Abstract

In Protein-losing enteropathy (PLE), proteins are lost from the gastrointestinal system exceeding their synthesis by other organs. Proteins entering the gut are degraded into amino acids and reabsorbed but conditions causing inflammation or erosion of the gastrointestinal tract increase mucosal permeability with excessive leakage and poor reabsorption. Clinical manifestations include edema due to decreased plasma oncotic pressure, ascites, and pleural effusions. Loss of immunoglobulins and lymphocytes predisposes to infection. Laboratory findings include hypoproteinemia, low serum globulins and Alpha 1 antitrypsin (A1AT) abnormal intestinal clearance [1] PLE precipitated by Norovirus infection has been described in immunocompromised pediatric patients but not in those immunocompetent. Here, we discuss a case of PLE precipitated by Norovirus in a immunocompetent 4-yearold patient. Treatment included intravenous (IV) fluids, furosemide and albumin. Along with a case description, we provide a summary of prior pediatrics PLE case reports from other causes as well as from Norovirus in immunocompromised patients. This case emphasizes the importance of recognizing the wide variety of etiologies for PLE, both established and novel. It also highlights the importance of recognizing PLE as a condition occurring in immunocompetent patients to prevent delays in diagnosis and treatment initiation, unnecessary testing, or increased length of hospital stay.

Keywords: Protein Losing Enteropathy (PLE); Norovirus; Infection; Immunocompetent; Children.

Citation: Xie E, Sprangers H, Mahoney K, McGill J, Camelo I, et al. Protein Losing Enteropathy (PLE) secondary to Norovirus infection in an immunocompetent 4-year-old patient: Case report and literature review. J Clin Images Med Case Rep. 2025; 6(3): 3524.

Introduction

PLE is a condition precipitated by multiple factors, whereby serum proteins leak into the intestinal tract and are lost faster than they are produced endogenously or reabsorbed via lymphatic flow [2]. Due to hypoproteinemia, fluid is more likely to leak out of vessels resulting in clinical manifestations predominantly diffuse edema, abdominal distension and diarrhea. Laboratory evidence include hypoproteinemia, leukocytosis, elevated acute inflammatory markers, and transaminitis. Radiological evidence shows pleural effusions or ascites. Generally, hypoproteinemia secondary to PLE is nonspecific and results in acute hypoalbuminemia and hypogammaglobulinemia. The gold standard for diagnosis of PLE includes obtaining a 24-hour alpha-l-antitrypsin (A1AT) fecal excretion rate, abnormal clearance is precipitated by gastrointestinal loss [3]. PLE in pediatric populations has previously been associated with autoimmune conditions such as Crohn’s Disease and gastrointestinal sarcoidosis [4-8]. However, to our knowledge, this is the first documented case of PLE occurring secondary to Norovirus infection in an immunocompetent pediatric patient.

Case presentation

A 4-year-old male with no significant past medical history was referred to our institution with complaints of severe abdominal pain, vomiting, decreased oral intake of 2 days duration, constipation followed by non-bloody diarrhea, dyspnea, and edema in his genital area and lower extremities. His mother noted that his symptoms started shortly after he was exposed to his grandmother who was previously diagnosed with a gastrointestinal illness. A computer tomography (CT) scan of the abdomen showed diffuse ascites and a borderline enlarged appendix prompting a transfer for further management.

On arrival at our institution, vital signs included a temperature of 37 (C), heart rate of 139 beats per minute, respiratory rate of 28 breaths/min, blood pressure of 102/64 mmHg, O2 saturation of 96% on room air. Upon physical exam, he was alert. A cardiopulmonary examination revealed diminished breath sounds in the left and right lower bases. Abdominal exam was notable for a diffusely tender abdomen, particularly below the umbilicus with guarding and dullness to percussion. Additionally, the patient had scrotal and pedal edema. On laboratory examination, White blood cells (WBC) 28 th/mm3 (RR 4.5-49.9), Sodium 127 mEq/L (RR 132-146), potassium 4.8 mEq/L (RR 3.5- 5.5), chloride 95 mEq/L (RR 99-109), Co2 17 mEq/L (RR 20-31), BUN 29mg/dL (RR 9-23), creatinine 0.35 mg/dL (RR 0.50-0.80), Aspartate aminotransferase (AST) 78 units/L (RR 11-35), Alanine aminotransferase (ALT) 25 units/L (RR 10-49), gamma-glutamyl transferase (GGT) 3 units/L (RR 8-50), albumin 2.8 g/dL, RR (3.2- 4.8 g/dL), IgA level 104 mg/dl (RR 29-256), IgG level 367 mg/ dL (RR 386-1470) and IgM level 27 mg/dL, (RR (37-224). On two different sample collections the same day, our patient had 236 mL of stool excretion. A random fecal A1AT of 30 mg/dl (RR <56) was used as a surrogate for the 24 hour collection. Serum A1AT was 235.5 mg/dL, RR (100-190 mg/dL). The normal clearance of A1AT should be under 13 ml/24 hours. A clearance greater than 27 ml/ day indicates increased gastrointestinal protein loss and points towards the diagnosis of PLE, the calculated A1AT clearance for him was consistent with PLE. A1A Clearance (c) = (stool volume (cc)) x A1A random fecal concentration (mg/ dL)/ serum A1AT (mg/dL), A1A(c) = 236 ml x 30 mg/dl / 235.5 mg/dl. A1A(c) = 30 ml/day [3]. Further testing included negative Antinuclear antibodies, normal Tissue Transglutaminase IgA antibody (tTG-IgA), T cell CD4 726 cells/ mcl (RR 700-2200)/22% (RR28-47), CD8 836 cells/mcL (RR 480-1300), Cytomegalovirus (CMV) IgM negative, Epstein-Barr Virus (EBV) serology negative for acute infection, a BioFire® FilmArray® gastrointestinal (GI) Polymerase chain reaction (PCR) panel was negative for Campylobacter, Plesiomonas shigelloides, Salmonella, Vibrio cholerae, Yersinia enterocolitica, Enteroaggregative E. coli (EAEC), Enteropathogenic E. coli (EPEC), Enterotoxigenic E. coli (ETEC), Shiga-like toxin-producing E. coli (STEC), E. coli 0157, Enteroinvasive E. coli (EIEC), Cryptosporidium, Cyclospora cayetanensis, Entamoeba histolytica, Giardia lamblia, Adenovirus, Astrovirus, Rotavirus and Sapovirus but positive for Norovirus. A respiratory Biofire® FilmArray® PCR panel was negative for Sars-CoV-2, Influenza A and B virus, Metapneumovirus, Parainfluenza, Respiratory Syncytial Virus (RSV), Bordetella, pertussis, Chlamydia pneumoniae, Mycoplasma pneumoniae, and Bordetella parapertussis. A chest x-ray (CXR) was notable for pleural effusion at the right lung base with mild linear opacities likely indicative of compressive atelectasis.

Based on this patient’s initial complaints of severe diarrhea and diffuse swelling, laboratory evidence of hypoproteinemia and hypoalbuminemia, radiological evidence of ascites and pleural effusions, abnormal A1AT clearance, and a positive GI PCR panel for norovirus, this patient was diagnosed with PLE most likely precipitated by Norovirus infection. Treatment included intermittent oxygen therapy via nasal cannula in order to keep oxygen levels above 92% and repeated albumin replacement infusion along with furosemide administration to manage fluid overload. A follow-up CXR showed interval improvement in the pleural effusions. Abdominal and scrotal edema as well as pleural effusions improved from initial values 11 days after admission and 7 days after initiating albumin and diuretics. IgG and IgM levels improved to 661 mg/dL and 46 mg/dL respectively. Furosemide and albumin were ultimately discontinued, and the patient was discharged home in stable condition and on room air.

Table 1: Immunocompetent patients’ cases.

*CMV: Cytomegalovirus; IVIG: Intravenous Immunoglobulin; HIV: Human Immunodeficiency Virus; ART: Anti-Retroviral Therapy; CVID: Common Variable Immunodeficiency; PLE: Protein Losing Enteropathy.

Discussion/conclusion

This is the first case to our knowledge of protein-losing enteropathy secondary to norovirus infection in an immunocompetent pediatric patient. There have been several cases of PLE secondary to norovirus in immunocompromised pediatric patients as well as secondary to several other conditions, outlined in the Table 1. Key findings in this patient indicative of PLE included diarrhea and generalized edema, as well as laboratory findings including hypoalbuminemia, hyponatremia, pleural effusions on CXR, both of which were managed with diuretics, albumin, supplemental oxygen, and supportive care, similar to treatment received by other children diagnosed with the same condition. While conducting this review, we found 13 manuscripts that linked infectious etiologies to PLE including cytomegalovirus (CMV), Human immunodeficiency virus (HIV), and SARS-CoV-2 [4-7,9,10]. We also found a study that linked Norovirus to PLE in an immunocompromised patient [11]. Given the frequency of Norovirus in children and prior reports of its association with PLE development, Norovirus should be considered as a precipitating factor for the development of PLE in patients with diarrhea in addition to fluid retention even when if the patient is immunocompetent.

Norovirus has long been recognized as a leading cause of viral gastroenteritis worldwide. To clear norovirus, CD8+ and CD4+ mediated responses are necessary. Symptoms of norovirus include diarrhea and vomiting [12]. Severe diarrhea caused by norovirus can lead to the elimination of proteins from the GI tract faster than they are produced, therefore resulting in hypoproteinemia, a defining feature of PLE. Leukocytosis, anemia, and transaminitis are also commonly seen [3]. Additionally, a normal rate of A1AT clearance is below 13 mL/day, with a clearance over 27 mL/day raising suspicion for PLE. Because our patient’s A1AT clearance rate was above 27 mL/day, this indicated a PLE diagnosis [3]. In immunocompetent patients with intact CD8+ and CD4+ mediated response, it may be less common for gastrointestinal infections such as Norovirus to cause clinical manifestations of PLE. However, this case highlights the importance of recognizing Norovirus as an etiology of PLE in immunocompetent patients.

Our literature review performed via PubMed search (summarized in Table 1) shows several cases of PLE in pediatric patients linked to infectious causes, including both immunocompetent and immunocompromised hosts. Since this patient was immunocompetent, consideration was not initially given to Norovirus as the primary etiology of PLE, which could have eliminated the need for further workup. Consequently, recognizing Norovirus as a possible etiology of PLE in pediatric patients, can prevent delays in diagnosis and management and avoid unnecessary testing.

This case presents a patient with PLE secondary to Norovirus infection, which had not been previously documented as a trigger for PLE in immunocompetent pediatric patients. This patient’s treatment course was delayed due to not including PLE in the initial differential diagnosis, resulting in an inability to promptly analyze the gold standard diagnostic testing, calculation of 24-hour alpha-1-antitrypsin fecal excretion rate [13]. This case thus highlights the importance of recognizing infections outside of the historically recognized etiologies of PLE to avoid delayed diagnosis, unnecessary testing, prolonged hospitalizations, and delays in treatment. Further, it is important to recognize PLE as a condition that can occur in immunocompetent pediatric patients.

Acknowledgements: Sadhabna Durbha, Edward Xie and Haylee Sprangers conducted the data gathering and literature review, Janelle McGill and Katherine Mahoney contributed by critically revising the manuscript. Ingrid Camelo provided intellectual content in infectious diseases, provided editing and final approval for submission (TABLE 1). Summary of Pediatric cases of Protein Losing Enteropathy (PLE) associated with infectious diseases in immunocompetent and immunocompromised patients.

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