Case Reports

Prostate cancer is the most common noncutaneous cancer in men, accounting for 29% of all incident cancer cases.¹ Typically, prostate cancer metastasizes to bone and regional lymph nodes.² However, intrathoracic manifestation may occur. This report presents 3 cases of rare intrathoracic manifestations of metastatic prostate cancer with a review of the current literature.

CASE PRESENTATIONS

Case 1

A 71-year-old male who was an active smoker and a long-standing employment as a plumber was diagnosed with rectal cancer in 2022. He completed neoadjuvant capecitabine and radiation therapy followed by a rectosigmoidectomy. Several weeks after surgery, the patient presented to the emergency department (ED) with a dry cough and worsening shortness of breath. Point-of-care ultrasound of the lungs revealed a moderate right pleural effusion with several nodular pleural masses. A chest computed tomography (CT) confirmed these findings (Figure 1). A CT of the abdomen and pelvis revealed prostatomegaly with the medial lobe of the prostate protruding into the bladder; however, no enlarged retroperitoneal, mesenteric or pelvic lymph nodes were noted. The patient underwent a right pleural fluid drainage and pleural mass biopsy. Pleural mass histomorphology as well as immunohistochemical (IHC) stains were consistent with metastatic prostate adenocarcinoma. The pleural fluid cytology also was consistent with metastatic prostate adenocarcinoma.

Immunohistochemistry showed weak positive staining for prostate-specific NK3 homeobox 1 gene (NKX3.1), alpha-methylacyl-CoA racemase gene (AMACR), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), keratin-20, and caudal type homeobox 2 gene (CDX2) (Figure 2) 2). The patient's prostate-specific antigen (PSA) was found to be elevated at 33.9 ng/mL (reference range, < 4 ng/mL).

Case 2

A 71-year-old male with a history of alcohol use disorder and a 30-year smoking history presented to the ED with worsening dyspnea on exertion. The patient’s baseline exercise tolerance decreased to walking for only 1 block. He reported unintentional weight loss of about 30 pounds over the prior year, no recent respiratory infections, no prior breathing problems, and no personal or family history of cancer. Chest CT revealed findings of bilateral peribronchial opacities as well as mediastinal and hilar lymphadenopathy (Figure 3). The patient developed hypoxic respiratory failure necessitating intubation, mechanical ventilation, and management in the medical intensive care unit, where he was treated for postobstructive pneumonia. Fiberoptic bronchoscopy revealed endobronchial lesions in the right and left upper lobe that were partially obstructing the airway (Figure 4).

The endobronchial masses were debulked using forceps, and samples were sent for surgical pathology evaluation. Staging was completed using linear endobronchial ultrasound, which revealed an enlarged subcarinal lymph node (S7). The surgical pathology of the endobronchial mass and the subcarinal lymph node cytology were consistent with metastatic adenocarcinoma of the prostate. The tumor cells were positive for AE1/AE3, PSA, and NKX3.1, but were negative for CK7 and TTF-1 (Figure 5). Further imaging revealed an enlarged heterogeneous prostate gland, prominent pelvic nodes, and left retroperitoneal lymphadenopathy, as well as sclerotic foci within the T10 vertebral body and right inferior pubic ramus. PSA was also found to be significantly elevated at 700 ng/mL.

Case 3

An 80-year-old male veteran with a history of prostate cancer and recently diagnosed T2N1M0 head and neck squamous cell carcinoma was referred to the Pulmonary service for evaluation of a pulmonary nodule. His medical history was notable for prostate cancer diagnosed 12 years earlier, with an unknown Gleason score. Initial treatment included prostatectomy followed by whole pelvic radiation therapy a year after, due to elevated PSA in surveillance monitoring. This treatment led to remission. After establishing remission for > 10 years, the patient was started on low-dose testosterone replacement therapy to address complications of radiation therapy, namely hypogonadism.

On evaluation, a chest CT was significant for a large 2-cm right middle lobe nodule (Figure 6). At that time, PSA was noted to be borderline elevated at 4.2 ng/mL, and whole-body imaging did not reveal any lesions elsewhere, specifically no bone metastasis. Biopsies of the right middle lobe lung nodule revealed adenocarcinoma consistent with metastatic prostate cancer. Testosterone therapy was promptly discontinued.

The patient initially refused androgen deprivation therapy owing to the antiandrogenic adverse effects. However, subsequent chest CTs revealed growing lung nodules, which convinced him to proceed with androgen deprivation therapy followed by palliative radiation, and chemotherapy and management of malignant pleural effusion with indwelling small bore pleural catheter for about 10 years. He died from COVID-19 during the pandemic.

DISCUSSION

These cases highlight the importance of including prostate cancer in the differential diagnoses of male patients with intrathoracic abnormalities, even in the absence of metastasis to the more common sites. In a large cohort study of 74,826 patients with metastatic prostate cancer, Gandaglia et al found that the most frequent sites of metastasis were bone (84.0%) and distant lymph nodes (10.6%).2 However, thoracic involvement was observed in 9.1% of cases, with isolated thoracic metastasis being rare. The cases described in this report exemplify exceptionally uncommon occurrences within that 9.1%.

Pleural metastases, as observed in Case 1, are a particularly rare manifestation. In a 10-year retrospective assessment, Vinjamoori et al discovered pleural nodules or masses in only 6 of 82 patients (7.3%) with atypical metastases.³ Adrenal and liver metastases accounted for 15% and 37% of cases with atypical distribution. As such, isolated pleural disease is rare even in atypical presentations.³

As seen in Case 2, endobronchial metastases producing airway obstruction are also rare, with the most common primary cancers associated with endobronchial metastasis being breast, colon, and renal cancer.⁴ The available literature on this presentation is confined to case reports. Hameed et al reported a case of synchronous biopsy-proven endobronchial metastasis from prostate cancer.⁵ These cases highlight the importance of maintaining a high level of clinical awareness when encountering endobronchial lesions in patients with prostate cancer.

Case 3 presents a unique situation of lung metastases without any involvement of the bones. It is well known—and was confirmed by Heidenreich et al—that lung metastases in prostate adenocarcinoma usually coincide with extensive osseous disease.⁶ This instance highlights the importance of watchful monitoring for unusual patterns of cancer recurrence.

Immunohistochemistry stains that are specific to prostate cancer include antibodies against PSA. Prostate-specific membrane antigen is another marker that is far more present in malignant than in benign prostate tissue.

The NKX3.1 gene encodes a homeobox protein, which is a transcription factor and tumor suppressor. In prostate cancer, there is loss of heterozygosity of the gene and stains for the IHC antibody to NKX3.1.⁷

On the other hand, lung cells stain positive for TTF-1, which is produced by surfactant-producing type 2 pneumocytes and club cells in the lung. Antibodies to TTF-1, a common IHC stain, are used to identify adenocarcinoma of lung origin and may carry a prognostic value.⁷

The immunohistochemistry profiles, specifically the presence of prostate-specific markers such as PSA and NKX3.1, played a vital role in making the diagnosis.

In Case 1, weak TTF-1 positivity was noted, an unusual finding in metastatic prostate adenocarcinoma. Marak et al documented a rare case of TTF-1–positive metastatic prostate cancer, illustrating the potential for diagnostic confusion with primary lung malignancies.⁸

The 3 cases described in this report demonstrate the importance of clinical consideration, serial follow-up of PSA levels, using more prostate-specific positron emission tomography tracers (eg, Pylarify) alongside traditional imaging, and tissue biopsy to detect unusual metastases.

CONCLUSIONS

Although thoracic metastases from prostate cancer are rare, these presentations highlight the importance of clinical awareness regarding atypical cases. Pleural disease, endobronchial lesions, and isolated pulmonary nodules might be the first clinical manifestation of metastatic prostate cancer. A high index of suspicion, appropriate imaging, and judicious use of immunohistochemistry are important to ensure accurate diagnosis and optimal patient management.

Prostate cancer is the most common noncutaneous cancer in men, accounting for 29% of all incident cancer cases.¹ Typically, prostate cancer metastasizes to bone and regional lymph nodes.² However, intrathoracic manifestation may occur. This report presents 3 cases of rare intrathoracic manifestations of metastatic prostate cancer with a review of the current literature.

CASE PRESENTATIONS

Case 1

A 71-year-old male who was an active smoker and a long-standing employment as a plumber was diagnosed with rectal cancer in 2022. He completed neoadjuvant capecitabine and radiation therapy followed by a rectosigmoidectomy. Several weeks after surgery, the patient presented to the emergency department (ED) with a dry cough and worsening shortness of breath. Point-of-care ultrasound of the lungs revealed a moderate right pleural effusion with several nodular pleural masses. A chest computed tomography (CT) confirmed these findings (Figure 1). A CT of the abdomen and pelvis revealed prostatomegaly with the medial lobe of the prostate protruding into the bladder; however, no enlarged retroperitoneal, mesenteric or pelvic lymph nodes were noted. The patient underwent a right pleural fluid drainage and pleural mass biopsy. Pleural mass histomorphology as well as immunohistochemical (IHC) stains were consistent with metastatic prostate adenocarcinoma. The pleural fluid cytology also was consistent with metastatic prostate adenocarcinoma.

Immunohistochemistry showed weak positive staining for prostate-specific NK3 homeobox 1 gene (NKX3.1), alpha-methylacyl-CoA racemase gene (AMACR), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), keratin-20, and caudal type homeobox 2 gene (CDX2) (Figure 2) 2). The patient's prostate-specific antigen (PSA) was found to be elevated at 33.9 ng/mL (reference range, < 4 ng/mL).

Case 2

A 71-year-old male with a history of alcohol use disorder and a 30-year smoking history presented to the ED with worsening dyspnea on exertion. The patient’s baseline exercise tolerance decreased to walking for only 1 block. He reported unintentional weight loss of about 30 pounds over the prior year, no recent respiratory infections, no prior breathing problems, and no personal or family history of cancer. Chest CT revealed findings of bilateral peribronchial opacities as well as mediastinal and hilar lymphadenopathy (Figure 3). The patient developed hypoxic respiratory failure necessitating intubation, mechanical ventilation, and management in the medical intensive care unit, where he was treated for postobstructive pneumonia. Fiberoptic bronchoscopy revealed endobronchial lesions in the right and left upper lobe that were partially obstructing the airway (Figure 4).

The endobronchial masses were debulked using forceps, and samples were sent for surgical pathology evaluation. Staging was completed using linear endobronchial ultrasound, which revealed an enlarged subcarinal lymph node (S7). The surgical pathology of the endobronchial mass and the subcarinal lymph node cytology were consistent with metastatic adenocarcinoma of the prostate. The tumor cells were positive for AE1/AE3, PSA, and NKX3.1, but were negative for CK7 and TTF-1 (Figure 5). Further imaging revealed an enlarged heterogeneous prostate gland, prominent pelvic nodes, and left retroperitoneal lymphadenopathy, as well as sclerotic foci within the T10 vertebral body and right inferior pubic ramus. PSA was also found to be significantly elevated at 700 ng/mL.

Case 3

An 80-year-old male veteran with a history of prostate cancer and recently diagnosed T2N1M0 head and neck squamous cell carcinoma was referred to the Pulmonary service for evaluation of a pulmonary nodule. His medical history was notable for prostate cancer diagnosed 12 years earlier, with an unknown Gleason score. Initial treatment included prostatectomy followed by whole pelvic radiation therapy a year after, due to elevated PSA in surveillance monitoring. This treatment led to remission. After establishing remission for > 10 years, the patient was started on low-dose testosterone replacement therapy to address complications of radiation therapy, namely hypogonadism.

On evaluation, a chest CT was significant for a large 2-cm right middle lobe nodule (Figure 6). At that time, PSA was noted to be borderline elevated at 4.2 ng/mL, and whole-body imaging did not reveal any lesions elsewhere, specifically no bone metastasis. Biopsies of the right middle lobe lung nodule revealed adenocarcinoma consistent with metastatic prostate cancer. Testosterone therapy was promptly discontinued.

The patient initially refused androgen deprivation therapy owing to the antiandrogenic adverse effects. However, subsequent chest CTs revealed growing lung nodules, which convinced him to proceed with androgen deprivation therapy followed by palliative radiation, and chemotherapy and management of malignant pleural effusion with indwelling small bore pleural catheter for about 10 years. He died from COVID-19 during the pandemic.

DISCUSSION

These cases highlight the importance of including prostate cancer in the differential diagnoses of male patients with intrathoracic abnormalities, even in the absence of metastasis to the more common sites. In a large cohort study of 74,826 patients with metastatic prostate cancer, Gandaglia et al found that the most frequent sites of metastasis were bone (84.0%) and distant lymph nodes (10.6%).2 However, thoracic involvement was observed in 9.1% of cases, with isolated thoracic metastasis being rare. The cases described in this report exemplify exceptionally uncommon occurrences within that 9.1%.

Pleural metastases, as observed in Case 1, are a particularly rare manifestation. In a 10-year retrospective assessment, Vinjamoori et al discovered pleural nodules or masses in only 6 of 82 patients (7.3%) with atypical metastases.³ Adrenal and liver metastases accounted for 15% and 37% of cases with atypical distribution. As such, isolated pleural disease is rare even in atypical presentations.³

As seen in Case 2, endobronchial metastases producing airway obstruction are also rare, with the most common primary cancers associated with endobronchial metastasis being breast, colon, and renal cancer.⁴ The available literature on this presentation is confined to case reports. Hameed et al reported a case of synchronous biopsy-proven endobronchial metastasis from prostate cancer.⁵ These cases highlight the importance of maintaining a high level of clinical awareness when encountering endobronchial lesions in patients with prostate cancer.

Case 3 presents a unique situation of lung metastases without any involvement of the bones. It is well known—and was confirmed by Heidenreich et al—that lung metastases in prostate adenocarcinoma usually coincide with extensive osseous disease.⁶ This instance highlights the importance of watchful monitoring for unusual patterns of cancer recurrence.

Immunohistochemistry stains that are specific to prostate cancer include antibodies against PSA. Prostate-specific membrane antigen is another marker that is far more present in malignant than in benign prostate tissue.

The NKX3.1 gene encodes a homeobox protein, which is a transcription factor and tumor suppressor. In prostate cancer, there is loss of heterozygosity of the gene and stains for the IHC antibody to NKX3.1.⁷

On the other hand, lung cells stain positive for TTF-1, which is produced by surfactant-producing type 2 pneumocytes and club cells in the lung. Antibodies to TTF-1, a common IHC stain, are used to identify adenocarcinoma of lung origin and may carry a prognostic value.⁷

The immunohistochemistry profiles, specifically the presence of prostate-specific markers such as PSA and NKX3.1, played a vital role in making the diagnosis.

In Case 1, weak TTF-1 positivity was noted, an unusual finding in metastatic prostate adenocarcinoma. Marak et al documented a rare case of TTF-1–positive metastatic prostate cancer, illustrating the potential for diagnostic confusion with primary lung malignancies.⁸

The 3 cases described in this report demonstrate the importance of clinical consideration, serial follow-up of PSA levels, using more prostate-specific positron emission tomography tracers (eg, Pylarify) alongside traditional imaging, and tissue biopsy to detect unusual metastases.

CONCLUSIONS

Although thoracic metastases from prostate cancer are rare, these presentations highlight the importance of clinical awareness regarding atypical cases. Pleural disease, endobronchial lesions, and isolated pulmonary nodules might be the first clinical manifestation of metastatic prostate cancer. A high index of suspicion, appropriate imaging, and judicious use of immunohistochemistry are important to ensure accurate diagnosis and optimal patient management.

Prostate cancer is the most common noncutaneous cancer in men, accounting for 29% of all incident cancer cases.¹ Typically, prostate cancer metastasizes to bone and regional lymph nodes.² However, intrathoracic manifestation may occur. This report presents 3 cases of rare intrathoracic manifestations of metastatic prostate cancer with a review of the current literature.

CASE PRESENTATIONS

Case 1

A 71-year-old male who was an active smoker and a long-standing employment as a plumber was diagnosed with rectal cancer in 2022. He completed neoadjuvant capecitabine and radiation therapy followed by a rectosigmoidectomy. Several weeks after surgery, the patient presented to the emergency department (ED) with a dry cough and worsening shortness of breath. Point-of-care ultrasound of the lungs revealed a moderate right pleural effusion with several nodular pleural masses. A chest computed tomography (CT) confirmed these findings (Figure 1). A CT of the abdomen and pelvis revealed prostatomegaly with the medial lobe of the prostate protruding into the bladder; however, no enlarged retroperitoneal, mesenteric or pelvic lymph nodes were noted. The patient underwent a right pleural fluid drainage and pleural mass biopsy. Pleural mass histomorphology as well as immunohistochemical (IHC) stains were consistent with metastatic prostate adenocarcinoma. The pleural fluid cytology also was consistent with metastatic prostate adenocarcinoma.

Immunohistochemistry showed weak positive staining for prostate-specific NK3 homeobox 1 gene (NKX3.1), alpha-methylacyl-CoA racemase gene (AMACR), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), keratin-20, and caudal type homeobox 2 gene (CDX2) (Figure 2) 2). The patient's prostate-specific antigen (PSA) was found to be elevated at 33.9 ng/mL (reference range, < 4 ng/mL).

Case 2

A 71-year-old male with a history of alcohol use disorder and a 30-year smoking history presented to the ED with worsening dyspnea on exertion. The patient’s baseline exercise tolerance decreased to walking for only 1 block. He reported unintentional weight loss of about 30 pounds over the prior year, no recent respiratory infections, no prior breathing problems, and no personal or family history of cancer. Chest CT revealed findings of bilateral peribronchial opacities as well as mediastinal and hilar lymphadenopathy (Figure 3). The patient developed hypoxic respiratory failure necessitating intubation, mechanical ventilation, and management in the medical intensive care unit, where he was treated for postobstructive pneumonia. Fiberoptic bronchoscopy revealed endobronchial lesions in the right and left upper lobe that were partially obstructing the airway (Figure 4).

The endobronchial masses were debulked using forceps, and samples were sent for surgical pathology evaluation. Staging was completed using linear endobronchial ultrasound, which revealed an enlarged subcarinal lymph node (S7). The surgical pathology of the endobronchial mass and the subcarinal lymph node cytology were consistent with metastatic adenocarcinoma of the prostate. The tumor cells were positive for AE1/AE3, PSA, and NKX3.1, but were negative for CK7 and TTF-1 (Figure 5). Further imaging revealed an enlarged heterogeneous prostate gland, prominent pelvic nodes, and left retroperitoneal lymphadenopathy, as well as sclerotic foci within the T10 vertebral body and right inferior pubic ramus. PSA was also found to be significantly elevated at 700 ng/mL.

Case 3

An 80-year-old male veteran with a history of prostate cancer and recently diagnosed T2N1M0 head and neck squamous cell carcinoma was referred to the Pulmonary service for evaluation of a pulmonary nodule. His medical history was notable for prostate cancer diagnosed 12 years earlier, with an unknown Gleason score. Initial treatment included prostatectomy followed by whole pelvic radiation therapy a year after, due to elevated PSA in surveillance monitoring. This treatment led to remission. After establishing remission for > 10 years, the patient was started on low-dose testosterone replacement therapy to address complications of radiation therapy, namely hypogonadism.

On evaluation, a chest CT was significant for a large 2-cm right middle lobe nodule (Figure 6). At that time, PSA was noted to be borderline elevated at 4.2 ng/mL, and whole-body imaging did not reveal any lesions elsewhere, specifically no bone metastasis. Biopsies of the right middle lobe lung nodule revealed adenocarcinoma consistent with metastatic prostate cancer. Testosterone therapy was promptly discontinued.

The patient initially refused androgen deprivation therapy owing to the antiandrogenic adverse effects. However, subsequent chest CTs revealed growing lung nodules, which convinced him to proceed with androgen deprivation therapy followed by palliative radiation, and chemotherapy and management of malignant pleural effusion with indwelling small bore pleural catheter for about 10 years. He died from COVID-19 during the pandemic.

DISCUSSION

These cases highlight the importance of including prostate cancer in the differential diagnoses of male patients with intrathoracic abnormalities, even in the absence of metastasis to the more common sites. In a large cohort study of 74,826 patients with metastatic prostate cancer, Gandaglia et al found that the most frequent sites of metastasis were bone (84.0%) and distant lymph nodes (10.6%).2 However, thoracic involvement was observed in 9.1% of cases, with isolated thoracic metastasis being rare. The cases described in this report exemplify exceptionally uncommon occurrences within that 9.1%.

Pleural metastases, as observed in Case 1, are a particularly rare manifestation. In a 10-year retrospective assessment, Vinjamoori et al discovered pleural nodules or masses in only 6 of 82 patients (7.3%) with atypical metastases.³ Adrenal and liver metastases accounted for 15% and 37% of cases with atypical distribution. As such, isolated pleural disease is rare even in atypical presentations.³

As seen in Case 2, endobronchial metastases producing airway obstruction are also rare, with the most common primary cancers associated with endobronchial metastasis being breast, colon, and renal cancer.⁴ The available literature on this presentation is confined to case reports. Hameed et al reported a case of synchronous biopsy-proven endobronchial metastasis from prostate cancer.⁵ These cases highlight the importance of maintaining a high level of clinical awareness when encountering endobronchial lesions in patients with prostate cancer.

Case 3 presents a unique situation of lung metastases without any involvement of the bones. It is well known—and was confirmed by Heidenreich et al—that lung metastases in prostate adenocarcinoma usually coincide with extensive osseous disease.⁶ This instance highlights the importance of watchful monitoring for unusual patterns of cancer recurrence.

Immunohistochemistry stains that are specific to prostate cancer include antibodies against PSA. Prostate-specific membrane antigen is another marker that is far more present in malignant than in benign prostate tissue.

The NKX3.1 gene encodes a homeobox protein, which is a transcription factor and tumor suppressor. In prostate cancer, there is loss of heterozygosity of the gene and stains for the IHC antibody to NKX3.1.⁷

On the other hand, lung cells stain positive for TTF-1, which is produced by surfactant-producing type 2 pneumocytes and club cells in the lung. Antibodies to TTF-1, a common IHC stain, are used to identify adenocarcinoma of lung origin and may carry a prognostic value.⁷

The immunohistochemistry profiles, specifically the presence of prostate-specific markers such as PSA and NKX3.1, played a vital role in making the diagnosis.

In Case 1, weak TTF-1 positivity was noted, an unusual finding in metastatic prostate adenocarcinoma. Marak et al documented a rare case of TTF-1–positive metastatic prostate cancer, illustrating the potential for diagnostic confusion with primary lung malignancies.⁸

The 3 cases described in this report demonstrate the importance of clinical consideration, serial follow-up of PSA levels, using more prostate-specific positron emission tomography tracers (eg, Pylarify) alongside traditional imaging, and tissue biopsy to detect unusual metastases.

CONCLUSIONS

Although thoracic metastases from prostate cancer are rare, these presentations highlight the importance of clinical awareness regarding atypical cases. Pleural disease, endobronchial lesions, and isolated pulmonary nodules might be the first clinical manifestation of metastatic prostate cancer. A high index of suspicion, appropriate imaging, and judicious use of immunohistochemistry are important to ensure accurate diagnosis and optimal patient management.

Pulmonary embolism (PE) is a common cause of morbidity and mortality in the general population.¹ The incidence of PE has been reported to range from 39 to 115 per 100,000 persons per year and has remained stable.² Although mortality rates have declined, they remain high.³ The clinical presentation is nonspecific, making diagnosis and management challenging. A crucial and difficult aspect in the management of patients with PE is weighing the risks vs benefits of treatment, including thrombolytic therapy and other invasive procedures, which carry inherent risks. These factors have led to the development of PE response teams (PERTs) in some hospitals to implement effective multidisciplinary protocols that facilitate prompt diagnosis, management, and follow-up.⁴

CASE PRESENTATIONS

Case 1

New onset seizures and cardiac arrest in the treatment of saddle PE. A 54-year-old male who worked as a draftsman and truck driver with a history of hypertension and nephrolithiasis presented to the emergency department (ED) with progressive shortness of breath for 2 weeks. On the morning of ED presentation the patient experienced an episode of severe shortness of breath, lightheadedness, and chest pressure. He reported no other symptoms such as palpitations, nausea, vomiting, abdominal discomfort, or extremity pain or swelling. He reported no recent travel, immunization, falls, or surgery. Upon evaluation, the patient was found to be in no acute distress, with stable vital signs and laboratory results except for 2 elevated results: > 20 μg/mL D-dimer (reference range, < 0.5 μg/mL) and N-terminal prohormone brain natriuretic peptide (proBNP) level, 3455 pg/mL (reference range, < 125 pg/mL for patients aged < 75 years). Electrocardiogram showed T-wave inversions in leads V2 to V4. Imaging revealed a saddle PE and left popliteal deep venous thrombosis (Figure 1). The patient received an anticoagulation loading dose and was started on heparin drip upon admission to the medical intensive care unit (MICU) for further management and monitoring. The Interventional Radiology Service recommended full anticoagulation with consideration of reperfusion therapies if deterioration developed.

While in the MICU, point-of-care ultrasound findings were confirmed with official echocardiogram by the cardiology service, which demonstrated a preserved ejection fraction of 60% to 65%, a D-shaped left ventricle with septal wall hypokinesis secondary to right heart strain (Figure 2), a markedly elevated right ventricular systolic pressure (RVSP) of 73 mm Hg, and a mean pulmonary artery pressure (mPAP) of 38 mm Hg. The patient’s blood pressure progressively decreased, heart rate increased, and he required increased oxygen supplementation. The case was discussed with the Pharmacy Service, and since the patient had no contraindications to thrombolytic therapy, the appropriate dosage was calculated and 100 mg intravenous (IV) tissue plasminogen activator (tPA) was administered over 2 hours.

About 40 minutes into tPA infusion, the patient suddenly experienced marked shortness of breath, diaphoresis, and anxiety with seizure-like involuntary movements; as a result, the infusion was stopped. He also had episodes of posturing, mental status decline, and briefly going in and out of consciousness, which lasted about 3 minutes before he lost consciousness and pulse. High-quality advanced cardiac life support was initiated, followed by endotracheal intubation. Despite a secured airway and return of spontaneous circulation, the patient remained hypotensive and continued to have seizure-like activity.

The patient was administered a total of 8 mg of lorazepam, sedated with propofol, initiated at 5 μg/kg/min, titrated to stop seizure activity at 15μg/kg/min, and later maintained at 10 μg/kg/min, for a RASS of -1, and started on norepinephrine 0.1 μg/kg/min for acute stabilization. Head computed tomography without contrast showed no acute intracranial pathology as etiology of seizures. Seizure etiology differential at this time was broad; however, hypoxemia due to PE and medication adverse effects were strongly suspected.

The patient’s condition improved, and vasopressor therapy was tapered off the next day. Four days later, the patient was weaned from mechanical ventilation and transferred to the step-down unit. Echocardiogram obtained 48 hours after tPA infusion showed essentially normal left ventricular function (60%-65%), a RVSP of 17 mm Hg and mPAP of 13 mm Hg. The patient’s ProBNP levels markedly decreased to 137 pg/mL. Postextubation, the neurologic examination was at baseline. The Neurology Service recommended temporary treatment with levetiracetam, 1000 mg every 12 hours, and the Hematology Service recommended transitioning to direct oral anticoagulation with follow-up. The patient presented significant clinical and respiratory improvement and was referred for home-based physical rehabilitation as recommended by the physical medicine and rehabilitation service before being discharged.

Case 2

Localized tPA infusion for bilateral PEs via infusion catheters. A 91-year-old male with no history of smoking and a medical history of hypertension, diabetes mellitus, prostate cancer (> 20 years postradiotherapy) and severe osteoarthritis was receiving treatment in the medical ward for medication-induced liver injury secondary to an antibiotic for a urinary tract infection. During the night the patient developed hypotension (86/46 mm Hg), shortness of breath, tachypnea, desaturation, nonradiating retrosternal chest pain, and tachycardia. The hypotension resolved after a 500-mL 0.9 normal saline bolus, and hypoxemia improved with supplemental oxygen via Venturi mask. Chest computed tomography angiography was performed immediately and revealed extensive bilateral acute PE, located most proximally in the right main pulmonary artery (PA) and on the left in the proximal lobar branches, with associated right heart strain. The patient was started on IV heparin with a bolus of 5000 units (80 u/kg) followed by a drip with a partial thromboplastin time goal of 62-103 seconds and transferred to MICU.

Laboratory findings were notable for proBNP that increased from 115 pg/mL to 4470 pg/mL (reference range, < 450 pg/mL for patients aged 75 years) and elevated troponin levels at 218 ng/L to 295 ng/L (reference range, < 22 ng/L), exhibiting chemical evidence of right heart strain. Initial echocardiogram showed mid-right ventricular free wall akinesis with a hypercontractile apex, suggestive of PE (McConnell’s sign) (Figure 3). Interventional Radiology Service was consulted and recommended tPA infusion given that the patient had bilateral PEs and stable blood pressure.

Pulmonary angiogram showed elevated pressures in the right PA of 64/21 mm Hg and the left PA pressures of 63/20 mm Hg. Mechanical disruption of the larger right lower PA thrombus was achieved via a pigtail catheter followed by bilateral catheter bolus infusions of 2 mg tPA (alteplase) and a continuous tPA infusion 0.5 mg/h for 24 hours, in conjunction with a heparin infusion.

After 24 hours of tPA infusion, the catheters were removed, with posttreatment pulmonary angiography demonstrating right and left PA pressures of 42/15 mm Hg and 40/16 mm Hg, respectively. Pre- and postlocalized tPA infusion treatment images are provided for visual comparison (Figure 4). An echocardiogram performed after tPA infusion showed no signs of pulmonary hypertension. The Hematology Service provided recommendations regarding anticoagulation, and after completion of tPA infusion, the patient was transitioned to an unfractioned heparin infusion and subsequently to direct oral anticoagulation prior to transfer back to the medical ward, hemodynamically stable and asymptomatic.

DISCUSSION

PE management can be a straightforward decision when the patient meets criteria for hemodynamic instability, or with small PE burden. In contrast, management can be more challenging in intermediate-risk (submassive) PE when patients remain hemodynamically stable but show signs of cardiopulmonary stress, such as right heart strain, elevated troponins, or increased proBNP levels.² In these situations, case-by- case evaluation is warranted. A PERT can assess the most beneficial treatment approach by considering factors such as right ventricular dysfunction, hemodynamic status, clot burden, and clinical deterioration despite appropriate anticoagulation. The evidence supporting the benefits these organized teams can provide is growing. These case reports emphasize the need for a multidisciplinary and systematic approach in these complex cases, especially in the management of intermediate-risk PE patients.

Currently, the Veterans Affairs Caribbean Healthcare System does not have an organized PERT, although a multidisciplinary approach was applied in the management of these patients. A systematic, structured team could have decreased time to interventions and alleviated the burden of physician decision-making. Having such a team would streamline the diagnostic pathway for patients presenting from a ward or emergency department with suspected PE.

We present 2 cases of patients found to have a high clot burden from PEs. The patients were initially hemodynamically stable (intermediate-risk PE), but later required systemic or localized thrombolysis due to hemodynamic deterioration despite adequate anticoagulation. Despite similar diagnoses and etiologies, these patients were successfully managed using different approaches, yielding positive outcomes. This reflects the complexity and variability in diagnosing and managing intermediate-risk PE in patients with different comorbidities and clot burden effects. In Case 1, our multidisciplinary approach was obtained via consults to selected services such as interventional radiology, cardiology, and direct involvement of pharmacy. An organized PERT conceivably would have allowed quicker discussions among these services, including hematology, to provide recommendations and collaborative support upon the patient’s arrival to the ED. Additionally, with a PERT team, a systematic approach to these patients could have allowed for an earlier official echocardiogram report for evaluation of right heart strain and develop an adequate therapeutic plan in a timely manner.

In Case 2, consultation with the Interventional Radiology Service yielded a better therapeutic plan, utilizing localized tPA infusion for this older adult patient with increased risk of bleeding with systemic tPA infusion. Having a PERT presents an opportunity to optimize PE management through early recognition, diagnosis, and treatment by institutional consensus from an interdisciplinary team.^5,6 These response teams may improve outcomes and prognosis for patients with PE, especially where diagnosis and management is not clear.

The definite etiology of seizure activity in the first case pre- and postcardiac arrest, in the context of no acute intracranial process, remains unknown. Reports have emerged about postreperfusion seizures in acute ischemic stroke, as well as cases of seizures masquerading as PE as the primary presentation. ^7,8 However, there were no reports of patients developing seizures post tPA infusion for the treatment of PE. This report may shed light into possible complications secondary to tPA infusion, raising awareness among physicians and encouraging further investigation into its possible etiologies.

CONCLUSIONS

Management of PE can be challenging in patients that meet criteria for intermediate risk. PERTs are a tool that allow for a multidisciplinary, standardized and systematic approach with a diagnostic and treatment algorithm that conceivably would result in a better consensus and therapeutic approach.

Pulmonary embolism (PE) is a common cause of morbidity and mortality in the general population.¹ The incidence of PE has been reported to range from 39 to 115 per 100,000 persons per year and has remained stable.² Although mortality rates have declined, they remain high.³ The clinical presentation is nonspecific, making diagnosis and management challenging. A crucial and difficult aspect in the management of patients with PE is weighing the risks vs benefits of treatment, including thrombolytic therapy and other invasive procedures, which carry inherent risks. These factors have led to the development of PE response teams (PERTs) in some hospitals to implement effective multidisciplinary protocols that facilitate prompt diagnosis, management, and follow-up.⁴

CASE PRESENTATIONS

Case 1

New onset seizures and cardiac arrest in the treatment of saddle PE. A 54-year-old male who worked as a draftsman and truck driver with a history of hypertension and nephrolithiasis presented to the emergency department (ED) with progressive shortness of breath for 2 weeks. On the morning of ED presentation the patient experienced an episode of severe shortness of breath, lightheadedness, and chest pressure. He reported no other symptoms such as palpitations, nausea, vomiting, abdominal discomfort, or extremity pain or swelling. He reported no recent travel, immunization, falls, or surgery. Upon evaluation, the patient was found to be in no acute distress, with stable vital signs and laboratory results except for 2 elevated results: > 20 μg/mL D-dimer (reference range, < 0.5 μg/mL) and N-terminal prohormone brain natriuretic peptide (proBNP) level, 3455 pg/mL (reference range, < 125 pg/mL for patients aged < 75 years). Electrocardiogram showed T-wave inversions in leads V2 to V4. Imaging revealed a saddle PE and left popliteal deep venous thrombosis (Figure 1). The patient received an anticoagulation loading dose and was started on heparin drip upon admission to the medical intensive care unit (MICU) for further management and monitoring. The Interventional Radiology Service recommended full anticoagulation with consideration of reperfusion therapies if deterioration developed.

While in the MICU, point-of-care ultrasound findings were confirmed with official echocardiogram by the cardiology service, which demonstrated a preserved ejection fraction of 60% to 65%, a D-shaped left ventricle with septal wall hypokinesis secondary to right heart strain (Figure 2), a markedly elevated right ventricular systolic pressure (RVSP) of 73 mm Hg, and a mean pulmonary artery pressure (mPAP) of 38 mm Hg. The patient’s blood pressure progressively decreased, heart rate increased, and he required increased oxygen supplementation. The case was discussed with the Pharmacy Service, and since the patient had no contraindications to thrombolytic therapy, the appropriate dosage was calculated and 100 mg intravenous (IV) tissue plasminogen activator (tPA) was administered over 2 hours.

About 40 minutes into tPA infusion, the patient suddenly experienced marked shortness of breath, diaphoresis, and anxiety with seizure-like involuntary movements; as a result, the infusion was stopped. He also had episodes of posturing, mental status decline, and briefly going in and out of consciousness, which lasted about 3 minutes before he lost consciousness and pulse. High-quality advanced cardiac life support was initiated, followed by endotracheal intubation. Despite a secured airway and return of spontaneous circulation, the patient remained hypotensive and continued to have seizure-like activity.

The patient was administered a total of 8 mg of lorazepam, sedated with propofol, initiated at 5 μg/kg/min, titrated to stop seizure activity at 15μg/kg/min, and later maintained at 10 μg/kg/min, for a RASS of -1, and started on norepinephrine 0.1 μg/kg/min for acute stabilization. Head computed tomography without contrast showed no acute intracranial pathology as etiology of seizures. Seizure etiology differential at this time was broad; however, hypoxemia due to PE and medication adverse effects were strongly suspected.

The patient’s condition improved, and vasopressor therapy was tapered off the next day. Four days later, the patient was weaned from mechanical ventilation and transferred to the step-down unit. Echocardiogram obtained 48 hours after tPA infusion showed essentially normal left ventricular function (60%-65%), a RVSP of 17 mm Hg and mPAP of 13 mm Hg. The patient’s ProBNP levels markedly decreased to 137 pg/mL. Postextubation, the neurologic examination was at baseline. The Neurology Service recommended temporary treatment with levetiracetam, 1000 mg every 12 hours, and the Hematology Service recommended transitioning to direct oral anticoagulation with follow-up. The patient presented significant clinical and respiratory improvement and was referred for home-based physical rehabilitation as recommended by the physical medicine and rehabilitation service before being discharged.

Case 2

Localized tPA infusion for bilateral PEs via infusion catheters. A 91-year-old male with no history of smoking and a medical history of hypertension, diabetes mellitus, prostate cancer (> 20 years postradiotherapy) and severe osteoarthritis was receiving treatment in the medical ward for medication-induced liver injury secondary to an antibiotic for a urinary tract infection. During the night the patient developed hypotension (86/46 mm Hg), shortness of breath, tachypnea, desaturation, nonradiating retrosternal chest pain, and tachycardia. The hypotension resolved after a 500-mL 0.9 normal saline bolus, and hypoxemia improved with supplemental oxygen via Venturi mask. Chest computed tomography angiography was performed immediately and revealed extensive bilateral acute PE, located most proximally in the right main pulmonary artery (PA) and on the left in the proximal lobar branches, with associated right heart strain. The patient was started on IV heparin with a bolus of 5000 units (80 u/kg) followed by a drip with a partial thromboplastin time goal of 62-103 seconds and transferred to MICU.

Laboratory findings were notable for proBNP that increased from 115 pg/mL to 4470 pg/mL (reference range, < 450 pg/mL for patients aged 75 years) and elevated troponin levels at 218 ng/L to 295 ng/L (reference range, < 22 ng/L), exhibiting chemical evidence of right heart strain. Initial echocardiogram showed mid-right ventricular free wall akinesis with a hypercontractile apex, suggestive of PE (McConnell’s sign) (Figure 3). Interventional Radiology Service was consulted and recommended tPA infusion given that the patient had bilateral PEs and stable blood pressure.

Pulmonary angiogram showed elevated pressures in the right PA of 64/21 mm Hg and the left PA pressures of 63/20 mm Hg. Mechanical disruption of the larger right lower PA thrombus was achieved via a pigtail catheter followed by bilateral catheter bolus infusions of 2 mg tPA (alteplase) and a continuous tPA infusion 0.5 mg/h for 24 hours, in conjunction with a heparin infusion.

After 24 hours of tPA infusion, the catheters were removed, with posttreatment pulmonary angiography demonstrating right and left PA pressures of 42/15 mm Hg and 40/16 mm Hg, respectively. Pre- and postlocalized tPA infusion treatment images are provided for visual comparison (Figure 4). An echocardiogram performed after tPA infusion showed no signs of pulmonary hypertension. The Hematology Service provided recommendations regarding anticoagulation, and after completion of tPA infusion, the patient was transitioned to an unfractioned heparin infusion and subsequently to direct oral anticoagulation prior to transfer back to the medical ward, hemodynamically stable and asymptomatic.

DISCUSSION

PE management can be a straightforward decision when the patient meets criteria for hemodynamic instability, or with small PE burden. In contrast, management can be more challenging in intermediate-risk (submassive) PE when patients remain hemodynamically stable but show signs of cardiopulmonary stress, such as right heart strain, elevated troponins, or increased proBNP levels.² In these situations, case-by- case evaluation is warranted. A PERT can assess the most beneficial treatment approach by considering factors such as right ventricular dysfunction, hemodynamic status, clot burden, and clinical deterioration despite appropriate anticoagulation. The evidence supporting the benefits these organized teams can provide is growing. These case reports emphasize the need for a multidisciplinary and systematic approach in these complex cases, especially in the management of intermediate-risk PE patients.

Currently, the Veterans Affairs Caribbean Healthcare System does not have an organized PERT, although a multidisciplinary approach was applied in the management of these patients. A systematic, structured team could have decreased time to interventions and alleviated the burden of physician decision-making. Having such a team would streamline the diagnostic pathway for patients presenting from a ward or emergency department with suspected PE.

We present 2 cases of patients found to have a high clot burden from PEs. The patients were initially hemodynamically stable (intermediate-risk PE), but later required systemic or localized thrombolysis due to hemodynamic deterioration despite adequate anticoagulation. Despite similar diagnoses and etiologies, these patients were successfully managed using different approaches, yielding positive outcomes. This reflects the complexity and variability in diagnosing and managing intermediate-risk PE in patients with different comorbidities and clot burden effects. In Case 1, our multidisciplinary approach was obtained via consults to selected services such as interventional radiology, cardiology, and direct involvement of pharmacy. An organized PERT conceivably would have allowed quicker discussions among these services, including hematology, to provide recommendations and collaborative support upon the patient’s arrival to the ED. Additionally, with a PERT team, a systematic approach to these patients could have allowed for an earlier official echocardiogram report for evaluation of right heart strain and develop an adequate therapeutic plan in a timely manner.

In Case 2, consultation with the Interventional Radiology Service yielded a better therapeutic plan, utilizing localized tPA infusion for this older adult patient with increased risk of bleeding with systemic tPA infusion. Having a PERT presents an opportunity to optimize PE management through early recognition, diagnosis, and treatment by institutional consensus from an interdisciplinary team.^5,6 These response teams may improve outcomes and prognosis for patients with PE, especially where diagnosis and management is not clear.

The definite etiology of seizure activity in the first case pre- and postcardiac arrest, in the context of no acute intracranial process, remains unknown. Reports have emerged about postreperfusion seizures in acute ischemic stroke, as well as cases of seizures masquerading as PE as the primary presentation. ^7,8 However, there were no reports of patients developing seizures post tPA infusion for the treatment of PE. This report may shed light into possible complications secondary to tPA infusion, raising awareness among physicians and encouraging further investigation into its possible etiologies.

CONCLUSIONS

Management of PE can be challenging in patients that meet criteria for intermediate risk. PERTs are a tool that allow for a multidisciplinary, standardized and systematic approach with a diagnostic and treatment algorithm that conceivably would result in a better consensus and therapeutic approach.

Pulmonary embolism (PE) is a common cause of morbidity and mortality in the general population.¹ The incidence of PE has been reported to range from 39 to 115 per 100,000 persons per year and has remained stable.² Although mortality rates have declined, they remain high.³ The clinical presentation is nonspecific, making diagnosis and management challenging. A crucial and difficult aspect in the management of patients with PE is weighing the risks vs benefits of treatment, including thrombolytic therapy and other invasive procedures, which carry inherent risks. These factors have led to the development of PE response teams (PERTs) in some hospitals to implement effective multidisciplinary protocols that facilitate prompt diagnosis, management, and follow-up.⁴

CASE PRESENTATIONS

Case 1

New onset seizures and cardiac arrest in the treatment of saddle PE. A 54-year-old male who worked as a draftsman and truck driver with a history of hypertension and nephrolithiasis presented to the emergency department (ED) with progressive shortness of breath for 2 weeks. On the morning of ED presentation the patient experienced an episode of severe shortness of breath, lightheadedness, and chest pressure. He reported no other symptoms such as palpitations, nausea, vomiting, abdominal discomfort, or extremity pain or swelling. He reported no recent travel, immunization, falls, or surgery. Upon evaluation, the patient was found to be in no acute distress, with stable vital signs and laboratory results except for 2 elevated results: > 20 μg/mL D-dimer (reference range, < 0.5 μg/mL) and N-terminal prohormone brain natriuretic peptide (proBNP) level, 3455 pg/mL (reference range, < 125 pg/mL for patients aged < 75 years). Electrocardiogram showed T-wave inversions in leads V2 to V4. Imaging revealed a saddle PE and left popliteal deep venous thrombosis (Figure 1). The patient received an anticoagulation loading dose and was started on heparin drip upon admission to the medical intensive care unit (MICU) for further management and monitoring. The Interventional Radiology Service recommended full anticoagulation with consideration of reperfusion therapies if deterioration developed.

While in the MICU, point-of-care ultrasound findings were confirmed with official echocardiogram by the cardiology service, which demonstrated a preserved ejection fraction of 60% to 65%, a D-shaped left ventricle with septal wall hypokinesis secondary to right heart strain (Figure 2), a markedly elevated right ventricular systolic pressure (RVSP) of 73 mm Hg, and a mean pulmonary artery pressure (mPAP) of 38 mm Hg. The patient’s blood pressure progressively decreased, heart rate increased, and he required increased oxygen supplementation. The case was discussed with the Pharmacy Service, and since the patient had no contraindications to thrombolytic therapy, the appropriate dosage was calculated and 100 mg intravenous (IV) tissue plasminogen activator (tPA) was administered over 2 hours.

About 40 minutes into tPA infusion, the patient suddenly experienced marked shortness of breath, diaphoresis, and anxiety with seizure-like involuntary movements; as a result, the infusion was stopped. He also had episodes of posturing, mental status decline, and briefly going in and out of consciousness, which lasted about 3 minutes before he lost consciousness and pulse. High-quality advanced cardiac life support was initiated, followed by endotracheal intubation. Despite a secured airway and return of spontaneous circulation, the patient remained hypotensive and continued to have seizure-like activity.

The patient was administered a total of 8 mg of lorazepam, sedated with propofol, initiated at 5 μg/kg/min, titrated to stop seizure activity at 15μg/kg/min, and later maintained at 10 μg/kg/min, for a RASS of -1, and started on norepinephrine 0.1 μg/kg/min for acute stabilization. Head computed tomography without contrast showed no acute intracranial pathology as etiology of seizures. Seizure etiology differential at this time was broad; however, hypoxemia due to PE and medication adverse effects were strongly suspected.

The patient’s condition improved, and vasopressor therapy was tapered off the next day. Four days later, the patient was weaned from mechanical ventilation and transferred to the step-down unit. Echocardiogram obtained 48 hours after tPA infusion showed essentially normal left ventricular function (60%-65%), a RVSP of 17 mm Hg and mPAP of 13 mm Hg. The patient’s ProBNP levels markedly decreased to 137 pg/mL. Postextubation, the neurologic examination was at baseline. The Neurology Service recommended temporary treatment with levetiracetam, 1000 mg every 12 hours, and the Hematology Service recommended transitioning to direct oral anticoagulation with follow-up. The patient presented significant clinical and respiratory improvement and was referred for home-based physical rehabilitation as recommended by the physical medicine and rehabilitation service before being discharged.

Case 2

Localized tPA infusion for bilateral PEs via infusion catheters. A 91-year-old male with no history of smoking and a medical history of hypertension, diabetes mellitus, prostate cancer (> 20 years postradiotherapy) and severe osteoarthritis was receiving treatment in the medical ward for medication-induced liver injury secondary to an antibiotic for a urinary tract infection. During the night the patient developed hypotension (86/46 mm Hg), shortness of breath, tachypnea, desaturation, nonradiating retrosternal chest pain, and tachycardia. The hypotension resolved after a 500-mL 0.9 normal saline bolus, and hypoxemia improved with supplemental oxygen via Venturi mask. Chest computed tomography angiography was performed immediately and revealed extensive bilateral acute PE, located most proximally in the right main pulmonary artery (PA) and on the left in the proximal lobar branches, with associated right heart strain. The patient was started on IV heparin with a bolus of 5000 units (80 u/kg) followed by a drip with a partial thromboplastin time goal of 62-103 seconds and transferred to MICU.

Laboratory findings were notable for proBNP that increased from 115 pg/mL to 4470 pg/mL (reference range, < 450 pg/mL for patients aged 75 years) and elevated troponin levels at 218 ng/L to 295 ng/L (reference range, < 22 ng/L), exhibiting chemical evidence of right heart strain. Initial echocardiogram showed mid-right ventricular free wall akinesis with a hypercontractile apex, suggestive of PE (McConnell’s sign) (Figure 3). Interventional Radiology Service was consulted and recommended tPA infusion given that the patient had bilateral PEs and stable blood pressure.

Pulmonary angiogram showed elevated pressures in the right PA of 64/21 mm Hg and the left PA pressures of 63/20 mm Hg. Mechanical disruption of the larger right lower PA thrombus was achieved via a pigtail catheter followed by bilateral catheter bolus infusions of 2 mg tPA (alteplase) and a continuous tPA infusion 0.5 mg/h for 24 hours, in conjunction with a heparin infusion.

After 24 hours of tPA infusion, the catheters were removed, with posttreatment pulmonary angiography demonstrating right and left PA pressures of 42/15 mm Hg and 40/16 mm Hg, respectively. Pre- and postlocalized tPA infusion treatment images are provided for visual comparison (Figure 4). An echocardiogram performed after tPA infusion showed no signs of pulmonary hypertension. The Hematology Service provided recommendations regarding anticoagulation, and after completion of tPA infusion, the patient was transitioned to an unfractioned heparin infusion and subsequently to direct oral anticoagulation prior to transfer back to the medical ward, hemodynamically stable and asymptomatic.

DISCUSSION

PE management can be a straightforward decision when the patient meets criteria for hemodynamic instability, or with small PE burden. In contrast, management can be more challenging in intermediate-risk (submassive) PE when patients remain hemodynamically stable but show signs of cardiopulmonary stress, such as right heart strain, elevated troponins, or increased proBNP levels.² In these situations, case-by- case evaluation is warranted. A PERT can assess the most beneficial treatment approach by considering factors such as right ventricular dysfunction, hemodynamic status, clot burden, and clinical deterioration despite appropriate anticoagulation. The evidence supporting the benefits these organized teams can provide is growing. These case reports emphasize the need for a multidisciplinary and systematic approach in these complex cases, especially in the management of intermediate-risk PE patients.

Currently, the Veterans Affairs Caribbean Healthcare System does not have an organized PERT, although a multidisciplinary approach was applied in the management of these patients. A systematic, structured team could have decreased time to interventions and alleviated the burden of physician decision-making. Having such a team would streamline the diagnostic pathway for patients presenting from a ward or emergency department with suspected PE.

We present 2 cases of patients found to have a high clot burden from PEs. The patients were initially hemodynamically stable (intermediate-risk PE), but later required systemic or localized thrombolysis due to hemodynamic deterioration despite adequate anticoagulation. Despite similar diagnoses and etiologies, these patients were successfully managed using different approaches, yielding positive outcomes. This reflects the complexity and variability in diagnosing and managing intermediate-risk PE in patients with different comorbidities and clot burden effects. In Case 1, our multidisciplinary approach was obtained via consults to selected services such as interventional radiology, cardiology, and direct involvement of pharmacy. An organized PERT conceivably would have allowed quicker discussions among these services, including hematology, to provide recommendations and collaborative support upon the patient’s arrival to the ED. Additionally, with a PERT team, a systematic approach to these patients could have allowed for an earlier official echocardiogram report for evaluation of right heart strain and develop an adequate therapeutic plan in a timely manner.

In Case 2, consultation with the Interventional Radiology Service yielded a better therapeutic plan, utilizing localized tPA infusion for this older adult patient with increased risk of bleeding with systemic tPA infusion. Having a PERT presents an opportunity to optimize PE management through early recognition, diagnosis, and treatment by institutional consensus from an interdisciplinary team.^5,6 These response teams may improve outcomes and prognosis for patients with PE, especially where diagnosis and management is not clear.

The definite etiology of seizure activity in the first case pre- and postcardiac arrest, in the context of no acute intracranial process, remains unknown. Reports have emerged about postreperfusion seizures in acute ischemic stroke, as well as cases of seizures masquerading as PE as the primary presentation. ^7,8 However, there were no reports of patients developing seizures post tPA infusion for the treatment of PE. This report may shed light into possible complications secondary to tPA infusion, raising awareness among physicians and encouraging further investigation into its possible etiologies.

CONCLUSIONS

Management of PE can be challenging in patients that meet criteria for intermediate risk. PERTs are a tool that allow for a multidisciplinary, standardized and systematic approach with a diagnostic and treatment algorithm that conceivably would result in a better consensus and therapeutic approach.

Obesity is a growing worldwide epidemic with significant implications for individual health and public health care costs. It is also associated with several medical conditions, including diabetes, cardiovascular disease, cancer, and mental health disorders.¹ Comprehensive lifestyle intervention is a first-line therapy for obesity consisting of dietary and exercise interventions. Despite initial success, long-term results and durability of weight loss with lifestyle modifications are limited. ² Bariatric surgery, including sleeve gastrectomy and gastric bypass surgery, is a more invasive approach that is highly effective in weight loss. However, these operations are not reversible, and patients may not be eligible for or may not desire surgery. Overall, bariatric surgery is widely underutilized, with < 1% of eligible patients ultimately undergoing surgery.^3,4

Endoscopic bariatric therapies are increasingly popular procedures that address the need for additional treatments for obesity among individuals who have not had success with lifestyle changes and are not surgical candidates. The most common procedure is the endoscopic sleeve gastroplasty (ESG), which applies full-thickness sutures in the stomach to reduce gastric volume, delay gastric emptying, and limit food intake while keeping the fundus intact compared with sleeve gastrectomy. This procedure is typically considered in patients with body mass index (BMI) ≥ 30, who do not qualify for or do not want traditional bariatric surgery. The literature supports robust outcomes after ESG, with studies demonstrating significant and sustained total body weight loss of up to 14% to 16% at 5 years and significant improvement in ≥ 1 metabolic comorbidities in 80% of patients.^5,6 ESG adverse events (AEs) include abdominal pain, nausea, and vomiting that are typically self-limited to 1 week. Rarer but more serious AEs include bleeding, perforation, or infection, and occur in 2% of cases based on large trial data.^5,7

Although the weight loss benefits of ESG are well established, to date, there are limited data on the effects of endoscopic bariatric therapies like ESG on mental health conditions. Here, we describe a case of a veteran with a history of mental health disorders that prevented him from completing bariatric surgery. The patient underwent ESG and had a successful clinical course.

CASE PRESENTATION

A 59-year-old male veteran with a medical history of class III obesity (42.4 BMI), obstructive sleep apnea, hypothyroidism, hypertension, type 2 diabetes mellitus, and a large ventral hernia was referred to the MOVE! (Management of Overweight/ Obese Veterans Everywhere!) multidisciplinary high-intensity weight loss program at the US Department of Veterans Affairs (VA) West Los Angeles VA Medical Center (WLAVAMC). His psychiatric history included generalized anxiety disorder, posttraumatic stress disorder (PTSD), and panic disorder, managed by the Psychiatry Service and treated with sertraline 25 mg daily, lorazepam 0.5 mg twice daily, and hydroxyzine 20 mg nightly. He had previously implemented lifestyle changes and attended MOVE! classes and nutrition coaching for 1 year but was unsuccessful in losing weight. He had also tried liraglutide 3 mg daily for weight loss but was unable to tolerate it and reported worsening medication-related anxiety.

The patient declined further weight loss pharmacotherapy and was referred to bariatric surgery. He was scheduled for a surgical sleeve gastrectomy. However, on the day he arrived at the hospital for surgery, he developed severe anxiety and had a panic attack, and it was canceled. Due to his mental health issues, he was no longer comfortable proceeding with surgery and was left without other options for obesity treatment. The veteran was extremely disappointed because the ventral hernia caused significant quality of life impairment, limited his ability to exercise, and caused him embarrassment in public settings. The hernia could not be surgically repaired until there was significant weight loss.

A bariatric endoscopy program within the Division of Gastroenterology was developed and implemented at the WLAVAMC in February 2023 in conjunction with MOVE! The patient was referred for consideration of an endoscopic weight loss procedure. He was determined to be a suitable candidate for ESG based on his BMI being > 40 and personal preference not to proceed with surgery to lose enough weight to qualify for hernia repair. The veteran underwent an endoscopy, which showed normal anatomy and gastric mucosa. ESG was performed in standard fashion (Figure).⁸ Three vertical lines were made using argon plasma coagulation from the incisura to 2 cm below the gastroesophageal junction along the anterior, posterior, and greater curvature of the stomach to mark the area for endoscopic suture placement. Starting at the incisura, 7 full-thickness sutures were placed to create a volume reduction plication, with preservation of the fundus. The patient did well postprocedure with no immediate or delayed AEs and was discharged home the same day.

Follow-up

The veteran followed a gradual dietary advancement from a clear liquid diet to pureed and soft texture food. The patient’s weight dropped from 359 lbs preprocedure to 304 lbs 6 months postprocedure, a total body weight loss (TWBL) of 15.3%. At 12 months the veteran weighed 299 lbs (16.7% TBWL). He also had notable improvements in metabolic parameters. His systolic blood pressure decreased from ≥ 140 mm Hg to 120 to 130 mm Hg and hemoglobin A_1c dropped from 7.0% to 6.3%. Remarkably, his psychiatrist noted significant improvement in his overall mental health. The veteran reported complete cessation of panic attacks since the ESG, improvements in PTSD and anxiety, and was able to discontinue lorazepam and decrease his dose of sertraline to 12.5 mg daily. He reported feeling more energetic and goal-oriented with increased clarity of thought. Perhaps the most significant outcome was that after the 55-lb weight loss at 6 months, the patient was eligible to undergo ventral hernia surgical repair, which had previously contributed to shame and social isolation. This, in turn, improved his quality of life, allowed him to start walking again, up to 8 miles daily, and to feel comfortable again going out in public settings.

DISCUSSION

Bariatric surgeries are an effective method of achieving weight loss and improving obesity-related comorbidities. However, only a small percentage of individuals with obesity are candidates for bariatric surgery. Given the dramatic increase in the prevalence of obesity, other options are needed. Specifically, within the VA, an estimated 80% of veterans are overweight or obese, but only about 500 bariatric surgeries are performed annually.⁹ With the need for additional weight loss therapies, VA programs are starting to offer endoscopic bariatric procedures as an alternative option. This may be a desirable choice for patients with obesity (BMI > 30), with or without associated metabolic comorbidities, who need more aggressive intervention beyond dietary and lifestyle changes and are either not interested in or not eligible for bariatric surgery or weight loss medications.

Although there is evidence that metabolic comorbidities are associated with obesity, there has been less research on obesity and mental health comorbidities such as depression and anxiety. These psychiatric conditions may even be more common among patients seeking weight loss procedures and more prominent in certain groups such as veterans, which may ultimately exclude these patients from bariatric surgery.¹⁰ Prior studies suggest that bariatric surgery can reduce the severity of depression and, to a lesser extent, anxiety symptoms at 2 years following the initial surgery; however, there is limited literature describing the impact of weight loss procedure on panic disorders.^11-14 We suspect that a weight loss procedure such as ESG may have indirectly improved the veteran’s mood disorder due to the weight loss it induced, increasing the ability to exercise, quality of sleep, and participation in public settings.

This case highlights a veteran who did not tolerate weight loss medication and had severe anxiety and PTSD that prevented him from going through with bariatric surgery. He then underwent an endoscopic weight loss procedure. The ESG helped him successfully achieve significant weight loss, increase his physical activity, reduce his anxiety and panic disorder, and overall, significantly improve his quality of life. More than 1 year after the procedure, the patient has sustained improvements in his psychiatric and emotional health along with durable weight loss, maintaining > 15% of his total weight lost. Additional studies are needed to further understand the prevalence and long-term outcomes of mental health comorbidities, as well as weight loss outcomes in this group of patients who undergo endoscopic bariatric procedures.

CONCLUSIONS

We describe a case of a veteran with severe obesity and significant psychiatric comorbidities that prevented him from undergoing bariatric surgery, who underwent an ESG. This procedure led to significant weight loss, improvement of metabolic parameters, reduction in anxiety and PTSD, and enhancement of his quality of life. This case emphasizes the unique advantages of ESG and supports the expansion of endoscopic bariatric programs in the VA.

Obesity is a growing worldwide epidemic with significant implications for individual health and public health care costs. It is also associated with several medical conditions, including diabetes, cardiovascular disease, cancer, and mental health disorders.¹ Comprehensive lifestyle intervention is a first-line therapy for obesity consisting of dietary and exercise interventions. Despite initial success, long-term results and durability of weight loss with lifestyle modifications are limited. ² Bariatric surgery, including sleeve gastrectomy and gastric bypass surgery, is a more invasive approach that is highly effective in weight loss. However, these operations are not reversible, and patients may not be eligible for or may not desire surgery. Overall, bariatric surgery is widely underutilized, with < 1% of eligible patients ultimately undergoing surgery.^3,4

Endoscopic bariatric therapies are increasingly popular procedures that address the need for additional treatments for obesity among individuals who have not had success with lifestyle changes and are not surgical candidates. The most common procedure is the endoscopic sleeve gastroplasty (ESG), which applies full-thickness sutures in the stomach to reduce gastric volume, delay gastric emptying, and limit food intake while keeping the fundus intact compared with sleeve gastrectomy. This procedure is typically considered in patients with body mass index (BMI) ≥ 30, who do not qualify for or do not want traditional bariatric surgery. The literature supports robust outcomes after ESG, with studies demonstrating significant and sustained total body weight loss of up to 14% to 16% at 5 years and significant improvement in ≥ 1 metabolic comorbidities in 80% of patients.^5,6 ESG adverse events (AEs) include abdominal pain, nausea, and vomiting that are typically self-limited to 1 week. Rarer but more serious AEs include bleeding, perforation, or infection, and occur in 2% of cases based on large trial data.^5,7

Although the weight loss benefits of ESG are well established, to date, there are limited data on the effects of endoscopic bariatric therapies like ESG on mental health conditions. Here, we describe a case of a veteran with a history of mental health disorders that prevented him from completing bariatric surgery. The patient underwent ESG and had a successful clinical course.

CASE PRESENTATION

A 59-year-old male veteran with a medical history of class III obesity (42.4 BMI), obstructive sleep apnea, hypothyroidism, hypertension, type 2 diabetes mellitus, and a large ventral hernia was referred to the MOVE! (Management of Overweight/ Obese Veterans Everywhere!) multidisciplinary high-intensity weight loss program at the US Department of Veterans Affairs (VA) West Los Angeles VA Medical Center (WLAVAMC). His psychiatric history included generalized anxiety disorder, posttraumatic stress disorder (PTSD), and panic disorder, managed by the Psychiatry Service and treated with sertraline 25 mg daily, lorazepam 0.5 mg twice daily, and hydroxyzine 20 mg nightly. He had previously implemented lifestyle changes and attended MOVE! classes and nutrition coaching for 1 year but was unsuccessful in losing weight. He had also tried liraglutide 3 mg daily for weight loss but was unable to tolerate it and reported worsening medication-related anxiety.

The patient declined further weight loss pharmacotherapy and was referred to bariatric surgery. He was scheduled for a surgical sleeve gastrectomy. However, on the day he arrived at the hospital for surgery, he developed severe anxiety and had a panic attack, and it was canceled. Due to his mental health issues, he was no longer comfortable proceeding with surgery and was left without other options for obesity treatment. The veteran was extremely disappointed because the ventral hernia caused significant quality of life impairment, limited his ability to exercise, and caused him embarrassment in public settings. The hernia could not be surgically repaired until there was significant weight loss.

A bariatric endoscopy program within the Division of Gastroenterology was developed and implemented at the WLAVAMC in February 2023 in conjunction with MOVE! The patient was referred for consideration of an endoscopic weight loss procedure. He was determined to be a suitable candidate for ESG based on his BMI being > 40 and personal preference not to proceed with surgery to lose enough weight to qualify for hernia repair. The veteran underwent an endoscopy, which showed normal anatomy and gastric mucosa. ESG was performed in standard fashion (Figure).⁸ Three vertical lines were made using argon plasma coagulation from the incisura to 2 cm below the gastroesophageal junction along the anterior, posterior, and greater curvature of the stomach to mark the area for endoscopic suture placement. Starting at the incisura, 7 full-thickness sutures were placed to create a volume reduction plication, with preservation of the fundus. The patient did well postprocedure with no immediate or delayed AEs and was discharged home the same day.

Follow-up

The veteran followed a gradual dietary advancement from a clear liquid diet to pureed and soft texture food. The patient’s weight dropped from 359 lbs preprocedure to 304 lbs 6 months postprocedure, a total body weight loss (TWBL) of 15.3%. At 12 months the veteran weighed 299 lbs (16.7% TBWL). He also had notable improvements in metabolic parameters. His systolic blood pressure decreased from ≥ 140 mm Hg to 120 to 130 mm Hg and hemoglobin A_1c dropped from 7.0% to 6.3%. Remarkably, his psychiatrist noted significant improvement in his overall mental health. The veteran reported complete cessation of panic attacks since the ESG, improvements in PTSD and anxiety, and was able to discontinue lorazepam and decrease his dose of sertraline to 12.5 mg daily. He reported feeling more energetic and goal-oriented with increased clarity of thought. Perhaps the most significant outcome was that after the 55-lb weight loss at 6 months, the patient was eligible to undergo ventral hernia surgical repair, which had previously contributed to shame and social isolation. This, in turn, improved his quality of life, allowed him to start walking again, up to 8 miles daily, and to feel comfortable again going out in public settings.

DISCUSSION

Bariatric surgeries are an effective method of achieving weight loss and improving obesity-related comorbidities. However, only a small percentage of individuals with obesity are candidates for bariatric surgery. Given the dramatic increase in the prevalence of obesity, other options are needed. Specifically, within the VA, an estimated 80% of veterans are overweight or obese, but only about 500 bariatric surgeries are performed annually.⁹ With the need for additional weight loss therapies, VA programs are starting to offer endoscopic bariatric procedures as an alternative option. This may be a desirable choice for patients with obesity (BMI > 30), with or without associated metabolic comorbidities, who need more aggressive intervention beyond dietary and lifestyle changes and are either not interested in or not eligible for bariatric surgery or weight loss medications.

Although there is evidence that metabolic comorbidities are associated with obesity, there has been less research on obesity and mental health comorbidities such as depression and anxiety. These psychiatric conditions may even be more common among patients seeking weight loss procedures and more prominent in certain groups such as veterans, which may ultimately exclude these patients from bariatric surgery.¹⁰ Prior studies suggest that bariatric surgery can reduce the severity of depression and, to a lesser extent, anxiety symptoms at 2 years following the initial surgery; however, there is limited literature describing the impact of weight loss procedure on panic disorders.^11-14 We suspect that a weight loss procedure such as ESG may have indirectly improved the veteran’s mood disorder due to the weight loss it induced, increasing the ability to exercise, quality of sleep, and participation in public settings.

This case highlights a veteran who did not tolerate weight loss medication and had severe anxiety and PTSD that prevented him from going through with bariatric surgery. He then underwent an endoscopic weight loss procedure. The ESG helped him successfully achieve significant weight loss, increase his physical activity, reduce his anxiety and panic disorder, and overall, significantly improve his quality of life. More than 1 year after the procedure, the patient has sustained improvements in his psychiatric and emotional health along with durable weight loss, maintaining > 15% of his total weight lost. Additional studies are needed to further understand the prevalence and long-term outcomes of mental health comorbidities, as well as weight loss outcomes in this group of patients who undergo endoscopic bariatric procedures.

CONCLUSIONS

We describe a case of a veteran with severe obesity and significant psychiatric comorbidities that prevented him from undergoing bariatric surgery, who underwent an ESG. This procedure led to significant weight loss, improvement of metabolic parameters, reduction in anxiety and PTSD, and enhancement of his quality of life. This case emphasizes the unique advantages of ESG and supports the expansion of endoscopic bariatric programs in the VA.

Obesity is a growing worldwide epidemic with significant implications for individual health and public health care costs. It is also associated with several medical conditions, including diabetes, cardiovascular disease, cancer, and mental health disorders.¹ Comprehensive lifestyle intervention is a first-line therapy for obesity consisting of dietary and exercise interventions. Despite initial success, long-term results and durability of weight loss with lifestyle modifications are limited. ² Bariatric surgery, including sleeve gastrectomy and gastric bypass surgery, is a more invasive approach that is highly effective in weight loss. However, these operations are not reversible, and patients may not be eligible for or may not desire surgery. Overall, bariatric surgery is widely underutilized, with < 1% of eligible patients ultimately undergoing surgery.^3,4

Endoscopic bariatric therapies are increasingly popular procedures that address the need for additional treatments for obesity among individuals who have not had success with lifestyle changes and are not surgical candidates. The most common procedure is the endoscopic sleeve gastroplasty (ESG), which applies full-thickness sutures in the stomach to reduce gastric volume, delay gastric emptying, and limit food intake while keeping the fundus intact compared with sleeve gastrectomy. This procedure is typically considered in patients with body mass index (BMI) ≥ 30, who do not qualify for or do not want traditional bariatric surgery. The literature supports robust outcomes after ESG, with studies demonstrating significant and sustained total body weight loss of up to 14% to 16% at 5 years and significant improvement in ≥ 1 metabolic comorbidities in 80% of patients.^5,6 ESG adverse events (AEs) include abdominal pain, nausea, and vomiting that are typically self-limited to 1 week. Rarer but more serious AEs include bleeding, perforation, or infection, and occur in 2% of cases based on large trial data.^5,7

Although the weight loss benefits of ESG are well established, to date, there are limited data on the effects of endoscopic bariatric therapies like ESG on mental health conditions. Here, we describe a case of a veteran with a history of mental health disorders that prevented him from completing bariatric surgery. The patient underwent ESG and had a successful clinical course.

CASE PRESENTATION

A 59-year-old male veteran with a medical history of class III obesity (42.4 BMI), obstructive sleep apnea, hypothyroidism, hypertension, type 2 diabetes mellitus, and a large ventral hernia was referred to the MOVE! (Management of Overweight/ Obese Veterans Everywhere!) multidisciplinary high-intensity weight loss program at the US Department of Veterans Affairs (VA) West Los Angeles VA Medical Center (WLAVAMC). His psychiatric history included generalized anxiety disorder, posttraumatic stress disorder (PTSD), and panic disorder, managed by the Psychiatry Service and treated with sertraline 25 mg daily, lorazepam 0.5 mg twice daily, and hydroxyzine 20 mg nightly. He had previously implemented lifestyle changes and attended MOVE! classes and nutrition coaching for 1 year but was unsuccessful in losing weight. He had also tried liraglutide 3 mg daily for weight loss but was unable to tolerate it and reported worsening medication-related anxiety.

The patient declined further weight loss pharmacotherapy and was referred to bariatric surgery. He was scheduled for a surgical sleeve gastrectomy. However, on the day he arrived at the hospital for surgery, he developed severe anxiety and had a panic attack, and it was canceled. Due to his mental health issues, he was no longer comfortable proceeding with surgery and was left without other options for obesity treatment. The veteran was extremely disappointed because the ventral hernia caused significant quality of life impairment, limited his ability to exercise, and caused him embarrassment in public settings. The hernia could not be surgically repaired until there was significant weight loss.

A bariatric endoscopy program within the Division of Gastroenterology was developed and implemented at the WLAVAMC in February 2023 in conjunction with MOVE! The patient was referred for consideration of an endoscopic weight loss procedure. He was determined to be a suitable candidate for ESG based on his BMI being > 40 and personal preference not to proceed with surgery to lose enough weight to qualify for hernia repair. The veteran underwent an endoscopy, which showed normal anatomy and gastric mucosa. ESG was performed in standard fashion (Figure).⁸ Three vertical lines were made using argon plasma coagulation from the incisura to 2 cm below the gastroesophageal junction along the anterior, posterior, and greater curvature of the stomach to mark the area for endoscopic suture placement. Starting at the incisura, 7 full-thickness sutures were placed to create a volume reduction plication, with preservation of the fundus. The patient did well postprocedure with no immediate or delayed AEs and was discharged home the same day.

Follow-up

The veteran followed a gradual dietary advancement from a clear liquid diet to pureed and soft texture food. The patient’s weight dropped from 359 lbs preprocedure to 304 lbs 6 months postprocedure, a total body weight loss (TWBL) of 15.3%. At 12 months the veteran weighed 299 lbs (16.7% TBWL). He also had notable improvements in metabolic parameters. His systolic blood pressure decreased from ≥ 140 mm Hg to 120 to 130 mm Hg and hemoglobin A_1c dropped from 7.0% to 6.3%. Remarkably, his psychiatrist noted significant improvement in his overall mental health. The veteran reported complete cessation of panic attacks since the ESG, improvements in PTSD and anxiety, and was able to discontinue lorazepam and decrease his dose of sertraline to 12.5 mg daily. He reported feeling more energetic and goal-oriented with increased clarity of thought. Perhaps the most significant outcome was that after the 55-lb weight loss at 6 months, the patient was eligible to undergo ventral hernia surgical repair, which had previously contributed to shame and social isolation. This, in turn, improved his quality of life, allowed him to start walking again, up to 8 miles daily, and to feel comfortable again going out in public settings.

DISCUSSION

Bariatric surgeries are an effective method of achieving weight loss and improving obesity-related comorbidities. However, only a small percentage of individuals with obesity are candidates for bariatric surgery. Given the dramatic increase in the prevalence of obesity, other options are needed. Specifically, within the VA, an estimated 80% of veterans are overweight or obese, but only about 500 bariatric surgeries are performed annually.⁹ With the need for additional weight loss therapies, VA programs are starting to offer endoscopic bariatric procedures as an alternative option. This may be a desirable choice for patients with obesity (BMI > 30), with or without associated metabolic comorbidities, who need more aggressive intervention beyond dietary and lifestyle changes and are either not interested in or not eligible for bariatric surgery or weight loss medications.

Although there is evidence that metabolic comorbidities are associated with obesity, there has been less research on obesity and mental health comorbidities such as depression and anxiety. These psychiatric conditions may even be more common among patients seeking weight loss procedures and more prominent in certain groups such as veterans, which may ultimately exclude these patients from bariatric surgery.¹⁰ Prior studies suggest that bariatric surgery can reduce the severity of depression and, to a lesser extent, anxiety symptoms at 2 years following the initial surgery; however, there is limited literature describing the impact of weight loss procedure on panic disorders.^11-14 We suspect that a weight loss procedure such as ESG may have indirectly improved the veteran’s mood disorder due to the weight loss it induced, increasing the ability to exercise, quality of sleep, and participation in public settings.

This case highlights a veteran who did not tolerate weight loss medication and had severe anxiety and PTSD that prevented him from going through with bariatric surgery. He then underwent an endoscopic weight loss procedure. The ESG helped him successfully achieve significant weight loss, increase his physical activity, reduce his anxiety and panic disorder, and overall, significantly improve his quality of life. More than 1 year after the procedure, the patient has sustained improvements in his psychiatric and emotional health along with durable weight loss, maintaining > 15% of his total weight lost. Additional studies are needed to further understand the prevalence and long-term outcomes of mental health comorbidities, as well as weight loss outcomes in this group of patients who undergo endoscopic bariatric procedures.

CONCLUSIONS

We describe a case of a veteran with severe obesity and significant psychiatric comorbidities that prevented him from undergoing bariatric surgery, who underwent an ESG. This procedure led to significant weight loss, improvement of metabolic parameters, reduction in anxiety and PTSD, and enhancement of his quality of life. This case emphasizes the unique advantages of ESG and supports the expansion of endoscopic bariatric programs in the VA.

Podocytes are terminally differentiated, highly specialized cells located in juxtaposition to the basement membrane over the abluminal surfaces of endothelial cells within the glomerular tuft. This triad structure is the site of the filtration barrier, which forms highly delicate and tightly regulated architecture to carry out the ultrafiltration function of the kidney.¹ The filtration barrier is characterized by foot processes that are connected by specialized junctions called slit diaphragms.

Insults to components of the filtration barrier can initiate cascading events and perpetuate structural alterations that may eventually result in sclerotic changes.² Common causes among children include minimal change disease (MCD) with the collapse of foot processes resulting in proteinuria, Alport syndrome due to mutation of collagen fibers within the basement membrane leading to hematuria and proteinuria, immune complex mediated nephropathy following common infections or autoimmune diseases, and focal segmental glomerulosclerosis (FSGS) that can show variable histopathology toward eventual glomerular scarring.^3,4 These children often clinically have minimal, if any, signs of systemic inflammation.^3-5 This has been a limiting factor for the commitment to immunomodulatory treatment, except for steroids for the treatment of MCD.⁶ Although prolonged steroid treatment may be efficacious, adverse effects are significant in a growing child. Alternative treatments, such as tacrolimus and rituximab have been suggested as second-line steroid-sparing agents.^7,8 Not uncommonly, however, these cases are managed by supportive measures only during the progression of the natural course of the disease, which may eventually lead to renal failure, requiring transplant for survival.^8,9

This case report highlights a child with a variant of uncertain significance (VUS) in genes involved in Alport syndrome and FSGS who developed an abrupt onset of proteinuria and hematuria after a respiratory illness. To our knowledge, he represents the youngest case demonstrating the benefit of targeted treatment against tumor necrosis factor-α (TNF-α) for glomerulopathy using biologic response modifiers.

Case Description

This is currently a 7-year-old male patient who was born at 39 weeks gestation to gravida 3 para 3 following induced labor due to elevated maternal blood pressure. During the first 2 years of life, his growth and development were normal and his immunizations were up to date. The patient's medical history included upper respiratory tract infections (URIs), respiratory syncytial virus, as well as 3 bouts of pneumonia and multiple otitis media that resulted in 18 rounds of antibiotics. The child was also allergic to nuts and milk protein. The patient’s parents are of Northern European and Native American descent. There is no known family history of eye, ear, or kidney diseases.

Renal concerns were first noted at the age of 2 years and 6 months when he presented to an emergency department in Fall 2019 (week 0) for several weeks of intermittent dark-colored urine. His mother reported that the discoloration recently progressed in intensity to cola-colored, along with the onset of persistent vomiting without any fever or diarrhea. On physical examination, the patient had normal vitals: weight 14.8 kg (68th percentile), height 91 cm (24th percentile), and body surface area 0.6 m². There was no edema, rash, or lymphadenopathy, but he appeared pale.
 

The patient’s initial laboratory results included: complete blood count with white blood cells (WBC) 10 x 10³/L (reference range, 4.5-13.5 x 10³/L); differential lymphocytes 69%; neutrophils 21%; hemoglobin 10 g/dL (reference range, 12-16 g/dL); hematocrit, 30%; (reference range, 37%-45%); platelets 437 10³/L (reference range, 150-450 x 10³/L); serum creatinine 0.46 mg/dL (reference range, 0.5-0.9 mg/dL); and albumin 3.1 g/dL (reference range, 3.5-5.2 g/dL). Serum electrolyte levels and liver enzymes were normal. A urine analysis revealed 3+ protein and 3+ blood with dysmorphic red blood cells (RBC) and RBC casts without WBC. The patient's spot urine protein-to-creatinine ratio was 4.3 and his renal ultrasound was normal. The patient was referred to Nephrology.

During the next 2 weeks, his protein-to-creatinine ratio progressed to 5.9 and serum albumin fell to 2.7 g/dL. His urine remained red colored, and a microscopic examination with RBC > 500 and WBC up to 10 on a high powered field. His workup was negative for antinuclear antibodies, antineutrophil cytoplasmic antibody, antistreptolysin-O (ASO) and anti-DNase B. Serum C3 was low at 81 mg/dL (reference range, 90-180 mg/dL), C4 was 13.3 mg/dL (reference range, 10-40 mg/dL), and immunoglobulin G was low at 452 mg/dL (reference range 719-1475 mg/dL). A baseline audiology test revealed normal hearing.

Percutaneous renal biopsy yielded about 12 glomeruli, all exhibiting mild mesangial matrix expansion and hypercellularity (Figure 1). One glomerulus had prominent parietal epithelial cells without endocapillary hypercellularity or crescent formation. There was no interstitial fibrosis or tubular atrophy. Immunofluorescence studies showed no evidence of immune complex deposition with negative staining for immunoglobulin heavy and light chains, C3 and C1q. Staining for α 2 and α 5 units of collagen was normal. Electron microscopy showed patchy areas of severe basement membrane thinning with frequent foci of mild to moderate lamina densa splitting and associated visceral epithelial cell foot process effacement (Figure 2).

These were reported as concerning findings for possible Alport syndrome by 3 independent pathology teams. The genetic testing was submitted at a commercial laboratory to screen 17 mutations, including COL4A3, COL4A4, and COL4A5. Results showed the presence of a heterozygous VUS in the COL4A4 gene (c.1055C > T; p.Pro352Leu; dbSNP ID: rs371717486; PolyPhen-2: Probably Damaging; SIFT: Deleterious) as well as the presence of a heterozygous VUS in TRPC6 gene (c2463A>T; p.Lys821Asn; dbSNP ID: rs199948731; PolyPhen-2: Benign; SIFT: Tolerated). Further genetic investigation by whole exome sequencing on approximately 20,000 genes through MNG Laboratories showed a new heterozygous VUS in the OSGEP gene [c.328T>C; p.Cys110Arg]. Additional studies ruled out mitochondrial disease, CoQ10 deficiency, and metabolic disorders upon normal findings for mitochondrial DNA, urine amino acids, plasma acylcarnitine profile, orotic acid, ammonia, and homocysteine levels.

Figure 3 summarizes the patient’s treatment response during 170 weeks of follow-up (Fall 2019 to Summer 2023). The patient was started on enalapril 0.6 mg/kg daily at week 3, which continued throughout treatment. Following a rheumatology consult at week 30, the patient was started on prednisolone 3 mg/mL to assess the role of inflammation through the treatment response. An initial dose of 2 mg/kg daily (9 mL) for 1 month was followed by every other day treatment that was tapered off by week 48. To control mild but noticeably increasing proteinuria in the interim, subcutaneous anakinra 50 mg (3 mg/kg daily) was added as a steroid-sparing agent at week 39 and increased to 100mg daily by week 41.His urine proteintocreatinineratiodecreasedfrom 1.720 to 0.575, andserumalbuminnormalizedbyweek 53. At that time, due to the patient’s up-trending proteinuria after a URI, as well as concerns for injection site skin reaction and quality of life on daily subcutaneous treatment, anakinra was substituted with subcutaneous adalimumab 20 mg every 2 weeks.

By week 80,the patient’s urineproteintocreatininerationormalized (< 0.2). Thiswasfollowedbynormalizedurine microalbumintocreatinineratio, andbyweek 130 hismicroscopichematuriaresolved. While onadalimumab, heremainedwellandwasabletomountan immune response to viralinfectionsuneventfully,including COVID-19. He tolerated agradual wean of adalimumab to every 3 weeks by week 139 and discontinuation at week 151. At week 204, the patient has normal renal function and urine findings; his growth parameters are at 20.3 percentile for weight and 15.3percentile for height.

DISCUSSION

This case describes a child with rapidly progressive proteinuria and hematuria following a URI who was found to have VUS mutations in 3 different genes associated with chronic kidney disease. Serology tests on the patient were negative for streptococcal antibodies and antinuclear antibodies, ruling out poststreptococcal glomerulonephritis, or systemic lupus erythematosus. His renal biopsy findings were concerning for altered podocytes, mesangial cells, and basement membrane without inflammatory infiltrate, immune complex, complements, immunoglobulin A, or vasculopathy. His blood inflammatory markers, erythrocyte sedimentation rate, C-reactive protein, and ferritin were normal when his care team initiated daily steroids.

Overall, the patient’s clinical presentation and histopathology findings were suggestive of Alport syndrome or thin basement membrane nephropathy with a high potential to progress into FSGS.^10-12 Alport syndrome affects 1 in 5000 to 10,000 children annually due to S-linked inheritance of COL4A5, or autosomal recessive inheritance of COL4A3 or COL4A4 genes. It presents with hematuria and hearing loss.¹⁰ Our patient had a single copy COL4A4 gene mutation that was classified as VUS. He also had 2 additional VUS affecting the TRPC6 and OSGEP genes. TRPC6 gene mutation can be associated with FSGS through autosomal dominant inheritance. Both COL4A4 and TRPC6 gene mutations were paternally inherited. Although the patient’s father not having renal disease argues against the clinical significance of these findings, there is literature on the potential role of heterozygous COL4A4 variant mimicking thin basement membrane nephropathy that can lead to renal impairment upon copresence of superimposed conditions.¹³ The patient’s rapidly progressing hematuria and changes in the basement membrane were worrisome for emerging FSGS. Furthermore, VUS of TRPC6 has been reported in late onset autosomal dominant FSGS and can be associated with early onset steroid-resistant nephrotic syndrome (NS) in children.¹⁴ This concern was voiced by 3 nephrology consultants during the initial evaluation, leading to the consensus that steroid treatment for podocytopathy would not alter the patient’s long-term outcomes (ie, progression to FSGS).

Immunomodulation

Our rationale for immunomodulatory treatment was based on the abrupt onset of renal concerns following a URI, suggesting the importance of an inflammatory trigger causing altered homeostasis in a genetically susceptible host. Preclinical models show that microbial products such as lipopolysaccharides can lead to podocytopathy by several mechanisms through activation of toll-like receptor signaling. It can directly cause apoptosis by downregulation of the intracellular Akt survival pathway.¹⁵ Lipopolysaccharide can also activate the NF-αB pathway and upregulate the production of interleukin-1 (IL-1) and TNF-α in mesangial cells.^16,17

Both cytokines can promote mesangial cell proliferation.¹⁸ Through autocrine and paracrine mechanisms, proinflammatory cytokines can further perpetuate somatic tissue changes and contribute to the development of podocytopathy. For instance, TNF-α can promote podocyte injury and proteinuria by downregulation of the slit diaphragm protein expression (ie, nephrin, ezrin, or podocin), and disruption of podocyte cytoskeleton.^19,20 TNF-α promotes the influx and activation of macrophages and inflammatory cells. It is actively involved in chronic alterations within the glomeruli by the upregulation of matrix metalloproteases by integrins, as well as activation of myofibroblast progenitors and extracellular matrix deposition in crosstalk with transforming growth factor and other key mediators.^17,21,22

For the patient described in this case report, initial improvement on steroids encouraged the pursuit of additional treatment to downregulate inflammatory pathways within the glomerular milieu. However, within the COVID-19 environment, escalating the patient’s treatment using traditional immunomodulators (ie, calcineurin inhibitors or mycophenolate mofetil) was not favored due to the risk of infection. Initially, anakinra, a recombinant IL-1 receptor antagonist, was preferred as a steroid-sparing agent for its short life and safety profile during the pandemic. At first, the patient responded well to anakinra and was allowed a steroid wean when the dose was titrated up to 6 mg/kg daily. However, anakinra did not prevent the escalation of proteinuria following a URI. After the treatment was changed to adalimumab, a fully humanized monoclonal antibody to TNF-α, the patient continued to improve and reach full remission despite experiencing a cold and the flu in the following months.

Literature Review

There is a paucity of literature on applications of biological response modifiers for idiopathic NS and FSGS.^23,24 Angeletti and colleagues reported that 3 patients with severe long-standing FSGS benefited from anakinra 4 mg/kg daily to reduce proteinuria and improve kidney function. All the patients had positive C3 staining in renal biopsy and treatment response, which supported the role of C3a in inducing podocyte injury through upregulated expression of IL-1 and IL-1R.²³ Trachtman and colleagues reported on the phase II FONT trial that included 14 of 21 patients aged < 18 years with advanced FSGS who were treated with adalimumab 24 mg/m², or ≤ 40 mg every other week.²⁴ Although, during a 6-month period, none of the 7 patients met the endpoint of reduced proteinuria by ≥ 50%, and the authors suggested that careful patient selection may improve the treatment response in future trials.²⁴

A recent study involving transcriptomics on renal tissue samples combined with available pathology (fibrosis), urinary markers, and clinical characteristics on 285 patients with MCD or FSGS from 3 different continents identified 3 distinct clusters. Patients with evidence of activated kidney TNF pathway (n = 72, aged > 18 years) were found to have poor clinical outcomes.²⁵ The study identified 2 urine markers associated with the TNF pathway (ie, tissue inhibitor of metalloproteinases-1 and monocyte chemoattractant protein-1), which aligns with the preclinical findings previously mentioned.²⁵

Conclusions

The patient’s condition in this case illustrates the complex nature of biologically predetermined cascading events in the emergence of glomerular disease upon environmental triggers under the influence of genetic factors. Observations on this child’s treatment response suggest that downregulation of somatic tissue-driven proinflammatory milieu originating from the constituents of glomerular microenvironment can help in recovery from emerging podocytopathy. The prolonged time span and stepwise resolution of proteinuria, followed by microalbuminuria (data not shown), and finally microscopic hematuria, supports the delicate balance and presence of reciprocal feedback loops between the podocytes and mesangial cells. Within this framework, blocking TNF-α, even temporarily, may allow time for the de novo regenerative process to prevail.

Chronic kidney disease affects 7.7% of veterans annually, illustrating the need for new therapeutics.²⁶ Based on our experience and literature review, upregulation of TNF-α is a root cause of glomerulopathy; further studies are warranted to evaluate the efficacy of anti-TNF biologic response modifiers for the treatment of these patients. Long-term postmarketing safety profile and steroid-sparing properties of adalimumab should allow inclusion of pediatric cases in future trials. Results may also contribute to identifying new predictive biomarkers related to the basement membrane when combined with precision nephrology to further advance patient selection and targeted treatment.^25,27

Acknowledgments

The authors thank the patient’s mother for providing consent to allow publication of this case report.

Podocytes are terminally differentiated, highly specialized cells located in juxtaposition to the basement membrane over the abluminal surfaces of endothelial cells within the glomerular tuft. This triad structure is the site of the filtration barrier, which forms highly delicate and tightly regulated architecture to carry out the ultrafiltration function of the kidney.¹ The filtration barrier is characterized by foot processes that are connected by specialized junctions called slit diaphragms.

Insults to components of the filtration barrier can initiate cascading events and perpetuate structural alterations that may eventually result in sclerotic changes.² Common causes among children include minimal change disease (MCD) with the collapse of foot processes resulting in proteinuria, Alport syndrome due to mutation of collagen fibers within the basement membrane leading to hematuria and proteinuria, immune complex mediated nephropathy following common infections or autoimmune diseases, and focal segmental glomerulosclerosis (FSGS) that can show variable histopathology toward eventual glomerular scarring.^3,4 These children often clinically have minimal, if any, signs of systemic inflammation.^3-5 This has been a limiting factor for the commitment to immunomodulatory treatment, except for steroids for the treatment of MCD.⁶ Although prolonged steroid treatment may be efficacious, adverse effects are significant in a growing child. Alternative treatments, such as tacrolimus and rituximab have been suggested as second-line steroid-sparing agents.^7,8 Not uncommonly, however, these cases are managed by supportive measures only during the progression of the natural course of the disease, which may eventually lead to renal failure, requiring transplant for survival.^8,9

This case report highlights a child with a variant of uncertain significance (VUS) in genes involved in Alport syndrome and FSGS who developed an abrupt onset of proteinuria and hematuria after a respiratory illness. To our knowledge, he represents the youngest case demonstrating the benefit of targeted treatment against tumor necrosis factor-α (TNF-α) for glomerulopathy using biologic response modifiers.

Case Description

This is currently a 7-year-old male patient who was born at 39 weeks gestation to gravida 3 para 3 following induced labor due to elevated maternal blood pressure. During the first 2 years of life, his growth and development were normal and his immunizations were up to date. The patient's medical history included upper respiratory tract infections (URIs), respiratory syncytial virus, as well as 3 bouts of pneumonia and multiple otitis media that resulted in 18 rounds of antibiotics. The child was also allergic to nuts and milk protein. The patient’s parents are of Northern European and Native American descent. There is no known family history of eye, ear, or kidney diseases.

Renal concerns were first noted at the age of 2 years and 6 months when he presented to an emergency department in Fall 2019 (week 0) for several weeks of intermittent dark-colored urine. His mother reported that the discoloration recently progressed in intensity to cola-colored, along with the onset of persistent vomiting without any fever or diarrhea. On physical examination, the patient had normal vitals: weight 14.8 kg (68th percentile), height 91 cm (24th percentile), and body surface area 0.6 m². There was no edema, rash, or lymphadenopathy, but he appeared pale.
 

The patient’s initial laboratory results included: complete blood count with white blood cells (WBC) 10 x 10³/L (reference range, 4.5-13.5 x 10³/L); differential lymphocytes 69%; neutrophils 21%; hemoglobin 10 g/dL (reference range, 12-16 g/dL); hematocrit, 30%; (reference range, 37%-45%); platelets 437 10³/L (reference range, 150-450 x 10³/L); serum creatinine 0.46 mg/dL (reference range, 0.5-0.9 mg/dL); and albumin 3.1 g/dL (reference range, 3.5-5.2 g/dL). Serum electrolyte levels and liver enzymes were normal. A urine analysis revealed 3+ protein and 3+ blood with dysmorphic red blood cells (RBC) and RBC casts without WBC. The patient's spot urine protein-to-creatinine ratio was 4.3 and his renal ultrasound was normal. The patient was referred to Nephrology.

During the next 2 weeks, his protein-to-creatinine ratio progressed to 5.9 and serum albumin fell to 2.7 g/dL. His urine remained red colored, and a microscopic examination with RBC > 500 and WBC up to 10 on a high powered field. His workup was negative for antinuclear antibodies, antineutrophil cytoplasmic antibody, antistreptolysin-O (ASO) and anti-DNase B. Serum C3 was low at 81 mg/dL (reference range, 90-180 mg/dL), C4 was 13.3 mg/dL (reference range, 10-40 mg/dL), and immunoglobulin G was low at 452 mg/dL (reference range 719-1475 mg/dL). A baseline audiology test revealed normal hearing.

Percutaneous renal biopsy yielded about 12 glomeruli, all exhibiting mild mesangial matrix expansion and hypercellularity (Figure 1). One glomerulus had prominent parietal epithelial cells without endocapillary hypercellularity or crescent formation. There was no interstitial fibrosis or tubular atrophy. Immunofluorescence studies showed no evidence of immune complex deposition with negative staining for immunoglobulin heavy and light chains, C3 and C1q. Staining for α 2 and α 5 units of collagen was normal. Electron microscopy showed patchy areas of severe basement membrane thinning with frequent foci of mild to moderate lamina densa splitting and associated visceral epithelial cell foot process effacement (Figure 2).

These were reported as concerning findings for possible Alport syndrome by 3 independent pathology teams. The genetic testing was submitted at a commercial laboratory to screen 17 mutations, including COL4A3, COL4A4, and COL4A5. Results showed the presence of a heterozygous VUS in the COL4A4 gene (c.1055C > T; p.Pro352Leu; dbSNP ID: rs371717486; PolyPhen-2: Probably Damaging; SIFT: Deleterious) as well as the presence of a heterozygous VUS in TRPC6 gene (c2463A>T; p.Lys821Asn; dbSNP ID: rs199948731; PolyPhen-2: Benign; SIFT: Tolerated). Further genetic investigation by whole exome sequencing on approximately 20,000 genes through MNG Laboratories showed a new heterozygous VUS in the OSGEP gene [c.328T>C; p.Cys110Arg]. Additional studies ruled out mitochondrial disease, CoQ10 deficiency, and metabolic disorders upon normal findings for mitochondrial DNA, urine amino acids, plasma acylcarnitine profile, orotic acid, ammonia, and homocysteine levels.

Figure 3 summarizes the patient’s treatment response during 170 weeks of follow-up (Fall 2019 to Summer 2023). The patient was started on enalapril 0.6 mg/kg daily at week 3, which continued throughout treatment. Following a rheumatology consult at week 30, the patient was started on prednisolone 3 mg/mL to assess the role of inflammation through the treatment response. An initial dose of 2 mg/kg daily (9 mL) for 1 month was followed by every other day treatment that was tapered off by week 48. To control mild but noticeably increasing proteinuria in the interim, subcutaneous anakinra 50 mg (3 mg/kg daily) was added as a steroid-sparing agent at week 39 and increased to 100mg daily by week 41.His urine proteintocreatinineratiodecreasedfrom 1.720 to 0.575, andserumalbuminnormalizedbyweek 53. At that time, due to the patient’s up-trending proteinuria after a URI, as well as concerns for injection site skin reaction and quality of life on daily subcutaneous treatment, anakinra was substituted with subcutaneous adalimumab 20 mg every 2 weeks.

By week 80,the patient’s urineproteintocreatininerationormalized (< 0.2). Thiswasfollowedbynormalizedurine microalbumintocreatinineratio, andbyweek 130 hismicroscopichematuriaresolved. While onadalimumab, heremainedwellandwasabletomountan immune response to viralinfectionsuneventfully,including COVID-19. He tolerated agradual wean of adalimumab to every 3 weeks by week 139 and discontinuation at week 151. At week 204, the patient has normal renal function and urine findings; his growth parameters are at 20.3 percentile for weight and 15.3percentile for height.

DISCUSSION

This case describes a child with rapidly progressive proteinuria and hematuria following a URI who was found to have VUS mutations in 3 different genes associated with chronic kidney disease. Serology tests on the patient were negative for streptococcal antibodies and antinuclear antibodies, ruling out poststreptococcal glomerulonephritis, or systemic lupus erythematosus. His renal biopsy findings were concerning for altered podocytes, mesangial cells, and basement membrane without inflammatory infiltrate, immune complex, complements, immunoglobulin A, or vasculopathy. His blood inflammatory markers, erythrocyte sedimentation rate, C-reactive protein, and ferritin were normal when his care team initiated daily steroids.

Overall, the patient’s clinical presentation and histopathology findings were suggestive of Alport syndrome or thin basement membrane nephropathy with a high potential to progress into FSGS.^10-12 Alport syndrome affects 1 in 5000 to 10,000 children annually due to S-linked inheritance of COL4A5, or autosomal recessive inheritance of COL4A3 or COL4A4 genes. It presents with hematuria and hearing loss.¹⁰ Our patient had a single copy COL4A4 gene mutation that was classified as VUS. He also had 2 additional VUS affecting the TRPC6 and OSGEP genes. TRPC6 gene mutation can be associated with FSGS through autosomal dominant inheritance. Both COL4A4 and TRPC6 gene mutations were paternally inherited. Although the patient’s father not having renal disease argues against the clinical significance of these findings, there is literature on the potential role of heterozygous COL4A4 variant mimicking thin basement membrane nephropathy that can lead to renal impairment upon copresence of superimposed conditions.¹³ The patient’s rapidly progressing hematuria and changes in the basement membrane were worrisome for emerging FSGS. Furthermore, VUS of TRPC6 has been reported in late onset autosomal dominant FSGS and can be associated with early onset steroid-resistant nephrotic syndrome (NS) in children.¹⁴ This concern was voiced by 3 nephrology consultants during the initial evaluation, leading to the consensus that steroid treatment for podocytopathy would not alter the patient’s long-term outcomes (ie, progression to FSGS).

Immunomodulation

Our rationale for immunomodulatory treatment was based on the abrupt onset of renal concerns following a URI, suggesting the importance of an inflammatory trigger causing altered homeostasis in a genetically susceptible host. Preclinical models show that microbial products such as lipopolysaccharides can lead to podocytopathy by several mechanisms through activation of toll-like receptor signaling. It can directly cause apoptosis by downregulation of the intracellular Akt survival pathway.¹⁵ Lipopolysaccharide can also activate the NF-αB pathway and upregulate the production of interleukin-1 (IL-1) and TNF-α in mesangial cells.^16,17

Both cytokines can promote mesangial cell proliferation.¹⁸ Through autocrine and paracrine mechanisms, proinflammatory cytokines can further perpetuate somatic tissue changes and contribute to the development of podocytopathy. For instance, TNF-α can promote podocyte injury and proteinuria by downregulation of the slit diaphragm protein expression (ie, nephrin, ezrin, or podocin), and disruption of podocyte cytoskeleton.^19,20 TNF-α promotes the influx and activation of macrophages and inflammatory cells. It is actively involved in chronic alterations within the glomeruli by the upregulation of matrix metalloproteases by integrins, as well as activation of myofibroblast progenitors and extracellular matrix deposition in crosstalk with transforming growth factor and other key mediators.^17,21,22

For the patient described in this case report, initial improvement on steroids encouraged the pursuit of additional treatment to downregulate inflammatory pathways within the glomerular milieu. However, within the COVID-19 environment, escalating the patient’s treatment using traditional immunomodulators (ie, calcineurin inhibitors or mycophenolate mofetil) was not favored due to the risk of infection. Initially, anakinra, a recombinant IL-1 receptor antagonist, was preferred as a steroid-sparing agent for its short life and safety profile during the pandemic. At first, the patient responded well to anakinra and was allowed a steroid wean when the dose was titrated up to 6 mg/kg daily. However, anakinra did not prevent the escalation of proteinuria following a URI. After the treatment was changed to adalimumab, a fully humanized monoclonal antibody to TNF-α, the patient continued to improve and reach full remission despite experiencing a cold and the flu in the following months.

Literature Review

There is a paucity of literature on applications of biological response modifiers for idiopathic NS and FSGS.^23,24 Angeletti and colleagues reported that 3 patients with severe long-standing FSGS benefited from anakinra 4 mg/kg daily to reduce proteinuria and improve kidney function. All the patients had positive C3 staining in renal biopsy and treatment response, which supported the role of C3a in inducing podocyte injury through upregulated expression of IL-1 and IL-1R.²³ Trachtman and colleagues reported on the phase II FONT trial that included 14 of 21 patients aged < 18 years with advanced FSGS who were treated with adalimumab 24 mg/m², or ≤ 40 mg every other week.²⁴ Although, during a 6-month period, none of the 7 patients met the endpoint of reduced proteinuria by ≥ 50%, and the authors suggested that careful patient selection may improve the treatment response in future trials.²⁴

A recent study involving transcriptomics on renal tissue samples combined with available pathology (fibrosis), urinary markers, and clinical characteristics on 285 patients with MCD or FSGS from 3 different continents identified 3 distinct clusters. Patients with evidence of activated kidney TNF pathway (n = 72, aged > 18 years) were found to have poor clinical outcomes.²⁵ The study identified 2 urine markers associated with the TNF pathway (ie, tissue inhibitor of metalloproteinases-1 and monocyte chemoattractant protein-1), which aligns with the preclinical findings previously mentioned.²⁵

Conclusions

The patient’s condition in this case illustrates the complex nature of biologically predetermined cascading events in the emergence of glomerular disease upon environmental triggers under the influence of genetic factors. Observations on this child’s treatment response suggest that downregulation of somatic tissue-driven proinflammatory milieu originating from the constituents of glomerular microenvironment can help in recovery from emerging podocytopathy. The prolonged time span and stepwise resolution of proteinuria, followed by microalbuminuria (data not shown), and finally microscopic hematuria, supports the delicate balance and presence of reciprocal feedback loops between the podocytes and mesangial cells. Within this framework, blocking TNF-α, even temporarily, may allow time for the de novo regenerative process to prevail.

Chronic kidney disease affects 7.7% of veterans annually, illustrating the need for new therapeutics.²⁶ Based on our experience and literature review, upregulation of TNF-α is a root cause of glomerulopathy; further studies are warranted to evaluate the efficacy of anti-TNF biologic response modifiers for the treatment of these patients. Long-term postmarketing safety profile and steroid-sparing properties of adalimumab should allow inclusion of pediatric cases in future trials. Results may also contribute to identifying new predictive biomarkers related to the basement membrane when combined with precision nephrology to further advance patient selection and targeted treatment.^25,27

Acknowledgments

The authors thank the patient’s mother for providing consent to allow publication of this case report.

Podocytes are terminally differentiated, highly specialized cells located in juxtaposition to the basement membrane over the abluminal surfaces of endothelial cells within the glomerular tuft. This triad structure is the site of the filtration barrier, which forms highly delicate and tightly regulated architecture to carry out the ultrafiltration function of the kidney.¹ The filtration barrier is characterized by foot processes that are connected by specialized junctions called slit diaphragms.

Insults to components of the filtration barrier can initiate cascading events and perpetuate structural alterations that may eventually result in sclerotic changes.² Common causes among children include minimal change disease (MCD) with the collapse of foot processes resulting in proteinuria, Alport syndrome due to mutation of collagen fibers within the basement membrane leading to hematuria and proteinuria, immune complex mediated nephropathy following common infections or autoimmune diseases, and focal segmental glomerulosclerosis (FSGS) that can show variable histopathology toward eventual glomerular scarring.^3,4 These children often clinically have minimal, if any, signs of systemic inflammation.^3-5 This has been a limiting factor for the commitment to immunomodulatory treatment, except for steroids for the treatment of MCD.⁶ Although prolonged steroid treatment may be efficacious, adverse effects are significant in a growing child. Alternative treatments, such as tacrolimus and rituximab have been suggested as second-line steroid-sparing agents.^7,8 Not uncommonly, however, these cases are managed by supportive measures only during the progression of the natural course of the disease, which may eventually lead to renal failure, requiring transplant for survival.^8,9

This case report highlights a child with a variant of uncertain significance (VUS) in genes involved in Alport syndrome and FSGS who developed an abrupt onset of proteinuria and hematuria after a respiratory illness. To our knowledge, he represents the youngest case demonstrating the benefit of targeted treatment against tumor necrosis factor-α (TNF-α) for glomerulopathy using biologic response modifiers.

Case Description

This is currently a 7-year-old male patient who was born at 39 weeks gestation to gravida 3 para 3 following induced labor due to elevated maternal blood pressure. During the first 2 years of life, his growth and development were normal and his immunizations were up to date. The patient's medical history included upper respiratory tract infections (URIs), respiratory syncytial virus, as well as 3 bouts of pneumonia and multiple otitis media that resulted in 18 rounds of antibiotics. The child was also allergic to nuts and milk protein. The patient’s parents are of Northern European and Native American descent. There is no known family history of eye, ear, or kidney diseases.

Renal concerns were first noted at the age of 2 years and 6 months when he presented to an emergency department in Fall 2019 (week 0) for several weeks of intermittent dark-colored urine. His mother reported that the discoloration recently progressed in intensity to cola-colored, along with the onset of persistent vomiting without any fever or diarrhea. On physical examination, the patient had normal vitals: weight 14.8 kg (68th percentile), height 91 cm (24th percentile), and body surface area 0.6 m². There was no edema, rash, or lymphadenopathy, but he appeared pale.
 

The patient’s initial laboratory results included: complete blood count with white blood cells (WBC) 10 x 10³/L (reference range, 4.5-13.5 x 10³/L); differential lymphocytes 69%; neutrophils 21%; hemoglobin 10 g/dL (reference range, 12-16 g/dL); hematocrit, 30%; (reference range, 37%-45%); platelets 437 10³/L (reference range, 150-450 x 10³/L); serum creatinine 0.46 mg/dL (reference range, 0.5-0.9 mg/dL); and albumin 3.1 g/dL (reference range, 3.5-5.2 g/dL). Serum electrolyte levels and liver enzymes were normal. A urine analysis revealed 3+ protein and 3+ blood with dysmorphic red blood cells (RBC) and RBC casts without WBC. The patient's spot urine protein-to-creatinine ratio was 4.3 and his renal ultrasound was normal. The patient was referred to Nephrology.

During the next 2 weeks, his protein-to-creatinine ratio progressed to 5.9 and serum albumin fell to 2.7 g/dL. His urine remained red colored, and a microscopic examination with RBC > 500 and WBC up to 10 on a high powered field. His workup was negative for antinuclear antibodies, antineutrophil cytoplasmic antibody, antistreptolysin-O (ASO) and anti-DNase B. Serum C3 was low at 81 mg/dL (reference range, 90-180 mg/dL), C4 was 13.3 mg/dL (reference range, 10-40 mg/dL), and immunoglobulin G was low at 452 mg/dL (reference range 719-1475 mg/dL). A baseline audiology test revealed normal hearing.

Percutaneous renal biopsy yielded about 12 glomeruli, all exhibiting mild mesangial matrix expansion and hypercellularity (Figure 1). One glomerulus had prominent parietal epithelial cells without endocapillary hypercellularity or crescent formation. There was no interstitial fibrosis or tubular atrophy. Immunofluorescence studies showed no evidence of immune complex deposition with negative staining for immunoglobulin heavy and light chains, C3 and C1q. Staining for α 2 and α 5 units of collagen was normal. Electron microscopy showed patchy areas of severe basement membrane thinning with frequent foci of mild to moderate lamina densa splitting and associated visceral epithelial cell foot process effacement (Figure 2).

These were reported as concerning findings for possible Alport syndrome by 3 independent pathology teams. The genetic testing was submitted at a commercial laboratory to screen 17 mutations, including COL4A3, COL4A4, and COL4A5. Results showed the presence of a heterozygous VUS in the COL4A4 gene (c.1055C > T; p.Pro352Leu; dbSNP ID: rs371717486; PolyPhen-2: Probably Damaging; SIFT: Deleterious) as well as the presence of a heterozygous VUS in TRPC6 gene (c2463A>T; p.Lys821Asn; dbSNP ID: rs199948731; PolyPhen-2: Benign; SIFT: Tolerated). Further genetic investigation by whole exome sequencing on approximately 20,000 genes through MNG Laboratories showed a new heterozygous VUS in the OSGEP gene [c.328T>C; p.Cys110Arg]. Additional studies ruled out mitochondrial disease, CoQ10 deficiency, and metabolic disorders upon normal findings for mitochondrial DNA, urine amino acids, plasma acylcarnitine profile, orotic acid, ammonia, and homocysteine levels.

Figure 3 summarizes the patient’s treatment response during 170 weeks of follow-up (Fall 2019 to Summer 2023). The patient was started on enalapril 0.6 mg/kg daily at week 3, which continued throughout treatment. Following a rheumatology consult at week 30, the patient was started on prednisolone 3 mg/mL to assess the role of inflammation through the treatment response. An initial dose of 2 mg/kg daily (9 mL) for 1 month was followed by every other day treatment that was tapered off by week 48. To control mild but noticeably increasing proteinuria in the interim, subcutaneous anakinra 50 mg (3 mg/kg daily) was added as a steroid-sparing agent at week 39 and increased to 100mg daily by week 41.His urine proteintocreatinineratiodecreasedfrom 1.720 to 0.575, andserumalbuminnormalizedbyweek 53. At that time, due to the patient’s up-trending proteinuria after a URI, as well as concerns for injection site skin reaction and quality of life on daily subcutaneous treatment, anakinra was substituted with subcutaneous adalimumab 20 mg every 2 weeks.

By week 80,the patient’s urineproteintocreatininerationormalized (< 0.2). Thiswasfollowedbynormalizedurine microalbumintocreatinineratio, andbyweek 130 hismicroscopichematuriaresolved. While onadalimumab, heremainedwellandwasabletomountan immune response to viralinfectionsuneventfully,including COVID-19. He tolerated agradual wean of adalimumab to every 3 weeks by week 139 and discontinuation at week 151. At week 204, the patient has normal renal function and urine findings; his growth parameters are at 20.3 percentile for weight and 15.3percentile for height.

DISCUSSION

This case describes a child with rapidly progressive proteinuria and hematuria following a URI who was found to have VUS mutations in 3 different genes associated with chronic kidney disease. Serology tests on the patient were negative for streptococcal antibodies and antinuclear antibodies, ruling out poststreptococcal glomerulonephritis, or systemic lupus erythematosus. His renal biopsy findings were concerning for altered podocytes, mesangial cells, and basement membrane without inflammatory infiltrate, immune complex, complements, immunoglobulin A, or vasculopathy. His blood inflammatory markers, erythrocyte sedimentation rate, C-reactive protein, and ferritin were normal when his care team initiated daily steroids.

Overall, the patient’s clinical presentation and histopathology findings were suggestive of Alport syndrome or thin basement membrane nephropathy with a high potential to progress into FSGS.^10-12 Alport syndrome affects 1 in 5000 to 10,000 children annually due to S-linked inheritance of COL4A5, or autosomal recessive inheritance of COL4A3 or COL4A4 genes. It presents with hematuria and hearing loss.¹⁰ Our patient had a single copy COL4A4 gene mutation that was classified as VUS. He also had 2 additional VUS affecting the TRPC6 and OSGEP genes. TRPC6 gene mutation can be associated with FSGS through autosomal dominant inheritance. Both COL4A4 and TRPC6 gene mutations were paternally inherited. Although the patient’s father not having renal disease argues against the clinical significance of these findings, there is literature on the potential role of heterozygous COL4A4 variant mimicking thin basement membrane nephropathy that can lead to renal impairment upon copresence of superimposed conditions.¹³ The patient’s rapidly progressing hematuria and changes in the basement membrane were worrisome for emerging FSGS. Furthermore, VUS of TRPC6 has been reported in late onset autosomal dominant FSGS and can be associated with early onset steroid-resistant nephrotic syndrome (NS) in children.¹⁴ This concern was voiced by 3 nephrology consultants during the initial evaluation, leading to the consensus that steroid treatment for podocytopathy would not alter the patient’s long-term outcomes (ie, progression to FSGS).

Immunomodulation

Our rationale for immunomodulatory treatment was based on the abrupt onset of renal concerns following a URI, suggesting the importance of an inflammatory trigger causing altered homeostasis in a genetically susceptible host. Preclinical models show that microbial products such as lipopolysaccharides can lead to podocytopathy by several mechanisms through activation of toll-like receptor signaling. It can directly cause apoptosis by downregulation of the intracellular Akt survival pathway.¹⁵ Lipopolysaccharide can also activate the NF-αB pathway and upregulate the production of interleukin-1 (IL-1) and TNF-α in mesangial cells.^16,17

Both cytokines can promote mesangial cell proliferation.¹⁸ Through autocrine and paracrine mechanisms, proinflammatory cytokines can further perpetuate somatic tissue changes and contribute to the development of podocytopathy. For instance, TNF-α can promote podocyte injury and proteinuria by downregulation of the slit diaphragm protein expression (ie, nephrin, ezrin, or podocin), and disruption of podocyte cytoskeleton.^19,20 TNF-α promotes the influx and activation of macrophages and inflammatory cells. It is actively involved in chronic alterations within the glomeruli by the upregulation of matrix metalloproteases by integrins, as well as activation of myofibroblast progenitors and extracellular matrix deposition in crosstalk with transforming growth factor and other key mediators.^17,21,22

For the patient described in this case report, initial improvement on steroids encouraged the pursuit of additional treatment to downregulate inflammatory pathways within the glomerular milieu. However, within the COVID-19 environment, escalating the patient’s treatment using traditional immunomodulators (ie, calcineurin inhibitors or mycophenolate mofetil) was not favored due to the risk of infection. Initially, anakinra, a recombinant IL-1 receptor antagonist, was preferred as a steroid-sparing agent for its short life and safety profile during the pandemic. At first, the patient responded well to anakinra and was allowed a steroid wean when the dose was titrated up to 6 mg/kg daily. However, anakinra did not prevent the escalation of proteinuria following a URI. After the treatment was changed to adalimumab, a fully humanized monoclonal antibody to TNF-α, the patient continued to improve and reach full remission despite experiencing a cold and the flu in the following months.

Literature Review

There is a paucity of literature on applications of biological response modifiers for idiopathic NS and FSGS.^23,24 Angeletti and colleagues reported that 3 patients with severe long-standing FSGS benefited from anakinra 4 mg/kg daily to reduce proteinuria and improve kidney function. All the patients had positive C3 staining in renal biopsy and treatment response, which supported the role of C3a in inducing podocyte injury through upregulated expression of IL-1 and IL-1R.²³ Trachtman and colleagues reported on the phase II FONT trial that included 14 of 21 patients aged < 18 years with advanced FSGS who were treated with adalimumab 24 mg/m², or ≤ 40 mg every other week.²⁴ Although, during a 6-month period, none of the 7 patients met the endpoint of reduced proteinuria by ≥ 50%, and the authors suggested that careful patient selection may improve the treatment response in future trials.²⁴

A recent study involving transcriptomics on renal tissue samples combined with available pathology (fibrosis), urinary markers, and clinical characteristics on 285 patients with MCD or FSGS from 3 different continents identified 3 distinct clusters. Patients with evidence of activated kidney TNF pathway (n = 72, aged > 18 years) were found to have poor clinical outcomes.²⁵ The study identified 2 urine markers associated with the TNF pathway (ie, tissue inhibitor of metalloproteinases-1 and monocyte chemoattractant protein-1), which aligns with the preclinical findings previously mentioned.²⁵

Conclusions

The patient’s condition in this case illustrates the complex nature of biologically predetermined cascading events in the emergence of glomerular disease upon environmental triggers under the influence of genetic factors. Observations on this child’s treatment response suggest that downregulation of somatic tissue-driven proinflammatory milieu originating from the constituents of glomerular microenvironment can help in recovery from emerging podocytopathy. The prolonged time span and stepwise resolution of proteinuria, followed by microalbuminuria (data not shown), and finally microscopic hematuria, supports the delicate balance and presence of reciprocal feedback loops between the podocytes and mesangial cells. Within this framework, blocking TNF-α, even temporarily, may allow time for the de novo regenerative process to prevail.

Chronic kidney disease affects 7.7% of veterans annually, illustrating the need for new therapeutics.²⁶ Based on our experience and literature review, upregulation of TNF-α is a root cause of glomerulopathy; further studies are warranted to evaluate the efficacy of anti-TNF biologic response modifiers for the treatment of these patients. Long-term postmarketing safety profile and steroid-sparing properties of adalimumab should allow inclusion of pediatric cases in future trials. Results may also contribute to identifying new predictive biomarkers related to the basement membrane when combined with precision nephrology to further advance patient selection and targeted treatment.^25,27

Acknowledgments

The authors thank the patient’s mother for providing consent to allow publication of this case report.