Abstract

Leukocyte chemotactic factor 2 amyloidosis (ALECT2) is a recently discovered amyloidosis generally characterized by distinct globular hepatic deposits and renal involvement. The amyloidogenic protein, LECT2, is an obesity-associated hepatokine with complex associations with inflammatory cytokines; including those regulating the cytokine storm observed in COVID-19. However, no research has explored the interaction between

ALECT2 and systemic COVID-19. We present a case report detailing an incidental finding of systemic ALECT2 during the autopsy of a patient who expired from complications of severe COVID-19. Amyloid deposition within the liver, kidneys, spleen, and lungs may have contributed to the declining organ function observed in this case. We propose two mechanisms by which ALECT2 potentially compounded the effects of COVID-19, including worsening hypoxia through alveolar amyloid deposition and intensifying the inflammatory response through upregulation of cytokines such as IL-6.

Keywords: Amyloidosis; ALECT2; COVID-19; SARS-Cov-2; IL-6; Cytokine Storm

Introduction

Amyloidosis describes a variety of disorders exhibiting abnormally folded protein depositing as insoluble fibrils in tissue, with the two most common types being AA and AL [1]. A novel type of amyloidosis, ALECT2, was reported by Benson et al [2] in 2008 as isolated amyloid deposition in the glomerulus. The amyloidogenic protein was identified as protein leukocyte chemotactic factor 2 (LECT2), a pleiotropic cytokine produced in hepatocytes that has been implicated in various processes, including cell proliferation, neuronal development, tumor suppression, and regulation of inflammation [3-5]. ALECT2 is now recognized as the 3 rd most common amyloidosis in the United States 6 and has a high prevalence among Mexican Americans in the Southwest [7]. Initially, ALECT2 amyloidosis was only described in the kidney, with 30-40% of cases resulting in end stage renal disease (ESRD) [2,8]. However, subsequent reports have highlighted characteristic globular amyloid deposits in the liver and systemic involvement of the spleen, bowel, adrenal glands, prostate, gallbladder, pancreas, parathyroids, and, interestingly, the lungs, specifically in alveolar septa [6-8]. Here, we report a case of fatal COVID-19 with multiorgan ALECT2 amyloidosis discovered during autopsy. When SARS-CoV-2 targets respiratory epithelial of the lower respiratory tract, specifically Type II pneumocytes, the innate immune response is activated. This immune response can both damage and stimulate pulmonary capillary endothelial cells, leading to diffuse alveolar wall edema, vascular permeability, and leukocyte infiltration [9,10]. If the infection is severe, it can progress to respiratory failure and cytokine storm, with occasional multiorgan involvement including acute kidney injury, myocardial damage, and hepatic damage [9,11]. We note that the well described systemic inflammatory manifestations and multiorgan involvement characteristic of COVID-19 [12] echoes both inflammatory functions of LECT2 and distribution of systemic ALECT2. Several authors have posited linkages between systemic amyloidosis and COVID-19 disease severity [13-16], but to our knowledge, there are no previously reported cases of ALECT2 amyloidosis and COVID-19. We report a detailed clinicopathologic evaluation of a case of ALECT2 amyloidosis with concurrent COVID-19 and explore potential pathogenic interactions between the two conditions.

Case Report

A 68-year-old Hispanic woman with a past medical history of essential hypertension and moderate persistent asthma presented to a major academic medical center in Southeastern Texas with shortness of breath, cough, fever, and diffuse body aches starting two days prior. Upon presentation, she was afebrile, and her vital signs were within normal limits except for a pulseoximetry reading of 86%, which improved with six liters of oxygen through nasal cannula. Physical examination and review of systems was significant for morbid obesity (BMI of 58) and dyspnea with minimal exertion; however, her lungs were clear to auscultation bilaterally. Initial laboratory studies revealed a slight leukocytosis with a white blood cell count of 12.8 K/uL, anemia with a hemoglobin of 10.1 g/dL, elevated creatinine of 1.22 mg/dL with an unknown baseline; procalcitonin of 2.14 ng/mL, mildly elevated liver enzymes with an alkaline phosphate of 169 U/L, ALT of 86 U/L, and AST of 79 U/L with no reported history of liver disease, and a positive ID Now rapid nucleic acid test for SARS-CoV-2. She was up to date on the pneumococcal and influenza vaccines and self-reported receiving two doses of the Pfizer SARS-CoV-2 vaccine prior to admission. Of note, her hemoglobin A1C was 7.1%, but she had no known history of diabetes. A CT chest showed patchy ground glass attenuation suggestive of multifocal pneumonia. She was admitted to the hospital for close monitoring and started on albuterol/ipratropium breathing treatments, a five-day course of Remdesivir, intravenous dexamethasone, a seven-day course of empiric antibiotics, and enhanced dose DVT prophylaxis. The patient’s creatinine decreased to 0.88 mg/dL the next day after receiving fluid hydration. She was started on Baricitinib during hospital day one with plans to continue this medication for fourteen days. She was transferred to the ICU on hospital day two due to increased oxygen requirements necessitating BiPAP and 55 liters of high flow oxygen. The patient was unable to tolerate attempts to wean her off BiPAP. Her creatinine had been up trending during this admission, and she was found to have acute kidney injury (AKI) on hospital day eight with a creatinine of 1.86 mg/dL. On hospital day nine, the patient developed sudden onset tachycardia and hypoxia necessitating emergent intubation. An arterial blood gas showed severe acute metabolic acidosis, her creatinine peaked at 2.56 mg/dL, and she had a lactic acid of 12.23 mmol/L. She subsequently went into hypotensive shock and was started on four pressors. Nephrology was consulted and the patient was started on continuous renal replacement therapy on the same day. Although the patient has no reported history of kidney disease, nephrology suspected an AKI on chronic kidney disease stage 3. Unfortunately, the patient expired on hospital day ten with clinical impression of septic shock and multiorgan failure secondary to COVID-19 pneumonia.

Autopsy Findings

On gross examination during autopsy, the lungs were markedly heavy (790 g Right, 670 g Left) with diffuse parenchymal consolidation bilaterally. Microscopic examination revealed severe diffuse alveolar damage, exudative and proliferative phases, with diffuse thickening of the alveolar septa and prominent hyaline membranes. There was scarce type II pneumocyte proliferation but more marked foci of squamous metaplastic epithelium in the bronchi and alveoli (Figure 1). No thrombi or thromboemboli were identified. A small subacute peptic ulcer was found in the gastric antrum with an associated 650 cc of blood in the gastrointestinal lumen. GI bleeding was deemed a contributory cause of death and may have been responsible for her terminal decompensation in the setting of severe lung disease. The liver exhibited steatohepatitis with extensive macrovesicular steatosis, periportal and bridging fibrosis, and rare lobular foci of inflammation (steatohepatitis activity score 4/8, fibrosis score 3/4) [17]. An additional striking finding was prominent globular amorphous eosinophilic extracellular deposits, most prominent surrounding the terminal hepatic venules, and focally appearing as globules surrounded by zone 3 hepatocytes. These deposits were amphophilic on trichrome stain and positive on PAS. Congo Red staining demonstrated the requisite apple-green birefringence (Figure 2). This unusual appearance raised the possibility of ALECT2 amyloidosis [18]. Paraffin sections were therefore sent to Mayo Clinic for evaluation by mass spectrometry, confirming the diagnosis of LECT2 amyloidosis.

Figure 1: Lung pathology in COVID-19 with systemic LECT2 amyloidosis. A: The lungs exhibit prominent hyaline membranes (arrow) and interstitial edema with cellular infiltration (H&E X200). B: Atypia of hyperplastic type 2 pneumocytes (arrow). C: Squamous metaplasia of terminal airways (H&E X400). D: Under polarized light, there is evidence of focal alveolar septal birefringent amyloid deposits (arrow) (Congo Red X400).