutaneous nodules over the anterior chest wall which were not FDG-tracer-avid and no other lesions were defined. Notably the residual right testicular mass was also not FDG-tracer avid. An MRI brain was ordered due the patient's complaint of right jaw numbness, which demonstrated leukaemic invasion at the base of skull. A lumbar puncture was performed which demonstrated an expanded populations of monocytic cells which was suspicious for leukaemic involvement of the central nervous system.
He received induction chemotherapy of intrathecal 7 + 3 (cytarabine, methotrexate and dexamethasone). This was complicated by neutropenic colitis, an Escherichia coli and Staphylococcus haemolyticus bacteraemia, drug-induced hypersensitivity syndrome and severe delirium requiring intubation and ionotropic support for one week.
The patient improved clinically and returned home. Repeated FDG PET scan at did not demonstrate any avid lesions and the patient's right testis returned to pre-morbid size where previously it had a palpable mass centrally.
Discussion
In an audit of the National Cancer Centre Database from 2004 to 2013, only 746 patients out of all patients with diagnosed with AML presented with MS of any site, accounting for 0.8% of all AML cases.3 A systematic review of 68 cases of testicular MS diagnosed over 30 years identified that unilateral and bilateral testicular involvement was equivalent, but only four cases had bilateral testicular involvement at presentation without any prior diagnosis of blood dyscrasia.2
Testicular masses are deemed malignant until histologically disproven, although some features of the presenting symptoms of testicular MS may be unique. Mass growth is often rapid (appearing over one week in the case of our patient), and may be more associated with pain, nausea and extreme tenderness on examination. Ultrasound is useful in defining mass size and excluding epididymoorchitis as a differential, but lacks specificity and sensitivity to diagnose the type of malignancy.
The morphological appearance of MS is highly variable and is often similar to other lymphoid malignancies. IHC staining for chloroacetate esterase (CAE), CD43, myeloperoxidase (MPO) and lysozyme (Ly) characterises myeloid lineage and may reveal the correct diagnosis.2
Misdiagnosis continues to be of significant concern with these cancers, as noted by McIlwain et al., where six of eight cases of reviewed testicular MS were intially misdiagnosed.4 The most common misdiagnoses are lymphoma, infection, spermatocele and plasmacytoma. Flow cytometry's increasing availability has made it easier to distinguish between morphological variants and further emergence of the use of cytogenetics as a diagnostic tool for haematological malignancies can have important prognostic and treatment indications.2
There is no consensus on the best course of treatment for testicular MS. Management is often multimodal utilising orchidectomy as a diagnostic and therapeutic tool, followed by a chemotherapeutic regimen and, in some cases, radiation therapy. Due to the highly aggressive nature of MS, an early diagnosis of testicular MS is associated with better survival outcomes for patients.5 The mean time to develop AML from the diagnosis of isolated MS may be five months, and as such it is typically recommended that extramedullary lesions are treated with upfront chemotherapy following an AML regimen immediately post diagnosis.3
There is an added layer of complexity for the treatment of cancer in reproductive organs due the effect of treatment on fertility. Whilst this was not a concern for the patient presented above, fertility counselling should be a consideration for patients with family planning in mind.
Conclusion
This is a rare presentation of bilateral testicular MS presenting prior to any diagnosis of AML or blood dyscrasia. This patient's early review by a genitourinary pathologist who had knowledge of the appropriate IHC stains led to rapid diagnosis, upfront treatment and early remission. This highlights the utility of being aware of testicular MS and appropriate IHC stain choice to ensure a correct and prompt diagnosis to allow for treatment, resulting in a positive treatment outcome.
Consent
Informed consent was obtained from the patient on which this case report was written.
Declaration of competing interest
The authors declare they have no conflict of interest. | Intrathecal | DrugAdministrationRoute | CC BY-NC-ND | 33552919 | 18,999,117 | 2021-05 |
What was the administration route of drug 'METHOTREXATE'? | Rare presentation of isolated bilateral testicular myeloid sarcoma: A case report.
Myeloid sarcoma (MS) of the testis is a rare soft tissue tumour which can herald the development of acute myeloid leukaemia (AML). The diagnosis of MS requires a high degree of suspicion as appropriate immunohistochemical staining must be performed to yield an early diagnosis. Whilst there is no consensus on treatment on MS involving the testis, most patients undergo orchidectomy and systemic chemotherapy, with or without radiation therapy. Early and aggressive treatment is key to achieving remission. This case report describes a patient with bilateral testicular MS which heralded the development of AML, who underwent induction chemotherapy and achieved remission.
Introduction
Primary testicular malignancy makes up approximately 1% of male cancers in Western society, and 1–2% of cases have bilateral testicular involvement.1 Testicular myeloid sarcoma (MS) is a highly aggressive extramedullary presentation of acute myeloid leukaemia (AML), secondary to rapid, uncontrolled expansion of immature blast cell populations beyond the bone marrow.2 Extramedullary deposits are more commonly found elsewhere in the body such as the lymph nodes, skin, eye orbits and connective tissue of the neck. MS involvement of the testicles has only been recorded in 68 cases and in only four of those cases was it defined as the presenting symptom, where bilateral testicles were involved.2 This case reviews the presentation and management of a rare case of bilateral testicular MS, preceding any diagnosis of AML or other blood dyscrasia.
Case presentation
A 67 year old male presented with a one week history of tender testicles bilaterally with newly palpable growing masses. The patient's medical history included hypertension and type 2 diabetes mellitus. He denied fevers, weight loss and had no history of undescended testicles or previous scrotal surgery. Examination demonstrated bilaterally tender testicles with firm central masses.
Ultrasound demonstrated hypervascular solid infiltrative masses within both testes (Fig. 1). Baseline bloods were all within normal limits as were alpha foetal protein (AFP) and human chorionic gonadotropin (hCG). Lactate dehydronegase was mildly elevated at 272 U/L (Table 1).Fig. 1 Ultrasound imaging of the testes demonstrating bilateral hypervascular solid infiltrative masses. The right testis in longitudinal (A) and transverse view (B), and the left testis in longitudinal (C) and transverse views (D).
Fig. 1Table 1 Laboratory investigations.
Table 1 Marker Result (reference range)
Blood Beta-HCG <1 IU/L (0–5 IU/L)
AFP 2 μg/L (<11 μg/L)
LDH 272 U/L (120–250 U/L)
Left testis immunohistochemistry MPO Negative
Ly Positive
CD43 Positive
A left inguinal orchidectomy was undertaken where histology was provisionally reported as non-Hodgkin lymphoma, and further immunohistochemistry (IHC) stains were required. Following review by a genitourinary pathologist, the diagnosis of MS of the testis was made (Table 1; Fig. 2). The case was reviewed at a multi-disciplinary meeting and the patient was subsequently transferred under the care of haematology at a tertiary hospital.Fig. 2 Histology of specimen. Haematoxylin and eosin stain at low (20x) (A) and high (100x) (B) power show the infiltrative growth of haemopoetic lesions without the destruction otherwise seen in most other malignant neoplasms. High power (400x) view (C) shows the cytological features of the myeloid sarcoma and an adjacent benign residual tubule (bottom left of image). (D) Cell membrane staining of CD43 and cytoplasmic staining of lysozyme, diagnostic for myeloid sarcoma (400x).
Fig. 2
A fluorodeoxyglucose (FDG)-positron emission tomography (PET) demonstrated multiple sub-centimetre, subcutaneous nodules over the anterior chest wall which were not FDG-tracer-avid and no other lesions were defined. Notably the residual right testicular mass was also not FDG-tracer avid. An MRI brain was ordered due the patient's complaint of right jaw numbness, which demonstrated leukaemic invasion at the base of skull. A lumbar puncture was performed which demonstrated an expanded populations of monocytic cells which was suspicious for leukaemic involvement of the central nervous system.
He received induction chemotherapy of intrathecal 7 + 3 (cytarabine, methotrexate and dexamethasone). This was complicated by neutropenic colitis, an Escherichia coli and Staphylococcus haemolyticus bacteraemia, drug-induced hypersensitivity syndrome and severe delirium requiring intubation and ionotropic support for one week.
The patient improved clinically and returned home. Repeated FDG PET scan at did not demonstrate any avid lesions and the patient's right testis returned to pre-morbid size where previously it had a palpable mass centrally.
Discussion
In an audit of the National Cancer Centre Database from 2004 to 2013, only 746 patients out of all patients with diagnosed with AML presented with MS of any site, accounting for 0.8% of all AML cases.3 A systematic review of 68 cases of testicular MS diagnosed over 30 years identified that unilateral and bilateral testicular involvement was equivalent, but only four cases had bilateral testicular involvement at presentation without any prior diagnosis of blood dyscrasia.2
Testicular masses are deemed malignant until histologically disproven, although some features of the presenting symptoms of testicular MS may be unique. Mass growth is often rapid (appearing over one week in the case of our patient), and may be more associated with pain, nausea and extreme tenderness on examination. Ultrasound is useful in defining mass size and excluding epididymoorchitis as a differential, but lacks specificity and sensitivity to diagnose the type of malignancy.
The morphological appearance of MS is highly variable and is often similar to other lymphoid malignancies. IHC staining for chloroacetate esterase (CAE), CD43, myeloperoxidase (MPO) and lysozyme (Ly) characterises myeloid lineage and may reveal the correct diagnosis.2
Misdiagnosis continues to be of significant concern with these cancers, as noted by McIlwain et al., where six of eight cases of reviewed testicular MS were intially misdiagnosed.4 The most common misdiagnoses are lymphoma, infection, spermatocele and plasmacytoma. Flow cytometry's increasing availability has made it easier to distinguish between morphological variants and further emergence of the use of cytogenetics as a diagnostic tool for haematological malignancies can have important prognostic and treatment indications.2
There is no consensus on the best course of treatment for testicular MS. Management is often multimodal utilising orchidectomy as a diagnostic and therapeutic tool, followed by a chemotherapeutic regimen and, in some cases, radiation therapy. Due to the highly aggressive nature of MS, an early diagnosis of testicular MS is associated with better survival outcomes for patients.5 The mean time to develop AML from the diagnosis of isolated MS may be five months, and as such it is typically recommended that extramedullary lesions are treated with upfront chemotherapy following an AML regimen immediately post diagnosis.3
There is an added layer of complexity for the treatment of cancer in reproductive organs due the effect of treatment on fertility. Whilst this was not a concern for the patient presented above, fertility counselling should be a consideration for patients with family planning in mind.
Conclusion
This is a rare presentation of bilateral testicular MS presenting prior to any diagnosis of AML or blood dyscrasia. This patient's early review by a genitourinary pathologist who had knowledge of the appropriate IHC stains led to rapid diagnosis, upfront treatment and early remission. This highlights the utility of being aware of testicular MS and appropriate IHC stain choice to ensure a correct and prompt diagnosis to allow for treatment, resulting in a positive treatment outcome.
Consent
Informed consent was obtained from the patient on which this case report was written.
Declaration of competing interest
The authors declare they have no conflict of interest. | Intrathecal | DrugAdministrationRoute | CC BY-NC-ND | 33552919 | 18,999,117 | 2021-05 |
What was the dosage of drug 'DEXAMETHASONE SODIUM PHOSPHATE'? | Rare presentation of isolated bilateral testicular myeloid sarcoma: A case report.
Myeloid sarcoma (MS) of the testis is a rare soft tissue tumour which can herald the development of acute myeloid leukaemia (AML). The diagnosis of MS requires a high degree of suspicion as appropriate immunohistochemical staining must be performed to yield an early diagnosis. Whilst there is no consensus on treatment on MS involving the testis, most patients undergo orchidectomy and systemic chemotherapy, with or without radiation therapy. Early and aggressive treatment is key to achieving remission. This case report describes a patient with bilateral testicular MS which heralded the development of AML, who underwent induction chemotherapy and achieved remission.
Introduction
Primary testicular malignancy makes up approximately 1% of male cancers in Western society, and 1–2% of cases have bilateral testicular involvement.1 Testicular myeloid sarcoma (MS) is a highly aggressive extramedullary presentation of acute myeloid leukaemia (AML), secondary to rapid, uncontrolled expansion of immature blast cell populations beyond the bone marrow.2 Extramedullary deposits are more commonly found elsewhere in the body such as the lymph nodes, skin, eye orbits and connective tissue of the neck. MS involvement of the testicles has only been recorded in 68 cases and in only four of those cases was it defined as the presenting symptom, where bilateral testicles were involved.2 This case reviews the presentation and management of a rare case of bilateral testicular MS, preceding any diagnosis of AML or other blood dyscrasia.
Case presentation
A 67 year old male presented with a one week history of tender testicles bilaterally with newly palpable growing masses. The patient's medical history included hypertension and type 2 diabetes mellitus. He denied fevers, weight loss and had no history of undescended testicles or previous scrotal surgery. Examination demonstrated bilaterally tender testicles with firm central masses.
Ultrasound demonstrated hypervascular solid infiltrative masses within both testes (Fig. 1). Baseline bloods were all within normal limits as were alpha foetal protein (AFP) and human chorionic gonadotropin (hCG). Lactate dehydronegase was mildly elevated at 272 U/L (Table 1).Fig. 1 Ultrasound imaging of the testes demonstrating bilateral hypervascular solid infiltrative masses. The right testis in longitudinal (A) and transverse view (B), and the left testis in longitudinal (C) and transverse views (D).
Fig. 1Table 1 Laboratory investigations.
Table 1 Marker Result (reference range)
Blood Beta-HCG <1 IU/L (0–5 IU/L)
AFP 2 μg/L (<11 μg/L)
LDH 272 U/L (120–250 U/L)
Left testis immunohistochemistry MPO Negative
Ly Positive
CD43 Positive
A left inguinal orchidectomy was undertaken where histology was provisionally reported as non-Hodgkin lymphoma, and further immunohistochemistry (IHC) stains were required. Following review by a genitourinary pathologist, the diagnosis of MS of the testis was made (Table 1; Fig. 2). The case was reviewed at a multi-disciplinary meeting and the patient was subsequently transferred under the care of haematology at a tertiary hospital.Fig. 2 Histology of specimen. Haematoxylin and eosin stain at low (20x) (A) and high (100x) (B) power show the infiltrative growth of haemopoetic lesions without the destruction otherwise seen in most other malignant neoplasms. High power (400x) view (C) shows the cytological features of the myeloid sarcoma and an adjacent benign residual tubule (bottom left of image). (D) Cell membrane staining of CD43 and cytoplasmic staining of lysozyme, diagnostic for myeloid sarcoma (400x).
Fig. 2
A fluorodeoxyglucose (FDG)-positron emission tomography (PET) demonstrated multiple sub-centimetre, subcutaneous nodules over the anterior chest wall which were not FDG-tracer-avid and no other lesions were defined. Notably the residual right testicular mass was also not FDG-tracer avid. An MRI brain was ordered due the patient's complaint of right jaw numbness, which demonstrated leukaemic invasion at the base of skull. A lumbar puncture was performed which demonstrated an expanded populations of monocytic cells which was suspicious for leukaemic involvement of the central nervous system.
He received induction chemotherapy of intrathecal 7 + 3 (cytarabine, methotrexate and dexamethasone). This was complicated by neutropenic colitis, an Escherichia coli and Staphylococcus haemolyticus bacteraemia, drug-induced hypersensitivity syndrome and severe delirium requiring intubation and ionotropic support for one week.
The patient improved clinically and returned home. Repeated FDG PET scan at did not demonstrate any avid lesions and the patient's right testis returned to pre-morbid size where previously it had a palpable mass centrally.
Discussion
In an audit of the National Cancer Centre Database from 2004 to 2013, only 746 patients out of all patients with diagnosed with AML presented with MS of any site, accounting for 0.8% of all AML cases.3 A systematic review of 68 cases of testicular MS diagnosed over 30 years identified that unilateral and bilateral testicular involvement was equivalent, but only four cases had bilateral testicular involvement at presentation without any prior diagnosis of blood dyscrasia.2
Testicular masses are deemed malignant until histologically disproven, although some features of the presenting symptoms of testicular MS may be unique. Mass growth is often rapid (appearing over one week in the case of our patient), and may be more associated with pain, nausea and extreme tenderness on examination. Ultrasound is useful in defining mass size and excluding epididymoorchitis as a differential, but lacks specificity and sensitivity to diagnose the type of malignancy.
The morphological appearance of MS is highly variable and is often similar to other lymphoid malignancies. IHC staining for chloroacetate esterase (CAE), CD43, myeloperoxidase (MPO) and lysozyme (Ly) characterises myeloid lineage and may reveal the correct diagnosis.2
Misdiagnosis continues to be of significant concern with these cancers, as noted by McIlwain et al., where six of eight cases of reviewed testicular MS were intially misdiagnosed.4 The most common misdiagnoses are lymphoma, infection, spermatocele and plasmacytoma. Flow cytometry's increasing availability has made it easier to distinguish between morphological variants and further emergence of the use of cytogenetics as a diagnostic tool for haematological malignancies can have important prognostic and treatment indications.2
There is no consensus on the best course of treatment for testicular MS. Management is often multimodal utilising orchidectomy as a diagnostic and therapeutic tool, followed by a chemotherapeutic regimen and, in some cases, radiation therapy. Due to the highly aggressive nature of MS, an early diagnosis of testicular MS is associated with better survival outcomes for patients.5 The mean time to develop AML from the diagnosis of isolated MS may be five months, and as such it is typically recommended that extramedullary lesions are treated with upfront chemotherapy following an AML regimen immediately post diagnosis.3
There is an added layer of complexity for the treatment of cancer in reproductive organs due the effect of treatment on fertility. Whilst this was not a concern for the patient presented above, fertility counselling should be a consideration for patients with family planning in mind.
Conclusion
This is a rare presentation of bilateral testicular MS presenting prior to any diagnosis of AML or blood dyscrasia. This patient's early review by a genitourinary pathologist who had knowledge of the appropriate IHC stains led to rapid diagnosis, upfront treatment and early remission. This highlights the utility of being aware of testicular MS and appropriate IHC stain choice to ensure a correct and prompt diagnosis to allow for treatment, resulting in a positive treatment outcome.
Consent
Informed consent was obtained from the patient on which this case report was written.
Declaration of competing interest
The authors declare they have no conflict of interest. | UNK UNK, CYCLIC (7 + 3 (CYTARABINE, METHOTREXATE AND DEXAMETHASONE)) | DrugDosageText | CC BY-NC-ND | 33552919 | 18,991,002 | 2021-05 |
What was the outcome of reaction 'Escherichia infection'? | Rare presentation of isolated bilateral testicular myeloid sarcoma: A case report.
Myeloid sarcoma (MS) of the testis is a rare soft tissue tumour which can herald the development of acute myeloid leukaemia (AML). The diagnosis of MS requires a high degree of suspicion as appropriate immunohistochemical staining must be performed to yield an early diagnosis. Whilst there is no consensus on treatment on MS involving the testis, most patients undergo orchidectomy and systemic chemotherapy, with or without radiation therapy. Early and aggressive treatment is key to achieving remission. This case report describes a patient with bilateral testicular MS which heralded the development of AML, who underwent induction chemotherapy and achieved remission.
Introduction
Primary testicular malignancy makes up approximately 1% of male cancers in Western society, and 1–2% of cases have bilateral testicular involvement.1 Testicular myeloid sarcoma (MS) is a highly aggressive extramedullary presentation of acute myeloid leukaemia (AML), secondary to rapid, uncontrolled expansion of immature blast cell populations beyond the bone marrow.2 Extramedullary deposits are more commonly found elsewhere in the body such as the lymph nodes, skin, eye orbits and connective tissue of the neck. MS involvement of the testicles has only been recorded in 68 cases and in only four of those cases was it defined as the presenting symptom, where bilateral testicles were involved.2 This case reviews the presentation and management of a rare case of bilateral testicular MS, preceding any diagnosis of AML or other blood dyscrasia.
Case presentation
A 67 year old male presented with a one week history of tender testicles bilaterally with newly palpable growing masses. The patient's medical history included hypertension and type 2 diabetes mellitus. He denied fevers, weight loss and had no history of undescended testicles or previous scrotal surgery. Examination demonstrated bilaterally tender testicles with firm central masses.
Ultrasound demonstrated hypervascular solid infiltrative masses within both testes (Fig. 1). Baseline bloods were all within normal limits as were alpha foetal protein (AFP) and human chorionic gonadotropin (hCG). Lactate dehydronegase was mildly elevated at 272 U/L (Table 1).Fig. 1 Ultrasound imaging of the testes demonstrating bilateral hypervascular solid infiltrative masses. The right testis in longitudinal (A) and transverse view (B), and the left testis in longitudinal (C) and transverse views (D).
Fig. 1Table 1 Laboratory investigations.
Table 1 Marker Result (reference range)
Blood Beta-HCG <1 IU/L (0–5 IU/L)
AFP 2 μg/L (<11 μg/L)
LDH 272 U/L (120–250 U/L)
Left testis immunohistochemistry MPO Negative
Ly Positive
CD43 Positive
A left inguinal orchidectomy was undertaken where histology was provisionally reported as non-Hodgkin lymphoma, and further immunohistochemistry (IHC) stains were required. Following review by a genitourinary pathologist, the diagnosis of MS of the testis was made (Table 1; Fig. 2). The case was reviewed at a multi-disciplinary meeting and the patient was subsequently transferred under the care of haematology at a tertiary hospital.Fig. 2 Histology of specimen. Haematoxylin and eosin stain at low (20x) (A) and high (100x) (B) power show the infiltrative growth of haemopoetic lesions without the destruction otherwise seen in most other malignant neoplasms. High power (400x) view (C) shows the cytological features of the myeloid sarcoma and an adjacent benign residual tubule (bottom left of image). (D) Cell membrane staining of CD43 and cytoplasmic staining of lysozyme, diagnostic for myeloid sarcoma (400x).
Fig. 2
A fluorodeoxyglucose (FDG)-positron emission tomography (PET) demonstrated multiple sub-centimetre, subcutaneous nodules over the anterior chest wall which were not FDG-tracer-avid and no other lesions were defined. Notably the residual right testicular mass was also not FDG-tracer avid. An MRI brain was ordered due the patient's complaint of right jaw numbness, which demonstrated leukaemic invasion at the base of skull. A lumbar puncture was performed which demonstrated an expanded populations of monocytic cells which was suspicious for leukaemic involvement of the central nervous system.
He received induction chemotherapy of intrathecal 7 + 3 (cytarabine, methotrexate and dexamethasone). This was complicated by neutropenic colitis, an Escherichia coli and Staphylococcus haemolyticus bacteraemia, drug-induced hypersensitivity syndrome and severe delirium requiring intubation and ionotropic support for one week.
The patient improved clinically and returned home. Repeated FDG PET scan at did not demonstrate any avid lesions and the patient's right testis returned to pre-morbid size where previously it had a palpable mass centrally.
Discussion
In an audit of the National Cancer Centre Database from 2004 to 2013, only 746 patients out of all patients with diagnosed with AML presented with MS of any site, accounting for 0.8% of all AML cases.3 A systematic review of 68 cases of testicular MS diagnosed over 30 years identified that unilateral and bilateral testicular involvement was equivalent, but only four cases had bilateral testicular involvement at presentation without any prior diagnosis of blood dyscrasia.2
Testicular masses are deemed malignant until histologically disproven, although some features of the presenting symptoms of testicular MS may be unique. Mass growth is often rapid (appearing over one week in the case of our patient), and may be more associated with pain, nausea and extreme tenderness on examination. Ultrasound is useful in defining mass size and excluding epididymoorchitis as a differential, but lacks specificity and sensitivity to diagnose the type of malignancy.
The morphological appearance of MS is highly variable and is often similar to other lymphoid malignancies. IHC staining for chloroacetate esterase (CAE), CD43, myeloperoxidase (MPO) and lysozyme (Ly) characterises myeloid lineage and may reveal the correct diagnosis.2
Misdiagnosis continues to be of significant concern with these cancers, as noted by McIlwain et al., where six of eight cases of reviewed testicular MS were intially misdiagnosed.4 The most common misdiagnoses are lymphoma, infection, spermatocele and plasmacytoma. Flow cytometry's increasing availability has made it easier to distinguish between morphological variants and further emergence of the use of cytogenetics as a diagnostic tool for haematological malignancies can have important prognostic and treatment indications.2
There is no consensus on the best course of treatment for testicular MS. Management is often multimodal utilising orchidectomy as a diagnostic and therapeutic tool, followed by a chemotherapeutic regimen and, in some cases, radiation therapy. Due to the highly aggressive nature of MS, an early diagnosis of testicular MS is associated with better survival outcomes for patients.5 The mean time to develop AML from the diagnosis of isolated MS may be five months, and as such it is typically recommended that extramedullary lesions are treated with upfront chemotherapy following an AML regimen immediately post diagnosis.3
There is an added layer of complexity for the treatment of cancer in reproductive organs due the effect of treatment on fertility. Whilst this was not a concern for the patient presented above, fertility counselling should be a consideration for patients with family planning in mind.
Conclusion
This is a rare presentation of bilateral testicular MS presenting prior to any diagnosis of AML or blood dyscrasia. This patient's early review by a genitourinary pathologist who had knowledge of the appropriate IHC stains led to rapid diagnosis, upfront treatment and early remission. This highlights the utility of being aware of testicular MS and appropriate IHC stain choice to ensure a correct and prompt diagnosis to allow for treatment, resulting in a positive treatment outcome.
Consent
Informed consent was obtained from the patient on which this case report was written.
Declaration of competing interest
The authors declare they have no conflict of interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33552919 | 18,999,117 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood loss anaemia'. | Prostate artery embolization in a patient with left ventricular assist device.
Increased number of left ventricular assist device placement in patients with end stage heart failure as well as years of survival increases the likelihood of need for non-cardiac procedures. Prostate artery embolization is a safe, minimally invasive procedure performed in the setting of lower urinary tract symptoms or refractory gross hematuria of prostatic origin. These patients require a multidisciplinary approach to weigh the benefits and risks of the procedure and provide optimal periprocedural care. We report a case of technically successful prostate artery embolization performed in a patient with HeartWare HVAD presenting with refractory hematuria of prostatic origin (RHPO).
Introduction
Increased survival in end stage heart failure patients with left ventricular assist devices (LVAD) has led to an increased need for non-cardiac procedures. Gross hematuria in the setting of benign prostatic hyperplasia (BPH) can be treated with prostate artery embolization. Patients with LVAD must be carefully evaluated for perioperative complications related to anticoagulation. Compared to traditional surgery, minimally invasive catheter directed therapy offer increased safety especially in patients with chronic anticoagulation, and therefore should be considered as first line treatment option when indicated.
Case presentation
A 73-year-old male with a history of paroxysmal atrial fibrillation on warfarin status post dual chamber implantable cardioverter defibrillator placement and nonischemic cardiomyopathy with HeartWare HVAD system (LVAD) as destination therapy implanted in an outside hospital 2 years prior to presentation.
The patient was seen at an outside hospital for gross hematuria and dysuria for one week which was conservatively managed with Foley catheter and antibiotics. The patient returned to the outside hospital after the completion of an antibiotic regimen with persistent hematuria. Continuous bladder irrigation was started during which the patient received 2 units of packed red blood cells for acute blood loss anemia. The patient was eventually transferred to our medical center for cystoscopy given the patient's complex medical history and the probable requirement for cardiac anesthesia during the procedure.
CT urogram obtained prior to cystoscopy showed marked prostatomegaly measuring approximately 175 cc with median lobe projecting into bladder neck and significant clot burden within the bladder lumen. Warfarin was held and therapeutic heparin was started. Cystoscopy performed under anesthesia showed severe trilobar hypertrophy of the prostate with friable enlarged median lobe consistent with BPH. The formed clot was evacuated, and the following re-examination of the bladder showed normal-appearing mucosa without evidence of urothelial cancer. Interventional radiology was consulted for prostate artery embolization (PAE). Prior to having hematuria, the patient's international prostate symptom score (IPSS) was 18 and the quality of life score (QOL) was 3 which were managed with alpha-blockers. On the day of the procedure, transfemoral approach prostate artery embolization was performed under general anesthesia using 300–500 μm embospheres (Fig. 1). The procedure was technically successful without acute complications and an estimated blood loss of less than 5 ml. Hematuria completely resolved and CBI was stopped on postoperative day (POD) 2. The patient was able to spontaneously void on POD 3 with postvoid residual (PVR) of approximately 300ml and was then discharged home on POD 5 after resuming warfarin. At the post discharge follow up at the cardiology clinic, the patient reported good activity tolerance without issues with LVAD, ICD, or hematuria. At 2 weeks follow up with urology, hematuria remained completely resolved while on anticoagulation, along with significant improvement of urinary stream with PVR of 90ml (previously 300ml). At 3 month follow up with IR, he remained asymptomatic and reported significant improvement of IPSS 1 (mild LUTs) previously 18 (moderate LUTs), and QOL 0 (delighted), previously 3 (mixed) and PVR of 9ml (previously 90 at 2 weeks follow up) (Fig. 2).Fig. 1 A: Right internal iliac angiogram showing right prostate artery (Red arrow) arising from right obturator artery. B: Right prostate artery angiogram opacifying branches supplying median and lateral lobes of the right side of prostate gland. C: Intra-procedure CT scan showing enhancement of right hemi-prostate gland with no enhancement of adjacent organs. D: Left internal iliac angiogram showing left prostate artery (red arrow) arising as a common origin with inferior vesicle artery. E: Left prostate artery angiogram showing branches supplying the left hemi-prostate. F: Cone beam CT showing enhancement of the left side of the prostate gland without enhancement of adjacent structures. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 1Fig. 2 A & B: 3-month Pre-void Ultrasound (US) of urinary bladder in longitudinal and transverse planes (respectively) measuring 7.9 × 9.47 x 7.17 (Pre-void volume 280ml). C & D: 3 month Post Void US of the urinary bladder in longitudinal and transverse planes (respectively) measuring 3.2 × 2.7 × 2.1 cm (Post void volume 9 ml).
Fig. 2
Discussion
Left ventricular assist device (LVAD) is an implantable device that has been introduced in 1990s to bridge patients with end stage heart failure refractory to maximal medical therapy to heart transplant. Continued development and resulting improvement of hemodynamics, end organ function, and quality of life in patients with LVAD has led to its usage as long term mechanical circulatory support in non-transplant patients as a destination therapy. LVAD also shows clinically significant improvement of survival benefit over optimal medical therapy at 1 or 2 years after device implantation.1 Prior studies have shown that 20–50% of patients with LVAD undergo non-cardiac surgical procedures.2
Hematuria is the presence of red blood cells in the urine accounting for 4–20% of inpatient urology consultations and hospitalizations.3 Common causes of hematuria include malignancy, benign prostatic hyperplasia, urinary tract infection, and urolithiasis. Prostatic hyperplasia can be considered a cause of hematuria after the patient has been evaluated for urologic malignancy. Gross hematuria, defined as blood visible in urine, especially in adults is highly suspicious for urologic malignancy thus appropriate imaging and cystoscopic evaluations are necessary in establishing the diagnosis. Hematuria in the setting of prostatic hyperplasia can result from the increased expression of vascular endothelial growth factor, anticoagulation, Foley catheterization, and infection. The management of hematuria encompasses continuous bladder irrigation, fulguration, and embolization.
Prostate artery embolization (PAE) is a minimally invasive procedure in which bilateral prostate arteries are embolized in the setting of moderate or severe lower urinary tract syndrome (LUTS) refractory to medications. PAE along with catheter directed arterial embolization of other pelvic vessels can also be performed to treat severe hematuria in high risk population whose conventional therapies have failed. Technical success, defined as bilateral prostate artery embolization, can be achieved at 100% with very low recurrence rate at one year when cone beam computed tomography is used during the procedure.4 CBCT can help visualize the prostatic arteries and detect accessory or collateral supplying vessels and in turn decrease the risks of non-target embolization. In addition to recurrence of hematuria, questionnaires such as international prostate symptoms score (IPSS) and quality of life score (QOL) are used to assess the outcome of the procedure.
Continuous flow LVADs are at increased risk of nonsurgical bleeding from arteriovenous malformations in gastrointestinal tract and acquired von Willebrand disease secondary to nonphysiological sheer stress on blood components and reduced pulse pressure.5 This, coupled with thrombotic risk from the mechanical circulatory device, poses a clinical dilemma in physicians performing endovascular procedures.
Conclusion
Prostate artery embolization can be performed safely with favorable outcome for patients with left ventricular assist device presenting with hematuria refractory to conventional therapy. PAE should also be considered as an alternative treatment option in patients with moderate LUTs secondary to BPH, especially in those patients who are on chronic anticoagulation.
Consent
Informed consent was obtained from the patient and patient information was de-identified prior to submission of the case report.
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
None. | WARFARIN SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33552921 | 19,000,350 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haematuria'. | Prostate artery embolization in a patient with left ventricular assist device.
Increased number of left ventricular assist device placement in patients with end stage heart failure as well as years of survival increases the likelihood of need for non-cardiac procedures. Prostate artery embolization is a safe, minimally invasive procedure performed in the setting of lower urinary tract symptoms or refractory gross hematuria of prostatic origin. These patients require a multidisciplinary approach to weigh the benefits and risks of the procedure and provide optimal periprocedural care. We report a case of technically successful prostate artery embolization performed in a patient with HeartWare HVAD presenting with refractory hematuria of prostatic origin (RHPO).
Introduction
Increased survival in end stage heart failure patients with left ventricular assist devices (LVAD) has led to an increased need for non-cardiac procedures. Gross hematuria in the setting of benign prostatic hyperplasia (BPH) can be treated with prostate artery embolization. Patients with LVAD must be carefully evaluated for perioperative complications related to anticoagulation. Compared to traditional surgery, minimally invasive catheter directed therapy offer increased safety especially in patients with chronic anticoagulation, and therefore should be considered as first line treatment option when indicated.
Case presentation
A 73-year-old male with a history of paroxysmal atrial fibrillation on warfarin status post dual chamber implantable cardioverter defibrillator placement and nonischemic cardiomyopathy with HeartWare HVAD system (LVAD) as destination therapy implanted in an outside hospital 2 years prior to presentation.
The patient was seen at an outside hospital for gross hematuria and dysuria for one week which was conservatively managed with Foley catheter and antibiotics. The patient returned to the outside hospital after the completion of an antibiotic regimen with persistent hematuria. Continuous bladder irrigation was started during which the patient received 2 units of packed red blood cells for acute blood loss anemia. The patient was eventually transferred to our medical center for cystoscopy given the patient's complex medical history and the probable requirement for cardiac anesthesia during the procedure.
CT urogram obtained prior to cystoscopy showed marked prostatomegaly measuring approximately 175 cc with median lobe projecting into bladder neck and significant clot burden within the bladder lumen. Warfarin was held and therapeutic heparin was started. Cystoscopy performed under anesthesia showed severe trilobar hypertrophy of the prostate with friable enlarged median lobe consistent with BPH. The formed clot was evacuated, and the following re-examination of the bladder showed normal-appearing mucosa without evidence of urothelial cancer. Interventional radiology was consulted for prostate artery embolization (PAE). Prior to having hematuria, the patient's international prostate symptom score (IPSS) was 18 and the quality of life score (QOL) was 3 which were managed with alpha-blockers. On the day of the procedure, transfemoral approach prostate artery embolization was performed under general anesthesia using 300–500 μm embospheres (Fig. 1). The procedure was technically successful without acute complications and an estimated blood loss of less than 5 ml. Hematuria completely resolved and CBI was stopped on postoperative day (POD) 2. The patient was able to spontaneously void on POD 3 with postvoid residual (PVR) of approximately 300ml and was then discharged home on POD 5 after resuming warfarin. At the post discharge follow up at the cardiology clinic, the patient reported good activity tolerance without issues with LVAD, ICD, or hematuria. At 2 weeks follow up with urology, hematuria remained completely resolved while on anticoagulation, along with significant improvement of urinary stream with PVR of 90ml (previously 300ml). At 3 month follow up with IR, he remained asymptomatic and reported significant improvement of IPSS 1 (mild LUTs) previously 18 (moderate LUTs), and QOL 0 (delighted), previously 3 (mixed) and PVR of 9ml (previously 90 at 2 weeks follow up) (Fig. 2).Fig. 1 A: Right internal iliac angiogram showing right prostate artery (Red arrow) arising from right obturator artery. B: Right prostate artery angiogram opacifying branches supplying median and lateral lobes of the right side of prostate gland. C: Intra-procedure CT scan showing enhancement of right hemi-prostate gland with no enhancement of adjacent organs. D: Left internal iliac angiogram showing left prostate artery (red arrow) arising as a common origin with inferior vesicle artery. E: Left prostate artery angiogram showing branches supplying the left hemi-prostate. F: Cone beam CT showing enhancement of the left side of the prostate gland without enhancement of adjacent structures. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 1Fig. 2 A & B: 3-month Pre-void Ultrasound (US) of urinary bladder in longitudinal and transverse planes (respectively) measuring 7.9 × 9.47 x 7.17 (Pre-void volume 280ml). C & D: 3 month Post Void US of the urinary bladder in longitudinal and transverse planes (respectively) measuring 3.2 × 2.7 × 2.1 cm (Post void volume 9 ml).
Fig. 2
Discussion
Left ventricular assist device (LVAD) is an implantable device that has been introduced in 1990s to bridge patients with end stage heart failure refractory to maximal medical therapy to heart transplant. Continued development and resulting improvement of hemodynamics, end organ function, and quality of life in patients with LVAD has led to its usage as long term mechanical circulatory support in non-transplant patients as a destination therapy. LVAD also shows clinically significant improvement of survival benefit over optimal medical therapy at 1 or 2 years after device implantation.1 Prior studies have shown that 20–50% of patients with LVAD undergo non-cardiac surgical procedures.2
Hematuria is the presence of red blood cells in the urine accounting for 4–20% of inpatient urology consultations and hospitalizations.3 Common causes of hematuria include malignancy, benign prostatic hyperplasia, urinary tract infection, and urolithiasis. Prostatic hyperplasia can be considered a cause of hematuria after the patient has been evaluated for urologic malignancy. Gross hematuria, defined as blood visible in urine, especially in adults is highly suspicious for urologic malignancy thus appropriate imaging and cystoscopic evaluations are necessary in establishing the diagnosis. Hematuria in the setting of prostatic hyperplasia can result from the increased expression of vascular endothelial growth factor, anticoagulation, Foley catheterization, and infection. The management of hematuria encompasses continuous bladder irrigation, fulguration, and embolization.
Prostate artery embolization (PAE) is a minimally invasive procedure in which bilateral prostate arteries are embolized in the setting of moderate or severe lower urinary tract syndrome (LUTS) refractory to medications. PAE along with catheter directed arterial embolization of other pelvic vessels can also be performed to treat severe hematuria in high risk population whose conventional therapies have failed. Technical success, defined as bilateral prostate artery embolization, can be achieved at 100% with very low recurrence rate at one year when cone beam computed tomography is used during the procedure.4 CBCT can help visualize the prostatic arteries and detect accessory or collateral supplying vessels and in turn decrease the risks of non-target embolization. In addition to recurrence of hematuria, questionnaires such as international prostate symptoms score (IPSS) and quality of life score (QOL) are used to assess the outcome of the procedure.
Continuous flow LVADs are at increased risk of nonsurgical bleeding from arteriovenous malformations in gastrointestinal tract and acquired von Willebrand disease secondary to nonphysiological sheer stress on blood components and reduced pulse pressure.5 This, coupled with thrombotic risk from the mechanical circulatory device, poses a clinical dilemma in physicians performing endovascular procedures.
Conclusion
Prostate artery embolization can be performed safely with favorable outcome for patients with left ventricular assist device presenting with hematuria refractory to conventional therapy. PAE should also be considered as an alternative treatment option in patients with moderate LUTs secondary to BPH, especially in those patients who are on chronic anticoagulation.
Consent
Informed consent was obtained from the patient and patient information was de-identified prior to submission of the case report.
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
None. | WARFARIN SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33552921 | 19,000,350 | 2021-05 |
What was the outcome of reaction 'Haematuria'? | Prostate artery embolization in a patient with left ventricular assist device.
Increased number of left ventricular assist device placement in patients with end stage heart failure as well as years of survival increases the likelihood of need for non-cardiac procedures. Prostate artery embolization is a safe, minimally invasive procedure performed in the setting of lower urinary tract symptoms or refractory gross hematuria of prostatic origin. These patients require a multidisciplinary approach to weigh the benefits and risks of the procedure and provide optimal periprocedural care. We report a case of technically successful prostate artery embolization performed in a patient with HeartWare HVAD presenting with refractory hematuria of prostatic origin (RHPO).
Introduction
Increased survival in end stage heart failure patients with left ventricular assist devices (LVAD) has led to an increased need for non-cardiac procedures. Gross hematuria in the setting of benign prostatic hyperplasia (BPH) can be treated with prostate artery embolization. Patients with LVAD must be carefully evaluated for perioperative complications related to anticoagulation. Compared to traditional surgery, minimally invasive catheter directed therapy offer increased safety especially in patients with chronic anticoagulation, and therefore should be considered as first line treatment option when indicated.
Case presentation
A 73-year-old male with a history of paroxysmal atrial fibrillation on warfarin status post dual chamber implantable cardioverter defibrillator placement and nonischemic cardiomyopathy with HeartWare HVAD system (LVAD) as destination therapy implanted in an outside hospital 2 years prior to presentation.
The patient was seen at an outside hospital for gross hematuria and dysuria for one week which was conservatively managed with Foley catheter and antibiotics. The patient returned to the outside hospital after the completion of an antibiotic regimen with persistent hematuria. Continuous bladder irrigation was started during which the patient received 2 units of packed red blood cells for acute blood loss anemia. The patient was eventually transferred to our medical center for cystoscopy given the patient's complex medical history and the probable requirement for cardiac anesthesia during the procedure.
CT urogram obtained prior to cystoscopy showed marked prostatomegaly measuring approximately 175 cc with median lobe projecting into bladder neck and significant clot burden within the bladder lumen. Warfarin was held and therapeutic heparin was started. Cystoscopy performed under anesthesia showed severe trilobar hypertrophy of the prostate with friable enlarged median lobe consistent with BPH. The formed clot was evacuated, and the following re-examination of the bladder showed normal-appearing mucosa without evidence of urothelial cancer. Interventional radiology was consulted for prostate artery embolization (PAE). Prior to having hematuria, the patient's international prostate symptom score (IPSS) was 18 and the quality of life score (QOL) was 3 which were managed with alpha-blockers. On the day of the procedure, transfemoral approach prostate artery embolization was performed under general anesthesia using 300–500 μm embospheres (Fig. 1). The procedure was technically successful without acute complications and an estimated blood loss of less than 5 ml. Hematuria completely resolved and CBI was stopped on postoperative day (POD) 2. The patient was able to spontaneously void on POD 3 with postvoid residual (PVR) of approximately 300ml and was then discharged home on POD 5 after resuming warfarin. At the post discharge follow up at the cardiology clinic, the patient reported good activity tolerance without issues with LVAD, ICD, or hematuria. At 2 weeks follow up with urology, hematuria remained completely resolved while on anticoagulation, along with significant improvement of urinary stream with PVR of 90ml (previously 300ml). At 3 month follow up with IR, he remained asymptomatic and reported significant improvement of IPSS 1 (mild LUTs) previously 18 (moderate LUTs), and QOL 0 (delighted), previously 3 (mixed) and PVR of 9ml (previously 90 at 2 weeks follow up) (Fig. 2).Fig. 1 A: Right internal iliac angiogram showing right prostate artery (Red arrow) arising from right obturator artery. B: Right prostate artery angiogram opacifying branches supplying median and lateral lobes of the right side of prostate gland. C: Intra-procedure CT scan showing enhancement of right hemi-prostate gland with no enhancement of adjacent organs. D: Left internal iliac angiogram showing left prostate artery (red arrow) arising as a common origin with inferior vesicle artery. E: Left prostate artery angiogram showing branches supplying the left hemi-prostate. F: Cone beam CT showing enhancement of the left side of the prostate gland without enhancement of adjacent structures. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 1Fig. 2 A & B: 3-month Pre-void Ultrasound (US) of urinary bladder in longitudinal and transverse planes (respectively) measuring 7.9 × 9.47 x 7.17 (Pre-void volume 280ml). C & D: 3 month Post Void US of the urinary bladder in longitudinal and transverse planes (respectively) measuring 3.2 × 2.7 × 2.1 cm (Post void volume 9 ml).
Fig. 2
Discussion
Left ventricular assist device (LVAD) is an implantable device that has been introduced in 1990s to bridge patients with end stage heart failure refractory to maximal medical therapy to heart transplant. Continued development and resulting improvement of hemodynamics, end organ function, and quality of life in patients with LVAD has led to its usage as long term mechanical circulatory support in non-transplant patients as a destination therapy. LVAD also shows clinically significant improvement of survival benefit over optimal medical therapy at 1 or 2 years after device implantation.1 Prior studies have shown that 20–50% of patients with LVAD undergo non-cardiac surgical procedures.2
Hematuria is the presence of red blood cells in the urine accounting for 4–20% of inpatient urology consultations and hospitalizations.3 Common causes of hematuria include malignancy, benign prostatic hyperplasia, urinary tract infection, and urolithiasis. Prostatic hyperplasia can be considered a cause of hematuria after the patient has been evaluated for urologic malignancy. Gross hematuria, defined as blood visible in urine, especially in adults is highly suspicious for urologic malignancy thus appropriate imaging and cystoscopic evaluations are necessary in establishing the diagnosis. Hematuria in the setting of prostatic hyperplasia can result from the increased expression of vascular endothelial growth factor, anticoagulation, Foley catheterization, and infection. The management of hematuria encompasses continuous bladder irrigation, fulguration, and embolization.
Prostate artery embolization (PAE) is a minimally invasive procedure in which bilateral prostate arteries are embolized in the setting of moderate or severe lower urinary tract syndrome (LUTS) refractory to medications. PAE along with catheter directed arterial embolization of other pelvic vessels can also be performed to treat severe hematuria in high risk population whose conventional therapies have failed. Technical success, defined as bilateral prostate artery embolization, can be achieved at 100% with very low recurrence rate at one year when cone beam computed tomography is used during the procedure.4 CBCT can help visualize the prostatic arteries and detect accessory or collateral supplying vessels and in turn decrease the risks of non-target embolization. In addition to recurrence of hematuria, questionnaires such as international prostate symptoms score (IPSS) and quality of life score (QOL) are used to assess the outcome of the procedure.
Continuous flow LVADs are at increased risk of nonsurgical bleeding from arteriovenous malformations in gastrointestinal tract and acquired von Willebrand disease secondary to nonphysiological sheer stress on blood components and reduced pulse pressure.5 This, coupled with thrombotic risk from the mechanical circulatory device, poses a clinical dilemma in physicians performing endovascular procedures.
Conclusion
Prostate artery embolization can be performed safely with favorable outcome for patients with left ventricular assist device presenting with hematuria refractory to conventional therapy. PAE should also be considered as an alternative treatment option in patients with moderate LUTs secondary to BPH, especially in those patients who are on chronic anticoagulation.
Consent
Informed consent was obtained from the patient and patient information was de-identified prior to submission of the case report.
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
None. | Recovered | ReactionOutcome | CC BY-NC-ND | 33552921 | 19,000,350 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood creatine phosphokinase increased'. | Late response to rosuvastatin and statin-related myalgia due to SLCO1B1, SLCO1B3, ABCB11, and CYP3A5 variants in a patient with Familial Hypercholesterolemia: a case report.
Statins are the most widely used cholesterol-lowering drugs for cardiovascular diseases prevention. However, some patients are refractory to treatment, whereas others experience statin-related adverse events (SRAE). It has been increasingly important to identify pharmacogenetic biomarkers for predicting statin response and adverse events. This case report describes a female patient with familial hypercholesterolemia (FH) who showed late response to rosuvastatin and experienced myalgia on statin treatment. In the first visit (V1), the patient reported myalgia to rosuvastatin 40 mg, which was interrupted for a 6-week wash-out period. In V2, rosuvastatin 20 mg was reintroduced, but her lipid profile did not show any changes after 6 weeks (V3) (LDL-c: 402 vs. 407 mg/dL). Her lipid profile markedly improved after 12 weeks of treatment (V4) (LDL-c: 208 mg/dL), suggesting a late rosuvastatin response. Her adherence to treatment was similar in V1 and V3 and no drug interactions were detected. Pharmacogenetic analysis revealed that the patient carries low-activity variants in SLCO1B1*1B and*5, SLCO1B3 (rs4149117 and rs7311358), and ABCB11 rs2287622, and the non-functional variant in CYP3A5*3. The combined effect of variants in pharmacokinetics-related genes may have contributed to the late response to rosuvastatin and statin-related myalgia. Therefore, they should be considered when assessing a patient's response to statin treatment. To the best of our knowledge, this is the first report of a pharmacogenetic analysis on a case of late rosuvastatin response.
pmcIntroduction
Familial hypercholesterolemia (FH) is a genetic metabolic disease that leads to increased high low-density lipoprotein (LDL) cholesterol, which is a risk factor for early atherosclerosis and cardiovascular diseases (1). FH is usually treated with high-dose statins, which are inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGR), a key enzyme in cholesterol biosynthesis pathway. Rosuvastatin is one of the most effective statins, probably due its hydrophilicity, that confers selectivity to hepatic cells, higher affinity to HMGR, and lower rates of statin-related adverse events (SRAE) compared to other statins. It is poorly metabolized by CYP2C9 and CYP2C19, while 72% of the non-metabolized molecules are excreted via biliary system. Therefore, rosuvastatin blood levels rely on the activity of membrane transporters, mainly of solute carrier (SLC) and ATP-binding cassette (ABC) families, highly expressed in intestine, liver, and kidney (2).
Pharmacogenetic studies have shown that loss-of-function variants in genes encoding OATPs, such as SLCO1B1, SLCO2B1, and SLCO1B3, and ABCs have been associated with variability in low-density lipoprotein cholesterol (LDL-c) reduction and higher risk of SRAE (3). The importance of considering the combined effect of variants in key genes for pharmacogenetic analyses has been increasingly evident (4). In this case report, we discuss how variants in genes participating in different stages of statin pharmacokinetics pathway possibly affected the time to response to rosuvastatin and the risk of SRAE in a female FH patient. To the best of our knowledge, this is the first report of a pharmacogenetic analysis on a case of late rosuvastatin response. This case is reported in accordance with the CARE reporting checklist (available at http://dx.doi.org/10.21037/atm-20-5540).
Case presentation
A 26-year-old Caucasian female patient with definite diagnosis of FH according to Dutch Lipid Clinic Network MEDPED criteria (5) was invited to participate in an intervention study in June 2019. She was previously included in a FH sequencing study (May 2018), in which a panel of 84 genes involved in lipid homeostasis and drug metabolism was sequenced using exon-targeted gene sequencing (NGS). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committees and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for both studies.
The patient carries the variant LDLR rs28941776 (c.1646G>A, p.Gly549Asp), which has been associated with FH and is classified as pathogenic according to the American College of Medical Genetics (ACMG) guidelines (6).
Her clinical history included high levels of total cholesterol and LDL-c since childhood. In 2008, at the age of 15 years, she had an abnormal lipid profile even under a daily treatment with simvastatin 10 mg and ezetimibe 10 mg. Laboratory analyses showed a total cholesterol of 324 mg/dL, LDL-c 264 mg/dL, high-density lipoprotein cholesterol (HDL-c) 46 mg/dL, and triglycerides 71 mg/dL. In 2014, she was diagnosed with hypothyroidism and treated with levothyroxine 25 µg/day, which was gradually increased to 100 µg/day in 2019. She also had a pregnancy history in January 2017.
Her therapy history included simvastatin, which led to severe myopathy in 2008, with marked increase in serum creatine kinase (CK) to 1,080 U/L (4.7-fold the upper reference value). The cholesterol-lowering therapy was changed to pravastatin 20 mg and ezetimibe 10 mg daily until May 2011, when she reported another episode of myalgia. Pravastatin was withdrawn and atorvastatin 20 mg was introduced, also associated with ezetimibe 10 mg. Three months later, in August 2011, she reported interrupting atorvastatin treatment due to myalgia. Rosuvastatin 10 mg was then introduced, also associated with ezetimibe 10 mg, after which she showed an LDL-c level of 125 mg/dL and never reported myalgia again. However, her lipid profile worsened throughout the years even under rosuvastatin treatment, with her LDL-c reaching 194 mg/dL with rosuvastatin 20 mg.
The patient had no history of liver or kidney impartment, HIV, coronary artery disease (CAD), diabetes, obesity, cardiovascular events, and did not smoke or drink. Her mother and grandmother had a history of FH, but not CAD or cardiovascular events, while her father had hypertension and type 2 diabetes.
In the intervention study, the patient was seen four times (V1 to V4) in 5 months, and clinical history and therapy data were obtained. The protocol consisted of a 6-week rosuvastatin wash-out period, after which rosuvastatin was reintroduced for additional 6 weeks, when treatment response was evaluated. Adherence to treatment was assessed in each timepoint using the translated and validated version of the Brief Medication Questionnaire (BMQ) (7) and blood samples were taken in each visit for laboratory testing.
The lipid profile during the follow-up is shown in Figure 1. In April 2019 (V1), the patient was taking rosuvastatin 40 mg, ezetimibe 10 mg, and levothyroxine 88 µg daily. She reported experiencing muscle pain after recently increasing rosuvastatin dose from 20 to 40 mg/day. Her lipid profile was altered (total cholesterol 376 mg/dL, LDL-c 263 mg/dL, HDL-c 67 mg/dL, triglycerides 234 mg/dL) without increase in CK levels. She reported being active, running 2 km 2–3 times a week, and had a healthy diet, eating more than five portions of vegetables daily. Her TSH and T4 levels were normal. Rosuvastatin 40 mg was then discontinued for wash-out, ezetimibe was maintained, and levothyroxine dose was increased to 100 µg/day.
Figure 1 Plasma lipid profile and pharmacotherapy of the FH patient throughout the study period. EZT, ezetimibe; LVT, levothyroxine; RSV, rosuvastatin; SRAE, statin-related adverse events.
In June 2019 (V2), after undergoing a 6-week rosuvastatin wash-out period between V1 and V2, her lipid profile worsened (total cholesterol 512 mg/dL, LDL-c 405 mg/dL, HDL-c 65 mg/dL, triglycerides 213 mg/dL). Because the patient reported myalgia in V1 (rosuvastatin 40 mg), the physician prescribed rosuvastatin 20 mg/day for six weeks. Surprisingly, in August 2019 (V3), the lipid profile (total cholesterol 531 mg/dL, LDL-c 407 mg/dL, HDL-c 67 mg/dL, triglycerides 286 mg/dL) did not change compared to V2. The patient reported experiencing no myalgia to rosuvastatin 20 mg. In September 2019 (V4), her lipid profile improved (total cholesterol 299 mg/dL, LDL-c 208 mg/dL, HDL-c 59 mg/dL, triglycerides 158 mg/dL) and she continued not experiencing myalgia to rosuvastatin.
During the follow-up period, serum TSH and T4 levels remained unchanged, suggesting that her hypothyroidism was controlled and did not influence the lipid profile. Moreover, serum CK did not show any abnormality, which indicates no muscle damage due to statin treatment.
The patient also reported being adherent to treatment. In the BMQ adherence questionnaire, she reported forgetting the lipid-lowering medications 2 days in the week before V1 (71.4% adherence) and 1 day in the week before V3 (85.7% adherence).
The genetic profile of the patient is shown in Table 1. She carries five missense variants in SLCO1B1, SLCO1B3, and ABCB11. She is also homozygote for the CYP3A5*3 (rs776746) splicing variant. No other missense variants described as impacting rosuvastatin response were found in CYP3A4, CYP2C9, CYP2C19, or other drug transporters, such as ABCG2 (data not shown).
Table 1 Variants in pharmacokinetic-related genes of the FH patient with late response to rosuvastatin
Gene Variant code Variant type Nucleotide change (Amino acid change) Patient genotype Allele frequency (1,000 genomes, %) Functional impact Effects on rosuvastatin pharmacokinetics References
SLCO1B1 rs2306283 (SLCO1B1*1B) Missense c.388A>G (p.Asn130Asp) AG *1B: 54.4 Comparable to *1A No effect on plasma rosuvastatin levels Ho et al., 2006; Lee et al., 2013
SLCO1B1 rs4149056 (SLCO1B1*5) Missense c.521T>C p.(Val174Ala) TC *5: 8.8 Reduced activity Increased rosuvastatin plasma levels; Reduced hepatic uptake Kameyama et al., 2005; Lee et al., 2013
SLCO1B1 rs2306283, rs4149056 (SLCO1B1*15) Missense c.388A>G, c.521T>C (p.Asn130Asp, p.Val174Ala) AG, TC *15: 7.8 Reduced activity Increased rosuvastatin plasma levels; reduced hepatic uptake Kameyama et al., 2005; Birmingham et al., 2015
SLCO1B3 rs4149117 Missense c.334T>G (p.Ser112Ala) GG G: 70.2 Reduced activity Reduced hepatic uptake Schwarz et al. 2011
SLCO1B3 rs7311358 Missense c.699G>A (p.Met233Ile) AA A: 70.2 Reduced activity Reduced hepatic uptake Schwarz et al. 2011
ABCB11 rs2287622 Missense c.1331T>C (p.Val444Ala) TC C: 58.9 Reduced activity Increased rosuvastatin plasma levels Soko et al. 2019
CYP3A5 rs776746 (CYP3A5*3) Splicing c. 6986A>G GG *3: 62.1 No activity No rosuvastatin metabolism; Reduced LDL-c response Bailey et al. 2010
FH, familial hypercholesterolemia; LDL-c, low-density lipoprotein cholesterol.
Discussion
In heterozygous FH patients, LDL-c level reductions of 47.1% have been observed after a 6-week treatment with rosuvastatin 20 mg (8). The patient, however, did not experience any changes in LDL-c levels at week 6 (V3) of rosuvastatin 20 mg treatment, with a 48.9% LDL-c reduction only at week 12 (V4) of therapy.
The delayed rosuvastatin response could be explained by modifications in the therapy scheme during the follow-up period. However, the only change was in levothyroxine dose, that was increased from 88 to 100 µg in V1. It is unlikely that the late response is due to an adaptation to the new levothyroxine dose. The patient was already on treatment with levothyroxine 88 µg before V1; moreover, changes in cholesterol due to an adaptation period should be reflected in her lipid profile in V3, not only in V4. Another possible explanation is a lack of adherence from V2 to V3; however, the patient showed a similar treatment adherence in V3 and V1, which should lead to a similar lipid profile between visits. Furthermore, drug interactions between rosuvastatin, levothyroxine, and ezetimibe that could affect treatment response were not detected, excluding this possibility.
Pharmacokinetics-related genes may have contributed to the late response to rosuvastatin (Figure 2). The patient carries two variants in SLCO1B1, c.388A>G (SLCO1B1*1B) and c.521T>C (SLCO1B1*5), that are important determinants of rosuvastatin response. SLCO1B1*5 is a loss-of-function variant that decreases the hepatic uptake and increases blood levels of statins (9) (Table 1). SLCO1B1*1B has shown comparable activity to the functional *1A variant in in vitro functional studies (10). SLCO1B1*1B and *5 variants are in linkage disequilibrium (LD) and form the SLCO1B1*15 haplotype, that also reduced rosuvastatin uptake in functional studies with HEK293 and HeLa cells (11). The decreased liver uptake caused by these SLCO1B1 variants has been associated with increased plasma levels of rosuvastatin in pharmacokinetics studies (9) (Table 1).
Figure 2 Proposed mechanism for patient’s late rosuvastatin response and myalgia. 1. The hepatic uptake of rosuvastatin occurs through SLCO1B1 and SLCO1B3 influx transporters, while atorvastatin and simvastatin are internalized through SLCO1B1. The presence of deleterious variants in these transporters (SLCO1B1*15 and SLCO1B3 c.334T>G and c.699G>A) decreases statin uptake, therefore decreasing their concentration inside the hepatocyte and increasing statin plasma levels. 2. The lack of expression of CYP3A5 due to CYP3A5*3 also decreases atorvastatin and simvastatin metabolization, which contributes to increasing their plasma levels. This enzyme does not participate markedly in rosuvastatin metabolism. 3. The resulting higher blood statin levels increased the patient’s muscular exposure to statins, that are internalized through SLCO2B1 transporter into the skeletal muscle cell. The high concentrations in the skeletal muscle cell possibly caused patient’s myalgia. 4. Rosuvastatin’s bile excretion occurs through ABCB11 efflux protein. ABCB11 c.1331T>C variant results in a reduced activity ABCB11, which decreases rosuvastatin efflux; this increases rosuvastatin intrahepatic levels and blood levels. Although the patient had reduced function influx transporters, we suggest that the small portion of rosuvastatin absorbed in the beginning of the treatment accumulated due to the loss of function of the ABCB11 variant. This, together with rosuvastatin active metabolites generated by the normal function CYP2C9, allowed HMGR inhibition and therefore cholesterol lowering in the last visit.
SLCO1B3 is also an important gene that encodes an influx transporter for rosuvastatin. The patient was homozygous for both SLCO1B3 c.334T>G and c.699G>A, which are in strong LD (12). In an in vitro study, HeLa cells transfected with SLCO1B3 c.334G and c.699A haplotype showed a 13% decrease in rosuvastatin uptake, while for other substrates, such as cholecystokinin-8, an even more marked decrease of 57% was observed (13) (Table 1).
Although the effect of SLCO1B3 c.334G and c.699A haplotype in rosuvastatin uptake is not sufficient to explain the delayed response, it might be significant when combined with the effect of the decreased function haplotype SLCO1B1*15. While SLCO1B1*5 and SLCO1B1*15 are associated with higher plasma levels of rosuvastatin, previous studies failed to find an association between these variants and LDL-c reduction in response to short- and long-term rosuvastatin treatments (9). Therefore, the simultaneous presence of decreased function SLCO1B1 and SLCO1B3 haplotypes possibly caused a marked reduction of rosuvastatin intrahepatic concentration, resulting in the lack of response observed in V3.
ABCB11 encodes the efflux protein ABCB11, which plays an important role in rosuvastatin bile excretion. In a recent study, ABCB11 c.1331C allele has been associated to increased plasma rosuvastatin levels in healthy subjects (14) (Table 1). This variant possibly causes lower rosuvastatin excretion via bile, which in turn would increase intrahepatic rosuvastatin concentrations. Therefore, this mechanism could explain why even in the presence of low function SLC variants, the patient showed a late but evident LDL-c reduction after 12 weeks of rosuvastatin treatment.
The patient also carries the homozygous form of CYP3A5*3, an intronic variant that results in undetectable expression of CYP3A5 (15). The GEOSTAT-1 study reported that dyslipidemic patients carrying CYP3A5*3/*3 had lower LDL-c reduction after three-month rosuvastatin 10 mg treatment compared to carriers of *1/*1 or *1/*3 (Table 1). It was suggested that the metabolite produced by CYP3A5 also plays a role in HMGR inhibition, potentiating the response to rosuvastatin, which is why CYP3A5 non-expressors have reduced LDL-c response to rosuvastatin (16). CYP3A5*3 possibly impaired the patient’s response time to rosuvastatin, but in lower extent, as CYP3A5 does not participate markedly in rosuvastatin metabolism.
In addition to the delayed response to rosuvastatin, the patient experienced myalgia associated with rosuvastatin 40 mg/day and other statins, as previously commented. This SRAE may be due to SLCO1B1 variants. SLCO1B1*5 and SLCO1B1*15 have been extensively associated with myopathy to simvastatin. A systematic review and meta-analysis reported that carriers of the C allele of SLCO1B1*5 (c.521T>C) showed a higher risk of myotoxicity (17). Additionally, SLCO1B1*5 has been associated to rosuvastatin myotoxicity in previous studies (18,19). It has been suggested that it causes higher efflux of statins, increasing statin exposure and, therefore, the risk of myalgia (20). Also, a recent case report showed that variants in SLCO1B3 (c.334T>G and c.699G>A) and ABCB11 (c.1331T>C) and the interaction between rosuvastatin and ticagrelor led to rhabdomyolysis in a patient with chronic kidney disease and other chronic conditions (21), but no other reports were found.
CYP3A5*3 may also have contributed to statin myotoxicity, since it has been associated with increased risk to atorvastatin and rosuvastatin-related myalgia in South-Indian dyslipidemic patients (22). However, this variant was not associated to statin intolerance in another study (23). Most studies have evaluated the effect of individual variants in SRAE, and not the interaction between a group of variants in key genes in statin pharmacokinetics pathway. Therefore, we suggest that the combined effect of the low-activity variants in SLCO1B1 and SLCO1B3, the high-activity variant in ABCB11, and the lack of activity of CYP3A5*3 predisposed the patient to low hepatic uptake, metabolization and efflux, respectively. The resulting higher rosuvastatin plasma concentration increased its systemic exposure, which may have caused myalgia (Figure 2).
Importantly, the patient carries LDLR rs28941776 (c.1646G>A, p.Gly549Asp), a disruptive-missense variant that showed reduced LDL uptake in an in vitro study (24). LDLR variants have been associated with variability in statin response in FH patients (25), but we did not find studies that investigated the association between LDLR variants and time to statin response or myalgia. Nevertheless, this variant could have played a role in patient’s rosuvastatin time to response and it should be considered for further studies.
A limitation of this study is that plasma concentrations of rosuvastatin and its metabolites were not measured. However, the adherence of the patient to the prescribed treatment was ensured using a validated adherence questionnaire and regular follow-up calls.
In summary, the combination of four low-activity variants in SLC genes, a high-activity variant in ABCB11, and a non-functional variant in CYP3A5 may explain the observed late response to rosuvastatin and the statin-related myalgia. With this case report, we have shown the importance of considering a combination of variants in a pharmacogenetic analysis to predict individual responses to statin treatment and prevent adverse drug events. We believe this study contributes to precision medicine in future clinical settings.
Patient perspective
“I have had high cholesterol since I was a child and it has been an issue because of the delayed response to treatments and of many adverse reactions to medications, especially simvastatin. The authors have been very attentive towards me throughout the whole study and discovered possible variants that may delay my response to rosuvastatin and influence the pain that I have felt when using statins. I am very happy for knowing the cause of my problem and I would like to thank the authors for this possible diagnosis. This has improved my perspectives of cholesterol treatment.”
Supplementary
The article’s supplementary files as
10.21037/atm-20-5540 10.21037/atm-20-5540 10.21037/atm-20-5540
Acknowledgments
The authors thank Adriana Garofalo, Dr. Hui Tzu Lin Wang, colleagues from the Laboratory of Molecular Investigation in Cardiology, and the Divisions of Dyslipidemia and Pharmacy of the Institute Dante Pazzanese of Cardiology. Their immeasurable technical and logistic support in patient selection and data collection made this study possible.
Funding: This work was supported by Sao Paulo Research Foundation (FAPESP), Brazil [Research grant: #2016/12899-6 to MHH]; and National Council for Scientific and Technological Development [CNPq, grant: #447120/2014-0 to MHH], Brazil. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CDH is a recipient of a fellowship of the São Paulo Research Foundation (FAPESP), grant #2016/25637-0. RCCF, RHB, GMF and VFO are recipients of fellowships from FAPESP, Brazil. AAM is a recipient of fellowship from CAPES, Brazil. ESRM, MHH and RDCH are recipients of fellowships from CNPq, Brazil. BL was a recipient of fellowship from FAPESP, Brazil.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The intervention study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The DNA sequencing study was approved by the Ethics Committees of the Institute Dante Pazzanese of Cardiology (CAAE #4618713.0.1001.5462) and the School of Pharmaceutical Sciences of the University of Sao Paulo (CAAE #24618713.0.3001.0067), Sao Paulo, Brazil. The intervention study was approved by the Ethics Committee of the Institute Dante Pazzanese of Cardiology (CAAE #05234918.4.0000.5462). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committees. The patient signed the written informed consents before her enrollment in the studies. In the written informed consent of the DNA sequencing study, the patient was informed that clinical data and blood samples would be collected for laboratory tests and genetic analyses. As for the intervention study, the patient was informed on the intervention protocol and sample collections throughout the visits, and that this data would be used for genetic and epigenetic analyses.
Reporting Checklist: The authors have completed the CARE reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-5540
Peer Review File: Available at http://dx.doi.org/10.21037/atm-20-5540
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-5540). The authors have no conflicts of interest to declare. | ATORVASTATIN, EZETIMIBE, LEVOTHYROXINE, PRAVASTATIN SODIUM, ROSUVASTATIN, SIMVASTATIN | DrugsGivenReaction | CC BY-NC-ND | 33553369 | 18,931,409 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lipids abnormal'. | Late response to rosuvastatin and statin-related myalgia due to SLCO1B1, SLCO1B3, ABCB11, and CYP3A5 variants in a patient with Familial Hypercholesterolemia: a case report.
Statins are the most widely used cholesterol-lowering drugs for cardiovascular diseases prevention. However, some patients are refractory to treatment, whereas others experience statin-related adverse events (SRAE). It has been increasingly important to identify pharmacogenetic biomarkers for predicting statin response and adverse events. This case report describes a female patient with familial hypercholesterolemia (FH) who showed late response to rosuvastatin and experienced myalgia on statin treatment. In the first visit (V1), the patient reported myalgia to rosuvastatin 40 mg, which was interrupted for a 6-week wash-out period. In V2, rosuvastatin 20 mg was reintroduced, but her lipid profile did not show any changes after 6 weeks (V3) (LDL-c: 402 vs. 407 mg/dL). Her lipid profile markedly improved after 12 weeks of treatment (V4) (LDL-c: 208 mg/dL), suggesting a late rosuvastatin response. Her adherence to treatment was similar in V1 and V3 and no drug interactions were detected. Pharmacogenetic analysis revealed that the patient carries low-activity variants in SLCO1B1*1B and*5, SLCO1B3 (rs4149117 and rs7311358), and ABCB11 rs2287622, and the non-functional variant in CYP3A5*3. The combined effect of variants in pharmacokinetics-related genes may have contributed to the late response to rosuvastatin and statin-related myalgia. Therefore, they should be considered when assessing a patient's response to statin treatment. To the best of our knowledge, this is the first report of a pharmacogenetic analysis on a case of late rosuvastatin response.
pmcIntroduction
Familial hypercholesterolemia (FH) is a genetic metabolic disease that leads to increased high low-density lipoprotein (LDL) cholesterol, which is a risk factor for early atherosclerosis and cardiovascular diseases (1). FH is usually treated with high-dose statins, which are inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGR), a key enzyme in cholesterol biosynthesis pathway. Rosuvastatin is one of the most effective statins, probably due its hydrophilicity, that confers selectivity to hepatic cells, higher affinity to HMGR, and lower rates of statin-related adverse events (SRAE) compared to other statins. It is poorly metabolized by CYP2C9 and CYP2C19, while 72% of the non-metabolized molecules are excreted via biliary system. Therefore, rosuvastatin blood levels rely on the activity of membrane transporters, mainly of solute carrier (SLC) and ATP-binding cassette (ABC) families, highly expressed in intestine, liver, and kidney (2).
Pharmacogenetic studies have shown that loss-of-function variants in genes encoding OATPs, such as SLCO1B1, SLCO2B1, and SLCO1B3, and ABCs have been associated with variability in low-density lipoprotein cholesterol (LDL-c) reduction and higher risk of SRAE (3). The importance of considering the combined effect of variants in key genes for pharmacogenetic analyses has been increasingly evident (4). In this case report, we discuss how variants in genes participating in different stages of statin pharmacokinetics pathway possibly affected the time to response to rosuvastatin and the risk of SRAE in a female FH patient. To the best of our knowledge, this is the first report of a pharmacogenetic analysis on a case of late rosuvastatin response. This case is reported in accordance with the CARE reporting checklist (available at http://dx.doi.org/10.21037/atm-20-5540).
Case presentation
A 26-year-old Caucasian female patient with definite diagnosis of FH according to Dutch Lipid Clinic Network MEDPED criteria (5) was invited to participate in an intervention study in June 2019. She was previously included in a FH sequencing study (May 2018), in which a panel of 84 genes involved in lipid homeostasis and drug metabolism was sequenced using exon-targeted gene sequencing (NGS). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committees and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for both studies.
The patient carries the variant LDLR rs28941776 (c.1646G>A, p.Gly549Asp), which has been associated with FH and is classified as pathogenic according to the American College of Medical Genetics (ACMG) guidelines (6).
Her clinical history included high levels of total cholesterol and LDL-c since childhood. In 2008, at the age of 15 years, she had an abnormal lipid profile even under a daily treatment with simvastatin 10 mg and ezetimibe 10 mg. Laboratory analyses showed a total cholesterol of 324 mg/dL, LDL-c 264 mg/dL, high-density lipoprotein cholesterol (HDL-c) 46 mg/dL, and triglycerides 71 mg/dL. In 2014, she was diagnosed with hypothyroidism and treated with levothyroxine 25 µg/day, which was gradually increased to 100 µg/day in 2019. She also had a pregnancy history in January 2017.
Her therapy history included simvastatin, which led to severe myopathy in 2008, with marked increase in serum creatine kinase (CK) to 1,080 U/L (4.7-fold the upper reference value). The cholesterol-lowering therapy was changed to pravastatin 20 mg and ezetimibe 10 mg daily until May 2011, when she reported another episode of myalgia. Pravastatin was withdrawn and atorvastatin 20 mg was introduced, also associated with ezetimibe 10 mg. Three months later, in August 2011, she reported interrupting atorvastatin treatment due to myalgia. Rosuvastatin 10 mg was then introduced, also associated with ezetimibe 10 mg, after which she showed an LDL-c level of 125 mg/dL and never reported myalgia again. However, her lipid profile worsened throughout the years even under rosuvastatin treatment, with her LDL-c reaching 194 mg/dL with rosuvastatin 20 mg.
The patient had no history of liver or kidney impartment, HIV, coronary artery disease (CAD), diabetes, obesity, cardiovascular events, and did not smoke or drink. Her mother and grandmother had a history of FH, but not CAD or cardiovascular events, while her father had hypertension and type 2 diabetes.
In the intervention study, the patient was seen four times (V1 to V4) in 5 months, and clinical history and therapy data were obtained. The protocol consisted of a 6-week rosuvastatin wash-out period, after which rosuvastatin was reintroduced for additional 6 weeks, when treatment response was evaluated. Adherence to treatment was assessed in each timepoint using the translated and validated version of the Brief Medication Questionnaire (BMQ) (7) and blood samples were taken in each visit for laboratory testing.
The lipid profile during the follow-up is shown in Figure 1. In April 2019 (V1), the patient was taking rosuvastatin 40 mg, ezetimibe 10 mg, and levothyroxine 88 µg daily. She reported experiencing muscle pain after recently increasing rosuvastatin dose from 20 to 40 mg/day. Her lipid profile was altered (total cholesterol 376 mg/dL, LDL-c 263 mg/dL, HDL-c 67 mg/dL, triglycerides 234 mg/dL) without increase in CK levels. She reported being active, running 2 km 2–3 times a week, and had a healthy diet, eating more than five portions of vegetables daily. Her TSH and T4 levels were normal. Rosuvastatin 40 mg was then discontinued for wash-out, ezetimibe was maintained, and levothyroxine dose was increased to 100 µg/day.
Figure 1 Plasma lipid profile and pharmacotherapy of the FH patient throughout the study period. EZT, ezetimibe; LVT, levothyroxine; RSV, rosuvastatin; SRAE, statin-related adverse events.
In June 2019 (V2), after undergoing a 6-week rosuvastatin wash-out period between V1 and V2, her lipid profile worsened (total cholesterol 512 mg/dL, LDL-c 405 mg/dL, HDL-c 65 mg/dL, triglycerides 213 mg/dL). Because the patient reported myalgia in V1 (rosuvastatin 40 mg), the physician prescribed rosuvastatin 20 mg/day for six weeks. Surprisingly, in August 2019 (V3), the lipid profile (total cholesterol 531 mg/dL, LDL-c 407 mg/dL, HDL-c 67 mg/dL, triglycerides 286 mg/dL) did not change compared to V2. The patient reported experiencing no myalgia to rosuvastatin 20 mg. In September 2019 (V4), her lipid profile improved (total cholesterol 299 mg/dL, LDL-c 208 mg/dL, HDL-c 59 mg/dL, triglycerides 158 mg/dL) and she continued not experiencing myalgia to rosuvastatin.
During the follow-up period, serum TSH and T4 levels remained unchanged, suggesting that her hypothyroidism was controlled and did not influence the lipid profile. Moreover, serum CK did not show any abnormality, which indicates no muscle damage due to statin treatment.
The patient also reported being adherent to treatment. In the BMQ adherence questionnaire, she reported forgetting the lipid-lowering medications 2 days in the week before V1 (71.4% adherence) and 1 day in the week before V3 (85.7% adherence).
The genetic profile of the patient is shown in Table 1. She carries five missense variants in SLCO1B1, SLCO1B3, and ABCB11. She is also homozygote for the CYP3A5*3 (rs776746) splicing variant. No other missense variants described as impacting rosuvastatin response were found in CYP3A4, CYP2C9, CYP2C19, or other drug transporters, such as ABCG2 (data not shown).
Table 1 Variants in pharmacokinetic-related genes of the FH patient with late response to rosuvastatin
Gene Variant code Variant type Nucleotide change (Amino acid change) Patient genotype Allele frequency (1,000 genomes, %) Functional impact Effects on rosuvastatin pharmacokinetics References
SLCO1B1 rs2306283 (SLCO1B1*1B) Missense c.388A>G (p.Asn130Asp) AG *1B: 54.4 Comparable to *1A No effect on plasma rosuvastatin levels Ho et al., 2006; Lee et al., 2013
SLCO1B1 rs4149056 (SLCO1B1*5) Missense c.521T>C p.(Val174Ala) TC *5: 8.8 Reduced activity Increased rosuvastatin plasma levels; Reduced hepatic uptake Kameyama et al., 2005; Lee et al., 2013
SLCO1B1 rs2306283, rs4149056 (SLCO1B1*15) Missense c.388A>G, c.521T>C (p.Asn130Asp, p.Val174Ala) AG, TC *15: 7.8 Reduced activity Increased rosuvastatin plasma levels; reduced hepatic uptake Kameyama et al., 2005; Birmingham et al., 2015
SLCO1B3 rs4149117 Missense c.334T>G (p.Ser112Ala) GG G: 70.2 Reduced activity Reduced hepatic uptake Schwarz et al. 2011
SLCO1B3 rs7311358 Missense c.699G>A (p.Met233Ile) AA A: 70.2 Reduced activity Reduced hepatic uptake Schwarz et al. 2011
ABCB11 rs2287622 Missense c.1331T>C (p.Val444Ala) TC C: 58.9 Reduced activity Increased rosuvastatin plasma levels Soko et al. 2019
CYP3A5 rs776746 (CYP3A5*3) Splicing c. 6986A>G GG *3: 62.1 No activity No rosuvastatin metabolism; Reduced LDL-c response Bailey et al. 2010
FH, familial hypercholesterolemia; LDL-c, low-density lipoprotein cholesterol.
Discussion
In heterozygous FH patients, LDL-c level reductions of 47.1% have been observed after a 6-week treatment with rosuvastatin 20 mg (8). The patient, however, did not experience any changes in LDL-c levels at week 6 (V3) of rosuvastatin 20 mg treatment, with a 48.9% LDL-c reduction only at week 12 (V4) of therapy.
The delayed rosuvastatin response could be explained by modifications in the therapy scheme during the follow-up period. However, the only change was in levothyroxine dose, that was increased from 88 to 100 µg in V1. It is unlikely that the late response is due to an adaptation to the new levothyroxine dose. The patient was already on treatment with levothyroxine 88 µg before V1; moreover, changes in cholesterol due to an adaptation period should be reflected in her lipid profile in V3, not only in V4. Another possible explanation is a lack of adherence from V2 to V3; however, the patient showed a similar treatment adherence in V3 and V1, which should lead to a similar lipid profile between visits. Furthermore, drug interactions between rosuvastatin, levothyroxine, and ezetimibe that could affect treatment response were not detected, excluding this possibility.
Pharmacokinetics-related genes may have contributed to the late response to rosuvastatin (Figure 2). The patient carries two variants in SLCO1B1, c.388A>G (SLCO1B1*1B) and c.521T>C (SLCO1B1*5), that are important determinants of rosuvastatin response. SLCO1B1*5 is a loss-of-function variant that decreases the hepatic uptake and increases blood levels of statins (9) (Table 1). SLCO1B1*1B has shown comparable activity to the functional *1A variant in in vitro functional studies (10). SLCO1B1*1B and *5 variants are in linkage disequilibrium (LD) and form the SLCO1B1*15 haplotype, that also reduced rosuvastatin uptake in functional studies with HEK293 and HeLa cells (11). The decreased liver uptake caused by these SLCO1B1 variants has been associated with increased plasma levels of rosuvastatin in pharmacokinetics studies (9) (Table 1).
Figure 2 Proposed mechanism for patient’s late rosuvastatin response and myalgia. 1. The hepatic uptake of rosuvastatin occurs through SLCO1B1 and SLCO1B3 influx transporters, while atorvastatin and simvastatin are internalized through SLCO1B1. The presence of deleterious variants in these transporters (SLCO1B1*15 and SLCO1B3 c.334T>G and c.699G>A) decreases statin uptake, therefore decreasing their concentration inside the hepatocyte and increasing statin plasma levels. 2. The lack of expression of CYP3A5 due to CYP3A5*3 also decreases atorvastatin and simvastatin metabolization, which contributes to increasing their plasma levels. This enzyme does not participate markedly in rosuvastatin metabolism. 3. The resulting higher blood statin levels increased the patient’s muscular exposure to statins, that are internalized through SLCO2B1 transporter into the skeletal muscle cell. The high concentrations in the skeletal muscle cell possibly caused patient’s myalgia. 4. Rosuvastatin’s bile excretion occurs through ABCB11 efflux protein. ABCB11 c.1331T>C variant results in a reduced activity ABCB11, which decreases rosuvastatin efflux; this increases rosuvastatin intrahepatic levels and blood levels. Although the patient had reduced function influx transporters, we suggest that the small portion of rosuvastatin absorbed in the beginning of the treatment accumulated due to the loss of function of the ABCB11 variant. This, together with rosuvastatin active metabolites generated by the normal function CYP2C9, allowed HMGR inhibition and therefore cholesterol lowering in the last visit.
SLCO1B3 is also an important gene that encodes an influx transporter for rosuvastatin. The patient was homozygous for both SLCO1B3 c.334T>G and c.699G>A, which are in strong LD (12). In an in vitro study, HeLa cells transfected with SLCO1B3 c.334G and c.699A haplotype showed a 13% decrease in rosuvastatin uptake, while for other substrates, such as cholecystokinin-8, an even more marked decrease of 57% was observed (13) (Table 1).
Although the effect of SLCO1B3 c.334G and c.699A haplotype in rosuvastatin uptake is not sufficient to explain the delayed response, it might be significant when combined with the effect of the decreased function haplotype SLCO1B1*15. While SLCO1B1*5 and SLCO1B1*15 are associated with higher plasma levels of rosuvastatin, previous studies failed to find an association between these variants and LDL-c reduction in response to short- and long-term rosuvastatin treatments (9). Therefore, the simultaneous presence of decreased function SLCO1B1 and SLCO1B3 haplotypes possibly caused a marked reduction of rosuvastatin intrahepatic concentration, resulting in the lack of response observed in V3.
ABCB11 encodes the efflux protein ABCB11, which plays an important role in rosuvastatin bile excretion. In a recent study, ABCB11 c.1331C allele has been associated to increased plasma rosuvastatin levels in healthy subjects (14) (Table 1). This variant possibly causes lower rosuvastatin excretion via bile, which in turn would increase intrahepatic rosuvastatin concentrations. Therefore, this mechanism could explain why even in the presence of low function SLC variants, the patient showed a late but evident LDL-c reduction after 12 weeks of rosuvastatin treatment.
The patient also carries the homozygous form of CYP3A5*3, an intronic variant that results in undetectable expression of CYP3A5 (15). The GEOSTAT-1 study reported that dyslipidemic patients carrying CYP3A5*3/*3 had lower LDL-c reduction after three-month rosuvastatin 10 mg treatment compared to carriers of *1/*1 or *1/*3 (Table 1). It was suggested that the metabolite produced by CYP3A5 also plays a role in HMGR inhibition, potentiating the response to rosuvastatin, which is why CYP3A5 non-expressors have reduced LDL-c response to rosuvastatin (16). CYP3A5*3 possibly impaired the patient’s response time to rosuvastatin, but in lower extent, as CYP3A5 does not participate markedly in rosuvastatin metabolism.
In addition to the delayed response to rosuvastatin, the patient experienced myalgia associated with rosuvastatin 40 mg/day and other statins, as previously commented. This SRAE may be due to SLCO1B1 variants. SLCO1B1*5 and SLCO1B1*15 have been extensively associated with myopathy to simvastatin. A systematic review and meta-analysis reported that carriers of the C allele of SLCO1B1*5 (c.521T>C) showed a higher risk of myotoxicity (17). Additionally, SLCO1B1*5 has been associated to rosuvastatin myotoxicity in previous studies (18,19). It has been suggested that it causes higher efflux of statins, increasing statin exposure and, therefore, the risk of myalgia (20). Also, a recent case report showed that variants in SLCO1B3 (c.334T>G and c.699G>A) and ABCB11 (c.1331T>C) and the interaction between rosuvastatin and ticagrelor led to rhabdomyolysis in a patient with chronic kidney disease and other chronic conditions (21), but no other reports were found.
CYP3A5*3 may also have contributed to statin myotoxicity, since it has been associated with increased risk to atorvastatin and rosuvastatin-related myalgia in South-Indian dyslipidemic patients (22). However, this variant was not associated to statin intolerance in another study (23). Most studies have evaluated the effect of individual variants in SRAE, and not the interaction between a group of variants in key genes in statin pharmacokinetics pathway. Therefore, we suggest that the combined effect of the low-activity variants in SLCO1B1 and SLCO1B3, the high-activity variant in ABCB11, and the lack of activity of CYP3A5*3 predisposed the patient to low hepatic uptake, metabolization and efflux, respectively. The resulting higher rosuvastatin plasma concentration increased its systemic exposure, which may have caused myalgia (Figure 2).
Importantly, the patient carries LDLR rs28941776 (c.1646G>A, p.Gly549Asp), a disruptive-missense variant that showed reduced LDL uptake in an in vitro study (24). LDLR variants have been associated with variability in statin response in FH patients (25), but we did not find studies that investigated the association between LDLR variants and time to statin response or myalgia. Nevertheless, this variant could have played a role in patient’s rosuvastatin time to response and it should be considered for further studies.
A limitation of this study is that plasma concentrations of rosuvastatin and its metabolites were not measured. However, the adherence of the patient to the prescribed treatment was ensured using a validated adherence questionnaire and regular follow-up calls.
In summary, the combination of four low-activity variants in SLC genes, a high-activity variant in ABCB11, and a non-functional variant in CYP3A5 may explain the observed late response to rosuvastatin and the statin-related myalgia. With this case report, we have shown the importance of considering a combination of variants in a pharmacogenetic analysis to predict individual responses to statin treatment and prevent adverse drug events. We believe this study contributes to precision medicine in future clinical settings.
Patient perspective
“I have had high cholesterol since I was a child and it has been an issue because of the delayed response to treatments and of many adverse reactions to medications, especially simvastatin. The authors have been very attentive towards me throughout the whole study and discovered possible variants that may delay my response to rosuvastatin and influence the pain that I have felt when using statins. I am very happy for knowing the cause of my problem and I would like to thank the authors for this possible diagnosis. This has improved my perspectives of cholesterol treatment.”
Supplementary
The article’s supplementary files as
10.21037/atm-20-5540 10.21037/atm-20-5540 10.21037/atm-20-5540
Acknowledgments
The authors thank Adriana Garofalo, Dr. Hui Tzu Lin Wang, colleagues from the Laboratory of Molecular Investigation in Cardiology, and the Divisions of Dyslipidemia and Pharmacy of the Institute Dante Pazzanese of Cardiology. Their immeasurable technical and logistic support in patient selection and data collection made this study possible.
Funding: This work was supported by Sao Paulo Research Foundation (FAPESP), Brazil [Research grant: #2016/12899-6 to MHH]; and National Council for Scientific and Technological Development [CNPq, grant: #447120/2014-0 to MHH], Brazil. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CDH is a recipient of a fellowship of the São Paulo Research Foundation (FAPESP), grant #2016/25637-0. RCCF, RHB, GMF and VFO are recipients of fellowships from FAPESP, Brazil. AAM is a recipient of fellowship from CAPES, Brazil. ESRM, MHH and RDCH are recipients of fellowships from CNPq, Brazil. BL was a recipient of fellowship from FAPESP, Brazil.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The intervention study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The DNA sequencing study was approved by the Ethics Committees of the Institute Dante Pazzanese of Cardiology (CAAE #4618713.0.1001.5462) and the School of Pharmaceutical Sciences of the University of Sao Paulo (CAAE #24618713.0.3001.0067), Sao Paulo, Brazil. The intervention study was approved by the Ethics Committee of the Institute Dante Pazzanese of Cardiology (CAAE #05234918.4.0000.5462). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committees. The patient signed the written informed consents before her enrollment in the studies. In the written informed consent of the DNA sequencing study, the patient was informed that clinical data and blood samples would be collected for laboratory tests and genetic analyses. As for the intervention study, the patient was informed on the intervention protocol and sample collections throughout the visits, and that this data would be used for genetic and epigenetic analyses.
Reporting Checklist: The authors have completed the CARE reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-5540
Peer Review File: Available at http://dx.doi.org/10.21037/atm-20-5540
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-5540). The authors have no conflicts of interest to declare. | ATORVASTATIN, EZETIMIBE, LEVOTHYROXINE, PRAVASTATIN SODIUM, ROSUVASTATIN, SIMVASTATIN | DrugsGivenReaction | CC BY-NC-ND | 33553369 | 18,931,409 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myalgia'. | Late response to rosuvastatin and statin-related myalgia due to SLCO1B1, SLCO1B3, ABCB11, and CYP3A5 variants in a patient with Familial Hypercholesterolemia: a case report.
Statins are the most widely used cholesterol-lowering drugs for cardiovascular diseases prevention. However, some patients are refractory to treatment, whereas others experience statin-related adverse events (SRAE). It has been increasingly important to identify pharmacogenetic biomarkers for predicting statin response and adverse events. This case report describes a female patient with familial hypercholesterolemia (FH) who showed late response to rosuvastatin and experienced myalgia on statin treatment. In the first visit (V1), the patient reported myalgia to rosuvastatin 40 mg, which was interrupted for a 6-week wash-out period. In V2, rosuvastatin 20 mg was reintroduced, but her lipid profile did not show any changes after 6 weeks (V3) (LDL-c: 402 vs. 407 mg/dL). Her lipid profile markedly improved after 12 weeks of treatment (V4) (LDL-c: 208 mg/dL), suggesting a late rosuvastatin response. Her adherence to treatment was similar in V1 and V3 and no drug interactions were detected. Pharmacogenetic analysis revealed that the patient carries low-activity variants in SLCO1B1*1B and*5, SLCO1B3 (rs4149117 and rs7311358), and ABCB11 rs2287622, and the non-functional variant in CYP3A5*3. The combined effect of variants in pharmacokinetics-related genes may have contributed to the late response to rosuvastatin and statin-related myalgia. Therefore, they should be considered when assessing a patient's response to statin treatment. To the best of our knowledge, this is the first report of a pharmacogenetic analysis on a case of late rosuvastatin response.
pmcIntroduction
Familial hypercholesterolemia (FH) is a genetic metabolic disease that leads to increased high low-density lipoprotein (LDL) cholesterol, which is a risk factor for early atherosclerosis and cardiovascular diseases (1). FH is usually treated with high-dose statins, which are inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGR), a key enzyme in cholesterol biosynthesis pathway. Rosuvastatin is one of the most effective statins, probably due its hydrophilicity, that confers selectivity to hepatic cells, higher affinity to HMGR, and lower rates of statin-related adverse events (SRAE) compared to other statins. It is poorly metabolized by CYP2C9 and CYP2C19, while 72% of the non-metabolized molecules are excreted via biliary system. Therefore, rosuvastatin blood levels rely on the activity of membrane transporters, mainly of solute carrier (SLC) and ATP-binding cassette (ABC) families, highly expressed in intestine, liver, and kidney (2).
Pharmacogenetic studies have shown that loss-of-function variants in genes encoding OATPs, such as SLCO1B1, SLCO2B1, and SLCO1B3, and ABCs have been associated with variability in low-density lipoprotein cholesterol (LDL-c) reduction and higher risk of SRAE (3). The importance of considering the combined effect of variants in key genes for pharmacogenetic analyses has been increasingly evident (4). In this case report, we discuss how variants in genes participating in different stages of statin pharmacokinetics pathway possibly affected the time to response to rosuvastatin and the risk of SRAE in a female FH patient. To the best of our knowledge, this is the first report of a pharmacogenetic analysis on a case of late rosuvastatin response. This case is reported in accordance with the CARE reporting checklist (available at http://dx.doi.org/10.21037/atm-20-5540).
Case presentation
A 26-year-old Caucasian female patient with definite diagnosis of FH according to Dutch Lipid Clinic Network MEDPED criteria (5) was invited to participate in an intervention study in June 2019. She was previously included in a FH sequencing study (May 2018), in which a panel of 84 genes involved in lipid homeostasis and drug metabolism was sequenced using exon-targeted gene sequencing (NGS). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committees and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for both studies.
The patient carries the variant LDLR rs28941776 (c.1646G>A, p.Gly549Asp), which has been associated with FH and is classified as pathogenic according to the American College of Medical Genetics (ACMG) guidelines (6).
Her clinical history included high levels of total cholesterol and LDL-c since childhood. In 2008, at the age of 15 years, she had an abnormal lipid profile even under a daily treatment with simvastatin 10 mg and ezetimibe 10 mg. Laboratory analyses showed a total cholesterol of 324 mg/dL, LDL-c 264 mg/dL, high-density lipoprotein cholesterol (HDL-c) 46 mg/dL, and triglycerides 71 mg/dL. In 2014, she was diagnosed with hypothyroidism and treated with levothyroxine 25 µg/day, which was gradually increased to 100 µg/day in 2019. She also had a pregnancy history in January 2017.
Her therapy history included simvastatin, which led to severe myopathy in 2008, with marked increase in serum creatine kinase (CK) to 1,080 U/L (4.7-fold the upper reference value). The cholesterol-lowering therapy was changed to pravastatin 20 mg and ezetimibe 10 mg daily until May 2011, when she reported another episode of myalgia. Pravastatin was withdrawn and atorvastatin 20 mg was introduced, also associated with ezetimibe 10 mg. Three months later, in August 2011, she reported interrupting atorvastatin treatment due to myalgia. Rosuvastatin 10 mg was then introduced, also associated with ezetimibe 10 mg, after which she showed an LDL-c level of 125 mg/dL and never reported myalgia again. However, her lipid profile worsened throughout the years even under rosuvastatin treatment, with her LDL-c reaching 194 mg/dL with rosuvastatin 20 mg.
The patient had no history of liver or kidney impartment, HIV, coronary artery disease (CAD), diabetes, obesity, cardiovascular events, and did not smoke or drink. Her mother and grandmother had a history of FH, but not CAD or cardiovascular events, while her father had hypertension and type 2 diabetes.
In the intervention study, the patient was seen four times (V1 to V4) in 5 months, and clinical history and therapy data were obtained. The protocol consisted of a 6-week rosuvastatin wash-out period, after which rosuvastatin was reintroduced for additional 6 weeks, when treatment response was evaluated. Adherence to treatment was assessed in each timepoint using the translated and validated version of the Brief Medication Questionnaire (BMQ) (7) and blood samples were taken in each visit for laboratory testing.
The lipid profile during the follow-up is shown in Figure 1. In April 2019 (V1), the patient was taking rosuvastatin 40 mg, ezetimibe 10 mg, and levothyroxine 88 µg daily. She reported experiencing muscle pain after recently increasing rosuvastatin dose from 20 to 40 mg/day. Her lipid profile was altered (total cholesterol 376 mg/dL, LDL-c 263 mg/dL, HDL-c 67 mg/dL, triglycerides 234 mg/dL) without increase in CK levels. She reported being active, running 2 km 2–3 times a week, and had a healthy diet, eating more than five portions of vegetables daily. Her TSH and T4 levels were normal. Rosuvastatin 40 mg was then discontinued for wash-out, ezetimibe was maintained, and levothyroxine dose was increased to 100 µg/day.
Figure 1 Plasma lipid profile and pharmacotherapy of the FH patient throughout the study period. EZT, ezetimibe; LVT, levothyroxine; RSV, rosuvastatin; SRAE, statin-related adverse events.
In June 2019 (V2), after undergoing a 6-week rosuvastatin wash-out period between V1 and V2, her lipid profile worsened (total cholesterol 512 mg/dL, LDL-c 405 mg/dL, HDL-c 65 mg/dL, triglycerides 213 mg/dL). Because the patient reported myalgia in V1 (rosuvastatin 40 mg), the physician prescribed rosuvastatin 20 mg/day for six weeks. Surprisingly, in August 2019 (V3), the lipid profile (total cholesterol 531 mg/dL, LDL-c 407 mg/dL, HDL-c 67 mg/dL, triglycerides 286 mg/dL) did not change compared to V2. The patient reported experiencing no myalgia to rosuvastatin 20 mg. In September 2019 (V4), her lipid profile improved (total cholesterol 299 mg/dL, LDL-c 208 mg/dL, HDL-c 59 mg/dL, triglycerides 158 mg/dL) and she continued not experiencing myalgia to rosuvastatin.
During the follow-up period, serum TSH and T4 levels remained unchanged, suggesting that her hypothyroidism was controlled and did not influence the lipid profile. Moreover, serum CK did not show any abnormality, which indicates no muscle damage due to statin treatment.
The patient also reported being adherent to treatment. In the BMQ adherence questionnaire, she reported forgetting the lipid-lowering medications 2 days in the week before V1 (71.4% adherence) and 1 day in the week before V3 (85.7% adherence).
The genetic profile of the patient is shown in Table 1. She carries five missense variants in SLCO1B1, SLCO1B3, and ABCB11. She is also homozygote for the CYP3A5*3 (rs776746) splicing variant. No other missense variants described as impacting rosuvastatin response were found in CYP3A4, CYP2C9, CYP2C19, or other drug transporters, such as ABCG2 (data not shown).
Table 1 Variants in pharmacokinetic-related genes of the FH patient with late response to rosuvastatin
Gene Variant code Variant type Nucleotide change (Amino acid change) Patient genotype Allele frequency (1,000 genomes, %) Functional impact Effects on rosuvastatin pharmacokinetics References
SLCO1B1 rs2306283 (SLCO1B1*1B) Missense c.388A>G (p.Asn130Asp) AG *1B: 54.4 Comparable to *1A No effect on plasma rosuvastatin levels Ho et al., 2006; Lee et al., 2013
SLCO1B1 rs4149056 (SLCO1B1*5) Missense c.521T>C p.(Val174Ala) TC *5: 8.8 Reduced activity Increased rosuvastatin plasma levels; Reduced hepatic uptake Kameyama et al., 2005; Lee et al., 2013
SLCO1B1 rs2306283, rs4149056 (SLCO1B1*15) Missense c.388A>G, c.521T>C (p.Asn130Asp, p.Val174Ala) AG, TC *15: 7.8 Reduced activity Increased rosuvastatin plasma levels; reduced hepatic uptake Kameyama et al., 2005; Birmingham et al., 2015
SLCO1B3 rs4149117 Missense c.334T>G (p.Ser112Ala) GG G: 70.2 Reduced activity Reduced hepatic uptake Schwarz et al. 2011
SLCO1B3 rs7311358 Missense c.699G>A (p.Met233Ile) AA A: 70.2 Reduced activity Reduced hepatic uptake Schwarz et al. 2011
ABCB11 rs2287622 Missense c.1331T>C (p.Val444Ala) TC C: 58.9 Reduced activity Increased rosuvastatin plasma levels Soko et al. 2019
CYP3A5 rs776746 (CYP3A5*3) Splicing c. 6986A>G GG *3: 62.1 No activity No rosuvastatin metabolism; Reduced LDL-c response Bailey et al. 2010
FH, familial hypercholesterolemia; LDL-c, low-density lipoprotein cholesterol.
Discussion
In heterozygous FH patients, LDL-c level reductions of 47.1% have been observed after a 6-week treatment with rosuvastatin 20 mg (8). The patient, however, did not experience any changes in LDL-c levels at week 6 (V3) of rosuvastatin 20 mg treatment, with a 48.9% LDL-c reduction only at week 12 (V4) of therapy.
The delayed rosuvastatin response could be explained by modifications in the therapy scheme during the follow-up period. However, the only change was in levothyroxine dose, that was increased from 88 to 100 µg in V1. It is unlikely that the late response is due to an adaptation to the new levothyroxine dose. The patient was already on treatment with levothyroxine 88 µg before V1; moreover, changes in cholesterol due to an adaptation period should be reflected in her lipid profile in V3, not only in V4. Another possible explanation is a lack of adherence from V2 to V3; however, the patient showed a similar treatment adherence in V3 and V1, which should lead to a similar lipid profile between visits. Furthermore, drug interactions between rosuvastatin, levothyroxine, and ezetimibe that could affect treatment response were not detected, excluding this possibility.
Pharmacokinetics-related genes may have contributed to the late response to rosuvastatin (Figure 2). The patient carries two variants in SLCO1B1, c.388A>G (SLCO1B1*1B) and c.521T>C (SLCO1B1*5), that are important determinants of rosuvastatin response. SLCO1B1*5 is a loss-of-function variant that decreases the hepatic uptake and increases blood levels of statins (9) (Table 1). SLCO1B1*1B has shown comparable activity to the functional *1A variant in in vitro functional studies (10). SLCO1B1*1B and *5 variants are in linkage disequilibrium (LD) and form the SLCO1B1*15 haplotype, that also reduced rosuvastatin uptake in functional studies with HEK293 and HeLa cells (11). The decreased liver uptake caused by these SLCO1B1 variants has been associated with increased plasma levels of rosuvastatin in pharmacokinetics studies (9) (Table 1).
Figure 2 Proposed mechanism for patient’s late rosuvastatin response and myalgia. 1. The hepatic uptake of rosuvastatin occurs through SLCO1B1 and SLCO1B3 influx transporters, while atorvastatin and simvastatin are internalized through SLCO1B1. The presence of deleterious variants in these transporters (SLCO1B1*15 and SLCO1B3 c.334T>G and c.699G>A) decreases statin uptake, therefore decreasing their concentration inside the hepatocyte and increasing statin plasma levels. 2. The lack of expression of CYP3A5 due to CYP3A5*3 also decreases atorvastatin and simvastatin metabolization, which contributes to increasing their plasma levels. This enzyme does not participate markedly in rosuvastatin metabolism. 3. The resulting higher blood statin levels increased the patient’s muscular exposure to statins, that are internalized through SLCO2B1 transporter into the skeletal muscle cell. The high concentrations in the skeletal muscle cell possibly caused patient’s myalgia. 4. Rosuvastatin’s bile excretion occurs through ABCB11 efflux protein. ABCB11 c.1331T>C variant results in a reduced activity ABCB11, which decreases rosuvastatin efflux; this increases rosuvastatin intrahepatic levels and blood levels. Although the patient had reduced function influx transporters, we suggest that the small portion of rosuvastatin absorbed in the beginning of the treatment accumulated due to the loss of function of the ABCB11 variant. This, together with rosuvastatin active metabolites generated by the normal function CYP2C9, allowed HMGR inhibition and therefore cholesterol lowering in the last visit.
SLCO1B3 is also an important gene that encodes an influx transporter for rosuvastatin. The patient was homozygous for both SLCO1B3 c.334T>G and c.699G>A, which are in strong LD (12). In an in vitro study, HeLa cells transfected with SLCO1B3 c.334G and c.699A haplotype showed a 13% decrease in rosuvastatin uptake, while for other substrates, such as cholecystokinin-8, an even more marked decrease of 57% was observed (13) (Table 1).
Although the effect of SLCO1B3 c.334G and c.699A haplotype in rosuvastatin uptake is not sufficient to explain the delayed response, it might be significant when combined with the effect of the decreased function haplotype SLCO1B1*15. While SLCO1B1*5 and SLCO1B1*15 are associated with higher plasma levels of rosuvastatin, previous studies failed to find an association between these variants and LDL-c reduction in response to short- and long-term rosuvastatin treatments (9). Therefore, the simultaneous presence of decreased function SLCO1B1 and SLCO1B3 haplotypes possibly caused a marked reduction of rosuvastatin intrahepatic concentration, resulting in the lack of response observed in V3.
ABCB11 encodes the efflux protein ABCB11, which plays an important role in rosuvastatin bile excretion. In a recent study, ABCB11 c.1331C allele has been associated to increased plasma rosuvastatin levels in healthy subjects (14) (Table 1). This variant possibly causes lower rosuvastatin excretion via bile, which in turn would increase intrahepatic rosuvastatin concentrations. Therefore, this mechanism could explain why even in the presence of low function SLC variants, the patient showed a late but evident LDL-c reduction after 12 weeks of rosuvastatin treatment.
The patient also carries the homozygous form of CYP3A5*3, an intronic variant that results in undetectable expression of CYP3A5 (15). The GEOSTAT-1 study reported that dyslipidemic patients carrying CYP3A5*3/*3 had lower LDL-c reduction after three-month rosuvastatin 10 mg treatment compared to carriers of *1/*1 or *1/*3 (Table 1). It was suggested that the metabolite produced by CYP3A5 also plays a role in HMGR inhibition, potentiating the response to rosuvastatin, which is why CYP3A5 non-expressors have reduced LDL-c response to rosuvastatin (16). CYP3A5*3 possibly impaired the patient’s response time to rosuvastatin, but in lower extent, as CYP3A5 does not participate markedly in rosuvastatin metabolism.
In addition to the delayed response to rosuvastatin, the patient experienced myalgia associated with rosuvastatin 40 mg/day and other statins, as previously commented. This SRAE may be due to SLCO1B1 variants. SLCO1B1*5 and SLCO1B1*15 have been extensively associated with myopathy to simvastatin. A systematic review and meta-analysis reported that carriers of the C allele of SLCO1B1*5 (c.521T>C) showed a higher risk of myotoxicity (17). Additionally, SLCO1B1*5 has been associated to rosuvastatin myotoxicity in previous studies (18,19). It has been suggested that it causes higher efflux of statins, increasing statin exposure and, therefore, the risk of myalgia (20). Also, a recent case report showed that variants in SLCO1B3 (c.334T>G and c.699G>A) and ABCB11 (c.1331T>C) and the interaction between rosuvastatin and ticagrelor led to rhabdomyolysis in a patient with chronic kidney disease and other chronic conditions (21), but no other reports were found.
CYP3A5*3 may also have contributed to statin myotoxicity, since it has been associated with increased risk to atorvastatin and rosuvastatin-related myalgia in South-Indian dyslipidemic patients (22). However, this variant was not associated to statin intolerance in another study (23). Most studies have evaluated the effect of individual variants in SRAE, and not the interaction between a group of variants in key genes in statin pharmacokinetics pathway. Therefore, we suggest that the combined effect of the low-activity variants in SLCO1B1 and SLCO1B3, the high-activity variant in ABCB11, and the lack of activity of CYP3A5*3 predisposed the patient to low hepatic uptake, metabolization and efflux, respectively. The resulting higher rosuvastatin plasma concentration increased its systemic exposure, which may have caused myalgia (Figure 2).
Importantly, the patient carries LDLR rs28941776 (c.1646G>A, p.Gly549Asp), a disruptive-missense variant that showed reduced LDL uptake in an in vitro study (24). LDLR variants have been associated with variability in statin response in FH patients (25), but we did not find studies that investigated the association between LDLR variants and time to statin response or myalgia. Nevertheless, this variant could have played a role in patient’s rosuvastatin time to response and it should be considered for further studies.
A limitation of this study is that plasma concentrations of rosuvastatin and its metabolites were not measured. However, the adherence of the patient to the prescribed treatment was ensured using a validated adherence questionnaire and regular follow-up calls.
In summary, the combination of four low-activity variants in SLC genes, a high-activity variant in ABCB11, and a non-functional variant in CYP3A5 may explain the observed late response to rosuvastatin and the statin-related myalgia. With this case report, we have shown the importance of considering a combination of variants in a pharmacogenetic analysis to predict individual responses to statin treatment and prevent adverse drug events. We believe this study contributes to precision medicine in future clinical settings.
Patient perspective
“I have had high cholesterol since I was a child and it has been an issue because of the delayed response to treatments and of many adverse reactions to medications, especially simvastatin. The authors have been very attentive towards me throughout the whole study and discovered possible variants that may delay my response to rosuvastatin and influence the pain that I have felt when using statins. I am very happy for knowing the cause of my problem and I would like to thank the authors for this possible diagnosis. This has improved my perspectives of cholesterol treatment.”
Supplementary
The article’s supplementary files as
10.21037/atm-20-5540 10.21037/atm-20-5540 10.21037/atm-20-5540
Acknowledgments
The authors thank Adriana Garofalo, Dr. Hui Tzu Lin Wang, colleagues from the Laboratory of Molecular Investigation in Cardiology, and the Divisions of Dyslipidemia and Pharmacy of the Institute Dante Pazzanese of Cardiology. Their immeasurable technical and logistic support in patient selection and data collection made this study possible.
Funding: This work was supported by Sao Paulo Research Foundation (FAPESP), Brazil [Research grant: #2016/12899-6 to MHH]; and National Council for Scientific and Technological Development [CNPq, grant: #447120/2014-0 to MHH], Brazil. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CDH is a recipient of a fellowship of the São Paulo Research Foundation (FAPESP), grant #2016/25637-0. RCCF, RHB, GMF and VFO are recipients of fellowships from FAPESP, Brazil. AAM is a recipient of fellowship from CAPES, Brazil. ESRM, MHH and RDCH are recipients of fellowships from CNPq, Brazil. BL was a recipient of fellowship from FAPESP, Brazil.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The intervention study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The DNA sequencing study was approved by the Ethics Committees of the Institute Dante Pazzanese of Cardiology (CAAE #4618713.0.1001.5462) and the School of Pharmaceutical Sciences of the University of Sao Paulo (CAAE #24618713.0.3001.0067), Sao Paulo, Brazil. The intervention study was approved by the Ethics Committee of the Institute Dante Pazzanese of Cardiology (CAAE #05234918.4.0000.5462). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committees. The patient signed the written informed consents before her enrollment in the studies. In the written informed consent of the DNA sequencing study, the patient was informed that clinical data and blood samples would be collected for laboratory tests and genetic analyses. As for the intervention study, the patient was informed on the intervention protocol and sample collections throughout the visits, and that this data would be used for genetic and epigenetic analyses.
Reporting Checklist: The authors have completed the CARE reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-5540
Peer Review File: Available at http://dx.doi.org/10.21037/atm-20-5540
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-5540). The authors have no conflicts of interest to declare. | ATORVASTATIN, EZETIMIBE, LEVOTHYROXINE, PRAVASTATIN SODIUM, ROSUVASTATIN, SIMVASTATIN | DrugsGivenReaction | CC BY-NC-ND | 33553369 | 18,931,409 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myopathy'. | Late response to rosuvastatin and statin-related myalgia due to SLCO1B1, SLCO1B3, ABCB11, and CYP3A5 variants in a patient with Familial Hypercholesterolemia: a case report.
Statins are the most widely used cholesterol-lowering drugs for cardiovascular diseases prevention. However, some patients are refractory to treatment, whereas others experience statin-related adverse events (SRAE). It has been increasingly important to identify pharmacogenetic biomarkers for predicting statin response and adverse events. This case report describes a female patient with familial hypercholesterolemia (FH) who showed late response to rosuvastatin and experienced myalgia on statin treatment. In the first visit (V1), the patient reported myalgia to rosuvastatin 40 mg, which was interrupted for a 6-week wash-out period. In V2, rosuvastatin 20 mg was reintroduced, but her lipid profile did not show any changes after 6 weeks (V3) (LDL-c: 402 vs. 407 mg/dL). Her lipid profile markedly improved after 12 weeks of treatment (V4) (LDL-c: 208 mg/dL), suggesting a late rosuvastatin response. Her adherence to treatment was similar in V1 and V3 and no drug interactions were detected. Pharmacogenetic analysis revealed that the patient carries low-activity variants in SLCO1B1*1B and*5, SLCO1B3 (rs4149117 and rs7311358), and ABCB11 rs2287622, and the non-functional variant in CYP3A5*3. The combined effect of variants in pharmacokinetics-related genes may have contributed to the late response to rosuvastatin and statin-related myalgia. Therefore, they should be considered when assessing a patient's response to statin treatment. To the best of our knowledge, this is the first report of a pharmacogenetic analysis on a case of late rosuvastatin response.
pmcIntroduction
Familial hypercholesterolemia (FH) is a genetic metabolic disease that leads to increased high low-density lipoprotein (LDL) cholesterol, which is a risk factor for early atherosclerosis and cardiovascular diseases (1). FH is usually treated with high-dose statins, which are inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGR), a key enzyme in cholesterol biosynthesis pathway. Rosuvastatin is one of the most effective statins, probably due its hydrophilicity, that confers selectivity to hepatic cells, higher affinity to HMGR, and lower rates of statin-related adverse events (SRAE) compared to other statins. It is poorly metabolized by CYP2C9 and CYP2C19, while 72% of the non-metabolized molecules are excreted via biliary system. Therefore, rosuvastatin blood levels rely on the activity of membrane transporters, mainly of solute carrier (SLC) and ATP-binding cassette (ABC) families, highly expressed in intestine, liver, and kidney (2).
Pharmacogenetic studies have shown that loss-of-function variants in genes encoding OATPs, such as SLCO1B1, SLCO2B1, and SLCO1B3, and ABCs have been associated with variability in low-density lipoprotein cholesterol (LDL-c) reduction and higher risk of SRAE (3). The importance of considering the combined effect of variants in key genes for pharmacogenetic analyses has been increasingly evident (4). In this case report, we discuss how variants in genes participating in different stages of statin pharmacokinetics pathway possibly affected the time to response to rosuvastatin and the risk of SRAE in a female FH patient. To the best of our knowledge, this is the first report of a pharmacogenetic analysis on a case of late rosuvastatin response. This case is reported in accordance with the CARE reporting checklist (available at http://dx.doi.org/10.21037/atm-20-5540).
Case presentation
A 26-year-old Caucasian female patient with definite diagnosis of FH according to Dutch Lipid Clinic Network MEDPED criteria (5) was invited to participate in an intervention study in June 2019. She was previously included in a FH sequencing study (May 2018), in which a panel of 84 genes involved in lipid homeostasis and drug metabolism was sequenced using exon-targeted gene sequencing (NGS). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committees and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for both studies.
The patient carries the variant LDLR rs28941776 (c.1646G>A, p.Gly549Asp), which has been associated with FH and is classified as pathogenic according to the American College of Medical Genetics (ACMG) guidelines (6).
Her clinical history included high levels of total cholesterol and LDL-c since childhood. In 2008, at the age of 15 years, she had an abnormal lipid profile even under a daily treatment with simvastatin 10 mg and ezetimibe 10 mg. Laboratory analyses showed a total cholesterol of 324 mg/dL, LDL-c 264 mg/dL, high-density lipoprotein cholesterol (HDL-c) 46 mg/dL, and triglycerides 71 mg/dL. In 2014, she was diagnosed with hypothyroidism and treated with levothyroxine 25 µg/day, which was gradually increased to 100 µg/day in 2019. She also had a pregnancy history in January 2017.
Her therapy history included simvastatin, which led to severe myopathy in 2008, with marked increase in serum creatine kinase (CK) to 1,080 U/L (4.7-fold the upper reference value). The cholesterol-lowering therapy was changed to pravastatin 20 mg and ezetimibe 10 mg daily until May 2011, when she reported another episode of myalgia. Pravastatin was withdrawn and atorvastatin 20 mg was introduced, also associated with ezetimibe 10 mg. Three months later, in August 2011, she reported interrupting atorvastatin treatment due to myalgia. Rosuvastatin 10 mg was then introduced, also associated with ezetimibe 10 mg, after which she showed an LDL-c level of 125 mg/dL and never reported myalgia again. However, her lipid profile worsened throughout the years even under rosuvastatin treatment, with her LDL-c reaching 194 mg/dL with rosuvastatin 20 mg.
The patient had no history of liver or kidney impartment, HIV, coronary artery disease (CAD), diabetes, obesity, cardiovascular events, and did not smoke or drink. Her mother and grandmother had a history of FH, but not CAD or cardiovascular events, while her father had hypertension and type 2 diabetes.
In the intervention study, the patient was seen four times (V1 to V4) in 5 months, and clinical history and therapy data were obtained. The protocol consisted of a 6-week rosuvastatin wash-out period, after which rosuvastatin was reintroduced for additional 6 weeks, when treatment response was evaluated. Adherence to treatment was assessed in each timepoint using the translated and validated version of the Brief Medication Questionnaire (BMQ) (7) and blood samples were taken in each visit for laboratory testing.
The lipid profile during the follow-up is shown in Figure 1. In April 2019 (V1), the patient was taking rosuvastatin 40 mg, ezetimibe 10 mg, and levothyroxine 88 µg daily. She reported experiencing muscle pain after recently increasing rosuvastatin dose from 20 to 40 mg/day. Her lipid profile was altered (total cholesterol 376 mg/dL, LDL-c 263 mg/dL, HDL-c 67 mg/dL, triglycerides 234 mg/dL) without increase in CK levels. She reported being active, running 2 km 2–3 times a week, and had a healthy diet, eating more than five portions of vegetables daily. Her TSH and T4 levels were normal. Rosuvastatin 40 mg was then discontinued for wash-out, ezetimibe was maintained, and levothyroxine dose was increased to 100 µg/day.
Figure 1 Plasma lipid profile and pharmacotherapy of the FH patient throughout the study period. EZT, ezetimibe; LVT, levothyroxine; RSV, rosuvastatin; SRAE, statin-related adverse events.
In June 2019 (V2), after undergoing a 6-week rosuvastatin wash-out period between V1 and V2, her lipid profile worsened (total cholesterol 512 mg/dL, LDL-c 405 mg/dL, HDL-c 65 mg/dL, triglycerides 213 mg/dL). Because the patient reported myalgia in V1 (rosuvastatin 40 mg), the physician prescribed rosuvastatin 20 mg/day for six weeks. Surprisingly, in August 2019 (V3), the lipid profile (total cholesterol 531 mg/dL, LDL-c 407 mg/dL, HDL-c 67 mg/dL, triglycerides 286 mg/dL) did not change compared to V2. The patient reported experiencing no myalgia to rosuvastatin 20 mg. In September 2019 (V4), her lipid profile improved (total cholesterol 299 mg/dL, LDL-c 208 mg/dL, HDL-c 59 mg/dL, triglycerides 158 mg/dL) and she continued not experiencing myalgia to rosuvastatin.
During the follow-up period, serum TSH and T4 levels remained unchanged, suggesting that her hypothyroidism was controlled and did not influence the lipid profile. Moreover, serum CK did not show any abnormality, which indicates no muscle damage due to statin treatment.
The patient also reported being adherent to treatment. In the BMQ adherence questionnaire, she reported forgetting the lipid-lowering medications 2 days in the week before V1 (71.4% adherence) and 1 day in the week before V3 (85.7% adherence).
The genetic profile of the patient is shown in Table 1. She carries five missense variants in SLCO1B1, SLCO1B3, and ABCB11. She is also homozygote for the CYP3A5*3 (rs776746) splicing variant. No other missense variants described as impacting rosuvastatin response were found in CYP3A4, CYP2C9, CYP2C19, or other drug transporters, such as ABCG2 (data not shown).
Table 1 Variants in pharmacokinetic-related genes of the FH patient with late response to rosuvastatin
Gene Variant code Variant type Nucleotide change (Amino acid change) Patient genotype Allele frequency (1,000 genomes, %) Functional impact Effects on rosuvastatin pharmacokinetics References
SLCO1B1 rs2306283 (SLCO1B1*1B) Missense c.388A>G (p.Asn130Asp) AG *1B: 54.4 Comparable to *1A No effect on plasma rosuvastatin levels Ho et al., 2006; Lee et al., 2013
SLCO1B1 rs4149056 (SLCO1B1*5) Missense c.521T>C p.(Val174Ala) TC *5: 8.8 Reduced activity Increased rosuvastatin plasma levels; Reduced hepatic uptake Kameyama et al., 2005; Lee et al., 2013
SLCO1B1 rs2306283, rs4149056 (SLCO1B1*15) Missense c.388A>G, c.521T>C (p.Asn130Asp, p.Val174Ala) AG, TC *15: 7.8 Reduced activity Increased rosuvastatin plasma levels; reduced hepatic uptake Kameyama et al., 2005; Birmingham et al., 2015
SLCO1B3 rs4149117 Missense c.334T>G (p.Ser112Ala) GG G: 70.2 Reduced activity Reduced hepatic uptake Schwarz et al. 2011
SLCO1B3 rs7311358 Missense c.699G>A (p.Met233Ile) AA A: 70.2 Reduced activity Reduced hepatic uptake Schwarz et al. 2011
ABCB11 rs2287622 Missense c.1331T>C (p.Val444Ala) TC C: 58.9 Reduced activity Increased rosuvastatin plasma levels Soko et al. 2019
CYP3A5 rs776746 (CYP3A5*3) Splicing c. 6986A>G GG *3: 62.1 No activity No rosuvastatin metabolism; Reduced LDL-c response Bailey et al. 2010
FH, familial hypercholesterolemia; LDL-c, low-density lipoprotein cholesterol.
Discussion
In heterozygous FH patients, LDL-c level reductions of 47.1% have been observed after a 6-week treatment with rosuvastatin 20 mg (8). The patient, however, did not experience any changes in LDL-c levels at week 6 (V3) of rosuvastatin 20 mg treatment, with a 48.9% LDL-c reduction only at week 12 (V4) of therapy.
The delayed rosuvastatin response could be explained by modifications in the therapy scheme during the follow-up period. However, the only change was in levothyroxine dose, that was increased from 88 to 100 µg in V1. It is unlikely that the late response is due to an adaptation to the new levothyroxine dose. The patient was already on treatment with levothyroxine 88 µg before V1; moreover, changes in cholesterol due to an adaptation period should be reflected in her lipid profile in V3, not only in V4. Another possible explanation is a lack of adherence from V2 to V3; however, the patient showed a similar treatment adherence in V3 and V1, which should lead to a similar lipid profile between visits. Furthermore, drug interactions between rosuvastatin, levothyroxine, and ezetimibe that could affect treatment response were not detected, excluding this possibility.
Pharmacokinetics-related genes may have contributed to the late response to rosuvastatin (Figure 2). The patient carries two variants in SLCO1B1, c.388A>G (SLCO1B1*1B) and c.521T>C (SLCO1B1*5), that are important determinants of rosuvastatin response. SLCO1B1*5 is a loss-of-function variant that decreases the hepatic uptake and increases blood levels of statins (9) (Table 1). SLCO1B1*1B has shown comparable activity to the functional *1A variant in in vitro functional studies (10). SLCO1B1*1B and *5 variants are in linkage disequilibrium (LD) and form the SLCO1B1*15 haplotype, that also reduced rosuvastatin uptake in functional studies with HEK293 and HeLa cells (11). The decreased liver uptake caused by these SLCO1B1 variants has been associated with increased plasma levels of rosuvastatin in pharmacokinetics studies (9) (Table 1).
Figure 2 Proposed mechanism for patient’s late rosuvastatin response and myalgia. 1. The hepatic uptake of rosuvastatin occurs through SLCO1B1 and SLCO1B3 influx transporters, while atorvastatin and simvastatin are internalized through SLCO1B1. The presence of deleterious variants in these transporters (SLCO1B1*15 and SLCO1B3 c.334T>G and c.699G>A) decreases statin uptake, therefore decreasing their concentration inside the hepatocyte and increasing statin plasma levels. 2. The lack of expression of CYP3A5 due to CYP3A5*3 also decreases atorvastatin and simvastatin metabolization, which contributes to increasing their plasma levels. This enzyme does not participate markedly in rosuvastatin metabolism. 3. The resulting higher blood statin levels increased the patient’s muscular exposure to statins, that are internalized through SLCO2B1 transporter into the skeletal muscle cell. The high concentrations in the skeletal muscle cell possibly caused patient’s myalgia. 4. Rosuvastatin’s bile excretion occurs through ABCB11 efflux protein. ABCB11 c.1331T>C variant results in a reduced activity ABCB11, which decreases rosuvastatin efflux; this increases rosuvastatin intrahepatic levels and blood levels. Although the patient had reduced function influx transporters, we suggest that the small portion of rosuvastatin absorbed in the beginning of the treatment accumulated due to the loss of function of the ABCB11 variant. This, together with rosuvastatin active metabolites generated by the normal function CYP2C9, allowed HMGR inhibition and therefore cholesterol lowering in the last visit.
SLCO1B3 is also an important gene that encodes an influx transporter for rosuvastatin. The patient was homozygous for both SLCO1B3 c.334T>G and c.699G>A, which are in strong LD (12). In an in vitro study, HeLa cells transfected with SLCO1B3 c.334G and c.699A haplotype showed a 13% decrease in rosuvastatin uptake, while for other substrates, such as cholecystokinin-8, an even more marked decrease of 57% was observed (13) (Table 1).
Although the effect of SLCO1B3 c.334G and c.699A haplotype in rosuvastatin uptake is not sufficient to explain the delayed response, it might be significant when combined with the effect of the decreased function haplotype SLCO1B1*15. While SLCO1B1*5 and SLCO1B1*15 are associated with higher plasma levels of rosuvastatin, previous studies failed to find an association between these variants and LDL-c reduction in response to short- and long-term rosuvastatin treatments (9). Therefore, the simultaneous presence of decreased function SLCO1B1 and SLCO1B3 haplotypes possibly caused a marked reduction of rosuvastatin intrahepatic concentration, resulting in the lack of response observed in V3.
ABCB11 encodes the efflux protein ABCB11, which plays an important role in rosuvastatin bile excretion. In a recent study, ABCB11 c.1331C allele has been associated to increased plasma rosuvastatin levels in healthy subjects (14) (Table 1). This variant possibly causes lower rosuvastatin excretion via bile, which in turn would increase intrahepatic rosuvastatin concentrations. Therefore, this mechanism could explain why even in the presence of low function SLC variants, the patient showed a late but evident LDL-c reduction after 12 weeks of rosuvastatin treatment.
The patient also carries the homozygous form of CYP3A5*3, an intronic variant that results in undetectable expression of CYP3A5 (15). The GEOSTAT-1 study reported that dyslipidemic patients carrying CYP3A5*3/*3 had lower LDL-c reduction after three-month rosuvastatin 10 mg treatment compared to carriers of *1/*1 or *1/*3 (Table 1). It was suggested that the metabolite produced by CYP3A5 also plays a role in HMGR inhibition, potentiating the response to rosuvastatin, which is why CYP3A5 non-expressors have reduced LDL-c response to rosuvastatin (16). CYP3A5*3 possibly impaired the patient’s response time to rosuvastatin, but in lower extent, as CYP3A5 does not participate markedly in rosuvastatin metabolism.
In addition to the delayed response to rosuvastatin, the patient experienced myalgia associated with rosuvastatin 40 mg/day and other statins, as previously commented. This SRAE may be due to SLCO1B1 variants. SLCO1B1*5 and SLCO1B1*15 have been extensively associated with myopathy to simvastatin. A systematic review and meta-analysis reported that carriers of the C allele of SLCO1B1*5 (c.521T>C) showed a higher risk of myotoxicity (17). Additionally, SLCO1B1*5 has been associated to rosuvastatin myotoxicity in previous studies (18,19). It has been suggested that it causes higher efflux of statins, increasing statin exposure and, therefore, the risk of myalgia (20). Also, a recent case report showed that variants in SLCO1B3 (c.334T>G and c.699G>A) and ABCB11 (c.1331T>C) and the interaction between rosuvastatin and ticagrelor led to rhabdomyolysis in a patient with chronic kidney disease and other chronic conditions (21), but no other reports were found.
CYP3A5*3 may also have contributed to statin myotoxicity, since it has been associated with increased risk to atorvastatin and rosuvastatin-related myalgia in South-Indian dyslipidemic patients (22). However, this variant was not associated to statin intolerance in another study (23). Most studies have evaluated the effect of individual variants in SRAE, and not the interaction between a group of variants in key genes in statin pharmacokinetics pathway. Therefore, we suggest that the combined effect of the low-activity variants in SLCO1B1 and SLCO1B3, the high-activity variant in ABCB11, and the lack of activity of CYP3A5*3 predisposed the patient to low hepatic uptake, metabolization and efflux, respectively. The resulting higher rosuvastatin plasma concentration increased its systemic exposure, which may have caused myalgia (Figure 2).
Importantly, the patient carries LDLR rs28941776 (c.1646G>A, p.Gly549Asp), a disruptive-missense variant that showed reduced LDL uptake in an in vitro study (24). LDLR variants have been associated with variability in statin response in FH patients (25), but we did not find studies that investigated the association between LDLR variants and time to statin response or myalgia. Nevertheless, this variant could have played a role in patient’s rosuvastatin time to response and it should be considered for further studies.
A limitation of this study is that plasma concentrations of rosuvastatin and its metabolites were not measured. However, the adherence of the patient to the prescribed treatment was ensured using a validated adherence questionnaire and regular follow-up calls.
In summary, the combination of four low-activity variants in SLC genes, a high-activity variant in ABCB11, and a non-functional variant in CYP3A5 may explain the observed late response to rosuvastatin and the statin-related myalgia. With this case report, we have shown the importance of considering a combination of variants in a pharmacogenetic analysis to predict individual responses to statin treatment and prevent adverse drug events. We believe this study contributes to precision medicine in future clinical settings.
Patient perspective
“I have had high cholesterol since I was a child and it has been an issue because of the delayed response to treatments and of many adverse reactions to medications, especially simvastatin. The authors have been very attentive towards me throughout the whole study and discovered possible variants that may delay my response to rosuvastatin and influence the pain that I have felt when using statins. I am very happy for knowing the cause of my problem and I would like to thank the authors for this possible diagnosis. This has improved my perspectives of cholesterol treatment.”
Supplementary
The article’s supplementary files as
10.21037/atm-20-5540 10.21037/atm-20-5540 10.21037/atm-20-5540
Acknowledgments
The authors thank Adriana Garofalo, Dr. Hui Tzu Lin Wang, colleagues from the Laboratory of Molecular Investigation in Cardiology, and the Divisions of Dyslipidemia and Pharmacy of the Institute Dante Pazzanese of Cardiology. Their immeasurable technical and logistic support in patient selection and data collection made this study possible.
Funding: This work was supported by Sao Paulo Research Foundation (FAPESP), Brazil [Research grant: #2016/12899-6 to MHH]; and National Council for Scientific and Technological Development [CNPq, grant: #447120/2014-0 to MHH], Brazil. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CDH is a recipient of a fellowship of the São Paulo Research Foundation (FAPESP), grant #2016/25637-0. RCCF, RHB, GMF and VFO are recipients of fellowships from FAPESP, Brazil. AAM is a recipient of fellowship from CAPES, Brazil. ESRM, MHH and RDCH are recipients of fellowships from CNPq, Brazil. BL was a recipient of fellowship from FAPESP, Brazil.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The intervention study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The DNA sequencing study was approved by the Ethics Committees of the Institute Dante Pazzanese of Cardiology (CAAE #4618713.0.1001.5462) and the School of Pharmaceutical Sciences of the University of Sao Paulo (CAAE #24618713.0.3001.0067), Sao Paulo, Brazil. The intervention study was approved by the Ethics Committee of the Institute Dante Pazzanese of Cardiology (CAAE #05234918.4.0000.5462). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committees. The patient signed the written informed consents before her enrollment in the studies. In the written informed consent of the DNA sequencing study, the patient was informed that clinical data and blood samples would be collected for laboratory tests and genetic analyses. As for the intervention study, the patient was informed on the intervention protocol and sample collections throughout the visits, and that this data would be used for genetic and epigenetic analyses.
Reporting Checklist: The authors have completed the CARE reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-5540
Peer Review File: Available at http://dx.doi.org/10.21037/atm-20-5540
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-5540). The authors have no conflicts of interest to declare. | ATORVASTATIN, EZETIMIBE, LEVOTHYROXINE, PRAVASTATIN SODIUM, ROSUVASTATIN, SIMVASTATIN | DrugsGivenReaction | CC BY-NC-ND | 33553369 | 18,931,409 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapeutic response delayed'. | Late response to rosuvastatin and statin-related myalgia due to SLCO1B1, SLCO1B3, ABCB11, and CYP3A5 variants in a patient with Familial Hypercholesterolemia: a case report.
Statins are the most widely used cholesterol-lowering drugs for cardiovascular diseases prevention. However, some patients are refractory to treatment, whereas others experience statin-related adverse events (SRAE). It has been increasingly important to identify pharmacogenetic biomarkers for predicting statin response and adverse events. This case report describes a female patient with familial hypercholesterolemia (FH) who showed late response to rosuvastatin and experienced myalgia on statin treatment. In the first visit (V1), the patient reported myalgia to rosuvastatin 40 mg, which was interrupted for a 6-week wash-out period. In V2, rosuvastatin 20 mg was reintroduced, but her lipid profile did not show any changes after 6 weeks (V3) (LDL-c: 402 vs. 407 mg/dL). Her lipid profile markedly improved after 12 weeks of treatment (V4) (LDL-c: 208 mg/dL), suggesting a late rosuvastatin response. Her adherence to treatment was similar in V1 and V3 and no drug interactions were detected. Pharmacogenetic analysis revealed that the patient carries low-activity variants in SLCO1B1*1B and*5, SLCO1B3 (rs4149117 and rs7311358), and ABCB11 rs2287622, and the non-functional variant in CYP3A5*3. The combined effect of variants in pharmacokinetics-related genes may have contributed to the late response to rosuvastatin and statin-related myalgia. Therefore, they should be considered when assessing a patient's response to statin treatment. To the best of our knowledge, this is the first report of a pharmacogenetic analysis on a case of late rosuvastatin response.
pmcIntroduction
Familial hypercholesterolemia (FH) is a genetic metabolic disease that leads to increased high low-density lipoprotein (LDL) cholesterol, which is a risk factor for early atherosclerosis and cardiovascular diseases (1). FH is usually treated with high-dose statins, which are inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGR), a key enzyme in cholesterol biosynthesis pathway. Rosuvastatin is one of the most effective statins, probably due its hydrophilicity, that confers selectivity to hepatic cells, higher affinity to HMGR, and lower rates of statin-related adverse events (SRAE) compared to other statins. It is poorly metabolized by CYP2C9 and CYP2C19, while 72% of the non-metabolized molecules are excreted via biliary system. Therefore, rosuvastatin blood levels rely on the activity of membrane transporters, mainly of solute carrier (SLC) and ATP-binding cassette (ABC) families, highly expressed in intestine, liver, and kidney (2).
Pharmacogenetic studies have shown that loss-of-function variants in genes encoding OATPs, such as SLCO1B1, SLCO2B1, and SLCO1B3, and ABCs have been associated with variability in low-density lipoprotein cholesterol (LDL-c) reduction and higher risk of SRAE (3). The importance of considering the combined effect of variants in key genes for pharmacogenetic analyses has been increasingly evident (4). In this case report, we discuss how variants in genes participating in different stages of statin pharmacokinetics pathway possibly affected the time to response to rosuvastatin and the risk of SRAE in a female FH patient. To the best of our knowledge, this is the first report of a pharmacogenetic analysis on a case of late rosuvastatin response. This case is reported in accordance with the CARE reporting checklist (available at http://dx.doi.org/10.21037/atm-20-5540).
Case presentation
A 26-year-old Caucasian female patient with definite diagnosis of FH according to Dutch Lipid Clinic Network MEDPED criteria (5) was invited to participate in an intervention study in June 2019. She was previously included in a FH sequencing study (May 2018), in which a panel of 84 genes involved in lipid homeostasis and drug metabolism was sequenced using exon-targeted gene sequencing (NGS). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committees and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for both studies.
The patient carries the variant LDLR rs28941776 (c.1646G>A, p.Gly549Asp), which has been associated with FH and is classified as pathogenic according to the American College of Medical Genetics (ACMG) guidelines (6).
Her clinical history included high levels of total cholesterol and LDL-c since childhood. In 2008, at the age of 15 years, she had an abnormal lipid profile even under a daily treatment with simvastatin 10 mg and ezetimibe 10 mg. Laboratory analyses showed a total cholesterol of 324 mg/dL, LDL-c 264 mg/dL, high-density lipoprotein cholesterol (HDL-c) 46 mg/dL, and triglycerides 71 mg/dL. In 2014, she was diagnosed with hypothyroidism and treated with levothyroxine 25 µg/day, which was gradually increased to 100 µg/day in 2019. She also had a pregnancy history in January 2017.
Her therapy history included simvastatin, which led to severe myopathy in 2008, with marked increase in serum creatine kinase (CK) to 1,080 U/L (4.7-fold the upper reference value). The cholesterol-lowering therapy was changed to pravastatin 20 mg and ezetimibe 10 mg daily until May 2011, when she reported another episode of myalgia. Pravastatin was withdrawn and atorvastatin 20 mg was introduced, also associated with ezetimibe 10 mg. Three months later, in August 2011, she reported interrupting atorvastatin treatment due to myalgia. Rosuvastatin 10 mg was then introduced, also associated with ezetimibe 10 mg, after which she showed an LDL-c level of 125 mg/dL and never reported myalgia again. However, her lipid profile worsened throughout the years even under rosuvastatin treatment, with her LDL-c reaching 194 mg/dL with rosuvastatin 20 mg.
The patient had no history of liver or kidney impartment, HIV, coronary artery disease (CAD), diabetes, obesity, cardiovascular events, and did not smoke or drink. Her mother and grandmother had a history of FH, but not CAD or cardiovascular events, while her father had hypertension and type 2 diabetes.
In the intervention study, the patient was seen four times (V1 to V4) in 5 months, and clinical history and therapy data were obtained. The protocol consisted of a 6-week rosuvastatin wash-out period, after which rosuvastatin was reintroduced for additional 6 weeks, when treatment response was evaluated. Adherence to treatment was assessed in each timepoint using the translated and validated version of the Brief Medication Questionnaire (BMQ) (7) and blood samples were taken in each visit for laboratory testing.
The lipid profile during the follow-up is shown in Figure 1. In April 2019 (V1), the patient was taking rosuvastatin 40 mg, ezetimibe 10 mg, and levothyroxine 88 µg daily. She reported experiencing muscle pain after recently increasing rosuvastatin dose from 20 to 40 mg/day. Her lipid profile was altered (total cholesterol 376 mg/dL, LDL-c 263 mg/dL, HDL-c 67 mg/dL, triglycerides 234 mg/dL) without increase in CK levels. She reported being active, running 2 km 2–3 times a week, and had a healthy diet, eating more than five portions of vegetables daily. Her TSH and T4 levels were normal. Rosuvastatin 40 mg was then discontinued for wash-out, ezetimibe was maintained, and levothyroxine dose was increased to 100 µg/day.
Figure 1 Plasma lipid profile and pharmacotherapy of the FH patient throughout the study period. EZT, ezetimibe; LVT, levothyroxine; RSV, rosuvastatin; SRAE, statin-related adverse events.
In June 2019 (V2), after undergoing a 6-week rosuvastatin wash-out period between V1 and V2, her lipid profile worsened (total cholesterol 512 mg/dL, LDL-c 405 mg/dL, HDL-c 65 mg/dL, triglycerides 213 mg/dL). Because the patient reported myalgia in V1 (rosuvastatin 40 mg), the physician prescribed rosuvastatin 20 mg/day for six weeks. Surprisingly, in August 2019 (V3), the lipid profile (total cholesterol 531 mg/dL, LDL-c 407 mg/dL, HDL-c 67 mg/dL, triglycerides 286 mg/dL) did not change compared to V2. The patient reported experiencing no myalgia to rosuvastatin 20 mg. In September 2019 (V4), her lipid profile improved (total cholesterol 299 mg/dL, LDL-c 208 mg/dL, HDL-c 59 mg/dL, triglycerides 158 mg/dL) and she continued not experiencing myalgia to rosuvastatin.
During the follow-up period, serum TSH and T4 levels remained unchanged, suggesting that her hypothyroidism was controlled and did not influence the lipid profile. Moreover, serum CK did not show any abnormality, which indicates no muscle damage due to statin treatment.
The patient also reported being adherent to treatment. In the BMQ adherence questionnaire, she reported forgetting the lipid-lowering medications 2 days in the week before V1 (71.4% adherence) and 1 day in the week before V3 (85.7% adherence).
The genetic profile of the patient is shown in Table 1. She carries five missense variants in SLCO1B1, SLCO1B3, and ABCB11. She is also homozygote for the CYP3A5*3 (rs776746) splicing variant. No other missense variants described as impacting rosuvastatin response were found in CYP3A4, CYP2C9, CYP2C19, or other drug transporters, such as ABCG2 (data not shown).
Table 1 Variants in pharmacokinetic-related genes of the FH patient with late response to rosuvastatin
Gene Variant code Variant type Nucleotide change (Amino acid change) Patient genotype Allele frequency (1,000 genomes, %) Functional impact Effects on rosuvastatin pharmacokinetics References
SLCO1B1 rs2306283 (SLCO1B1*1B) Missense c.388A>G (p.Asn130Asp) AG *1B: 54.4 Comparable to *1A No effect on plasma rosuvastatin levels Ho et al., 2006; Lee et al., 2013
SLCO1B1 rs4149056 (SLCO1B1*5) Missense c.521T>C p.(Val174Ala) TC *5: 8.8 Reduced activity Increased rosuvastatin plasma levels; Reduced hepatic uptake Kameyama et al., 2005; Lee et al., 2013
SLCO1B1 rs2306283, rs4149056 (SLCO1B1*15) Missense c.388A>G, c.521T>C (p.Asn130Asp, p.Val174Ala) AG, TC *15: 7.8 Reduced activity Increased rosuvastatin plasma levels; reduced hepatic uptake Kameyama et al., 2005; Birmingham et al., 2015
SLCO1B3 rs4149117 Missense c.334T>G (p.Ser112Ala) GG G: 70.2 Reduced activity Reduced hepatic uptake Schwarz et al. 2011
SLCO1B3 rs7311358 Missense c.699G>A (p.Met233Ile) AA A: 70.2 Reduced activity Reduced hepatic uptake Schwarz et al. 2011
ABCB11 rs2287622 Missense c.1331T>C (p.Val444Ala) TC C: 58.9 Reduced activity Increased rosuvastatin plasma levels Soko et al. 2019
CYP3A5 rs776746 (CYP3A5*3) Splicing c. 6986A>G GG *3: 62.1 No activity No rosuvastatin metabolism; Reduced LDL-c response Bailey et al. 2010
FH, familial hypercholesterolemia; LDL-c, low-density lipoprotein cholesterol.
Discussion
In heterozygous FH patients, LDL-c level reductions of 47.1% have been observed after a 6-week treatment with rosuvastatin 20 mg (8). The patient, however, did not experience any changes in LDL-c levels at week 6 (V3) of rosuvastatin 20 mg treatment, with a 48.9% LDL-c reduction only at week 12 (V4) of therapy.
The delayed rosuvastatin response could be explained by modifications in the therapy scheme during the follow-up period. However, the only change was in levothyroxine dose, that was increased from 88 to 100 µg in V1. It is unlikely that the late response is due to an adaptation to the new levothyroxine dose. The patient was already on treatment with levothyroxine 88 µg before V1; moreover, changes in cholesterol due to an adaptation period should be reflected in her lipid profile in V3, not only in V4. Another possible explanation is a lack of adherence from V2 to V3; however, the patient showed a similar treatment adherence in V3 and V1, which should lead to a similar lipid profile between visits. Furthermore, drug interactions between rosuvastatin, levothyroxine, and ezetimibe that could affect treatment response were not detected, excluding this possibility.
Pharmacokinetics-related genes may have contributed to the late response to rosuvastatin (Figure 2). The patient carries two variants in SLCO1B1, c.388A>G (SLCO1B1*1B) and c.521T>C (SLCO1B1*5), that are important determinants of rosuvastatin response. SLCO1B1*5 is a loss-of-function variant that decreases the hepatic uptake and increases blood levels of statins (9) (Table 1). SLCO1B1*1B has shown comparable activity to the functional *1A variant in in vitro functional studies (10). SLCO1B1*1B and *5 variants are in linkage disequilibrium (LD) and form the SLCO1B1*15 haplotype, that also reduced rosuvastatin uptake in functional studies with HEK293 and HeLa cells (11). The decreased liver uptake caused by these SLCO1B1 variants has been associated with increased plasma levels of rosuvastatin in pharmacokinetics studies (9) (Table 1).
Figure 2 Proposed mechanism for patient’s late rosuvastatin response and myalgia. 1. The hepatic uptake of rosuvastatin occurs through SLCO1B1 and SLCO1B3 influx transporters, while atorvastatin and simvastatin are internalized through SLCO1B1. The presence of deleterious variants in these transporters (SLCO1B1*15 and SLCO1B3 c.334T>G and c.699G>A) decreases statin uptake, therefore decreasing their concentration inside the hepatocyte and increasing statin plasma levels. 2. The lack of expression of CYP3A5 due to CYP3A5*3 also decreases atorvastatin and simvastatin metabolization, which contributes to increasing their plasma levels. This enzyme does not participate markedly in rosuvastatin metabolism. 3. The resulting higher blood statin levels increased the patient’s muscular exposure to statins, that are internalized through SLCO2B1 transporter into the skeletal muscle cell. The high concentrations in the skeletal muscle cell possibly caused patient’s myalgia. 4. Rosuvastatin’s bile excretion occurs through ABCB11 efflux protein. ABCB11 c.1331T>C variant results in a reduced activity ABCB11, which decreases rosuvastatin efflux; this increases rosuvastatin intrahepatic levels and blood levels. Although the patient had reduced function influx transporters, we suggest that the small portion of rosuvastatin absorbed in the beginning of the treatment accumulated due to the loss of function of the ABCB11 variant. This, together with rosuvastatin active metabolites generated by the normal function CYP2C9, allowed HMGR inhibition and therefore cholesterol lowering in the last visit.
SLCO1B3 is also an important gene that encodes an influx transporter for rosuvastatin. The patient was homozygous for both SLCO1B3 c.334T>G and c.699G>A, which are in strong LD (12). In an in vitro study, HeLa cells transfected with SLCO1B3 c.334G and c.699A haplotype showed a 13% decrease in rosuvastatin uptake, while for other substrates, such as cholecystokinin-8, an even more marked decrease of 57% was observed (13) (Table 1).
Although the effect of SLCO1B3 c.334G and c.699A haplotype in rosuvastatin uptake is not sufficient to explain the delayed response, it might be significant when combined with the effect of the decreased function haplotype SLCO1B1*15. While SLCO1B1*5 and SLCO1B1*15 are associated with higher plasma levels of rosuvastatin, previous studies failed to find an association between these variants and LDL-c reduction in response to short- and long-term rosuvastatin treatments (9). Therefore, the simultaneous presence of decreased function SLCO1B1 and SLCO1B3 haplotypes possibly caused a marked reduction of rosuvastatin intrahepatic concentration, resulting in the lack of response observed in V3.
ABCB11 encodes the efflux protein ABCB11, which plays an important role in rosuvastatin bile excretion. In a recent study, ABCB11 c.1331C allele has been associated to increased plasma rosuvastatin levels in healthy subjects (14) (Table 1). This variant possibly causes lower rosuvastatin excretion via bile, which in turn would increase intrahepatic rosuvastatin concentrations. Therefore, this mechanism could explain why even in the presence of low function SLC variants, the patient showed a late but evident LDL-c reduction after 12 weeks of rosuvastatin treatment.
The patient also carries the homozygous form of CYP3A5*3, an intronic variant that results in undetectable expression of CYP3A5 (15). The GEOSTAT-1 study reported that dyslipidemic patients carrying CYP3A5*3/*3 had lower LDL-c reduction after three-month rosuvastatin 10 mg treatment compared to carriers of *1/*1 or *1/*3 (Table 1). It was suggested that the metabolite produced by CYP3A5 also plays a role in HMGR inhibition, potentiating the response to rosuvastatin, which is why CYP3A5 non-expressors have reduced LDL-c response to rosuvastatin (16). CYP3A5*3 possibly impaired the patient’s response time to rosuvastatin, but in lower extent, as CYP3A5 does not participate markedly in rosuvastatin metabolism.
In addition to the delayed response to rosuvastatin, the patient experienced myalgia associated with rosuvastatin 40 mg/day and other statins, as previously commented. This SRAE may be due to SLCO1B1 variants. SLCO1B1*5 and SLCO1B1*15 have been extensively associated with myopathy to simvastatin. A systematic review and meta-analysis reported that carriers of the C allele of SLCO1B1*5 (c.521T>C) showed a higher risk of myotoxicity (17). Additionally, SLCO1B1*5 has been associated to rosuvastatin myotoxicity in previous studies (18,19). It has been suggested that it causes higher efflux of statins, increasing statin exposure and, therefore, the risk of myalgia (20). Also, a recent case report showed that variants in SLCO1B3 (c.334T>G and c.699G>A) and ABCB11 (c.1331T>C) and the interaction between rosuvastatin and ticagrelor led to rhabdomyolysis in a patient with chronic kidney disease and other chronic conditions (21), but no other reports were found.
CYP3A5*3 may also have contributed to statin myotoxicity, since it has been associated with increased risk to atorvastatin and rosuvastatin-related myalgia in South-Indian dyslipidemic patients (22). However, this variant was not associated to statin intolerance in another study (23). Most studies have evaluated the effect of individual variants in SRAE, and not the interaction between a group of variants in key genes in statin pharmacokinetics pathway. Therefore, we suggest that the combined effect of the low-activity variants in SLCO1B1 and SLCO1B3, the high-activity variant in ABCB11, and the lack of activity of CYP3A5*3 predisposed the patient to low hepatic uptake, metabolization and efflux, respectively. The resulting higher rosuvastatin plasma concentration increased its systemic exposure, which may have caused myalgia (Figure 2).
Importantly, the patient carries LDLR rs28941776 (c.1646G>A, p.Gly549Asp), a disruptive-missense variant that showed reduced LDL uptake in an in vitro study (24). LDLR variants have been associated with variability in statin response in FH patients (25), but we did not find studies that investigated the association between LDLR variants and time to statin response or myalgia. Nevertheless, this variant could have played a role in patient’s rosuvastatin time to response and it should be considered for further studies.
A limitation of this study is that plasma concentrations of rosuvastatin and its metabolites were not measured. However, the adherence of the patient to the prescribed treatment was ensured using a validated adherence questionnaire and regular follow-up calls.
In summary, the combination of four low-activity variants in SLC genes, a high-activity variant in ABCB11, and a non-functional variant in CYP3A5 may explain the observed late response to rosuvastatin and the statin-related myalgia. With this case report, we have shown the importance of considering a combination of variants in a pharmacogenetic analysis to predict individual responses to statin treatment and prevent adverse drug events. We believe this study contributes to precision medicine in future clinical settings.
Patient perspective
“I have had high cholesterol since I was a child and it has been an issue because of the delayed response to treatments and of many adverse reactions to medications, especially simvastatin. The authors have been very attentive towards me throughout the whole study and discovered possible variants that may delay my response to rosuvastatin and influence the pain that I have felt when using statins. I am very happy for knowing the cause of my problem and I would like to thank the authors for this possible diagnosis. This has improved my perspectives of cholesterol treatment.”
Supplementary
The article’s supplementary files as
10.21037/atm-20-5540 10.21037/atm-20-5540 10.21037/atm-20-5540
Acknowledgments
The authors thank Adriana Garofalo, Dr. Hui Tzu Lin Wang, colleagues from the Laboratory of Molecular Investigation in Cardiology, and the Divisions of Dyslipidemia and Pharmacy of the Institute Dante Pazzanese of Cardiology. Their immeasurable technical and logistic support in patient selection and data collection made this study possible.
Funding: This work was supported by Sao Paulo Research Foundation (FAPESP), Brazil [Research grant: #2016/12899-6 to MHH]; and National Council for Scientific and Technological Development [CNPq, grant: #447120/2014-0 to MHH], Brazil. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CDH is a recipient of a fellowship of the São Paulo Research Foundation (FAPESP), grant #2016/25637-0. RCCF, RHB, GMF and VFO are recipients of fellowships from FAPESP, Brazil. AAM is a recipient of fellowship from CAPES, Brazil. ESRM, MHH and RDCH are recipients of fellowships from CNPq, Brazil. BL was a recipient of fellowship from FAPESP, Brazil.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The intervention study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The DNA sequencing study was approved by the Ethics Committees of the Institute Dante Pazzanese of Cardiology (CAAE #4618713.0.1001.5462) and the School of Pharmaceutical Sciences of the University of Sao Paulo (CAAE #24618713.0.3001.0067), Sao Paulo, Brazil. The intervention study was approved by the Ethics Committee of the Institute Dante Pazzanese of Cardiology (CAAE #05234918.4.0000.5462). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committees. The patient signed the written informed consents before her enrollment in the studies. In the written informed consent of the DNA sequencing study, the patient was informed that clinical data and blood samples would be collected for laboratory tests and genetic analyses. As for the intervention study, the patient was informed on the intervention protocol and sample collections throughout the visits, and that this data would be used for genetic and epigenetic analyses.
Reporting Checklist: The authors have completed the CARE reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-5540
Peer Review File: Available at http://dx.doi.org/10.21037/atm-20-5540
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-5540). The authors have no conflicts of interest to declare. | ATORVASTATIN, EZETIMIBE, LEVOTHYROXINE, PRAVASTATIN SODIUM, ROSUVASTATIN, SIMVASTATIN | DrugsGivenReaction | CC BY-NC-ND | 33553369 | 18,931,409 | 2021-01 |
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