IMMUNOLOGY CORNER

https://doi.org/10.5005/jp-journals-10081-1397
Pediatric Infectious Disease
Volume 5 | Issue 3 | Year 2023

Lymphoproliferation: How do You Evaluate for an Immune Deficiency?

Neha Singh¹, Sagar Bhattad²

^1,2Department of Pediatrics, Division of Pediatric Immunology and Rheumatology, Aster CMI Hospital, Bengaluru, Karnataka, India

Corresponding Author: Sagar Bhattad, Department of Pediatrics, Division of Pediatric Immunology and Rheumatology, Aster CMI Hospital, Bengaluru, Karnataka, India, Phone: +91 9779433934, e-mail: drsagarbhattad@gmail.com

Received on: 12 July 2023; Accepted on: 17 August 2023; Published on: 29 September 2023

ABSTRACT

Lymphoproliferation (LP) refers to the excessive proliferation of lymphocytes, causing nodal and extranodal infiltration triggered by infection, malignancy, and inflammation. LP in patients with inborn errors of immunity (IEI) could have different connotations based on the type of IEI. When LP is the presenting complaint, the diagnosis of IEI is often delayed. In this article, we discuss LP as the key manifestation in patients with IEI and present a few clinical cases highlighting the different patterns of LP in IEI.

How to cite this article: Singh N, Bhattad S. Lymphoproliferation: How do You Evaluate for an Immune Deficiency? Pediatr Inf Dis 2023;5(3):102–104.

Source of support: Nil

Conflict of interest: None

Keywords: Immune dysregulation, Inborn errors of Immunity, Lymphoproliferation

INTRODUCTION

Lymphoproliferation (LP) refers to an unregulated expansion of B and T lymphocytes, causing lymphocytosis in the blood and infiltration to extranodal sites. It manifests as generalized or recurrent lymphadenopathy, hepatomegaly, splenomegaly, mucosal nodular lymphoid hyperplasia involving the gut and respiratory system, and bone marrow infiltration. The underlying trigger of LP may be an infection, malignancy, or inflammation.

Inborn errors of immunity (IEI)—associated LP is a distinct clinical entity. The presentation ranges from an asymptomatic organomegaly, a harbinger of evolving malignancy, or a marker of the onset of hemophagocytic lymphohistiocytosis (HLH). The overall incidence of LP in IEI is variable and ranges from 0.7 to 18%.¹ Overlapping clinical clues and laboratory investigations make diagnosis difficult in these patients, especially when the underlying disease presents with isolated LP. Hence, it is important to investigate the underlying cause in a patient with LP.

PATHOPHYSIOLOGY

Lymphoproliferation (LP) has been broadly classified based on the morphology of cells and Epstein–Barr virus (EBV) status. In inherently immunodeficient patients, LP is largely B-cell driven and includes B-cell lymphoid hyperplasia [follicular, infectious mononucleosis like, and plasmocytic], polymorphous B-cell LP [aggressive non Hodgkin lymphomas (HL) and indolent lymphomas], and classical HL-like LP. T and natural killer cell LP are less known in IEI, and if present, these are mostly reactive or benign cluster of differentiation (CD) 8⁺ T-cell infiltrates. T-cell lymphomas have been reported sparingly in the context of DNA repair defects (Ataxia-telangiectasia and Nijmegen breakage syndrome).²^,³ Histopathology can be a useful guide to the underlying immunodeficiency. Granulomatous inflammation, B-cell lymphoid proliferation with a paucity of plasma cells, and expansion of CD8⁺ cytotoxic T-cells are characteristic of LP in common variable immunodeficiency (CVID). There is hyperplasia of IgM⁺ plasma cells and senescent T-cells with reduced IgG⁺ plasma cells in activated PI3 kinase δ syndrome (APDS). Autoimmune lymphoproliferative syndrome (ALPS) is associated with the characteristic proliferation of nonclonal double negative T cells (DNTs) (CD4-/CD8-CD45RA⁺ CD57⁺T-cell receptor αβ⁺ cytotoxic) in the peripheral blood, lymph nodes, liver, and spleen. Flowchart 1 is a concise algorithm to guide the physicians’ approach to LP in IEI patients.

Flowchart 1: Approach to suspected IEI with LPALPS, autoimmune lymphoproliferative disease; APDS, activated PI3 kinase δ syndrome; BENTA, β-cell expansion with NF-κβ and T-cell anergy, CVID, common variable immunodeficiency; EBER-ISH, EBV-encoded RNA automated in situ hybridization (ISH); EBNA, antibodies against Epstein–Barr nuclear antigen; GOF, gain of function; HIGM, hyper IgM syndrome; HPE, histopathology examination; IHC, immunohistochemistry, LMP, latent membrane protein; WES, whole exome sequencing; XLPD, X-linked lymphoproliferative disease

WHEN SHOULD ONE SUSPECT AN IEI IN A PATIENT WITH LP?

Onset in childhood.
Chronic or recurrent asymptomatic LP.
Presence of autoimmunity and/or infections with LP.
Family history of LP.

Let us discuss a few cases to understand the varied presentations of LP in patients with IEI.

CASE I

Miss B, a 6-year-old girl born to a nonconsanguineous married couple, had recurrent lymphadenopathy from 3 years of age. She had undergone a lymph node biopsy that ruled out lymphoma. At 5 years, she was diagnosed with adenotonsillar hypertrophy with sinusitis.

Investigations

Hemoglobin (Hb) 11 gm/dL, total cell count (TC) 8,500 cells/cu mm (N₅₆/L₃₉), platelet count (PC) 400,000/cu mm

Vitamin B₁₂: 2,000 pg/mL (high)

Immunological Workup

Cluster of differentiation (CD) 3 83% (516), CD19 8% (52), CD56 10.6% (66), CD4 50% (264), CD8 39.8% (207).
Immunoglobulin G (IgG) 1,852 mg/dL (608–1,572), IgA 86 mg/dL (33–236), IgM 62 mg/dL (43–207), IgE 366 IU/L.
Double-negative T cells (DNT): 10% of absolute lymphocyte count (N < 1.5%), 12% of CD3 cell count (N < 2.5%).

Genetic testing

Whole exome sequencing (WES): Heterozygous pathogenic variant (c.913dupA, p.Thr305AsnfsTer16) in exon 9 of FAS gene.

Diagnosis: ALPS

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by a defect in the lymphocyte apoptosis pathway, causing an imbalance of immune homeostasis.
Defects in the first apoptosis signal (FAS)—mediated pathway genes cause the expansion of autoreactive DNT cells.
Associated with chronic nonmalignant LP, autoimmune diseases, and increased risk of lymphoma.
Elevated vitamin B₁₂ levels, plasma soluble Fas ligand (sFASL) levels, interleukin (IL)—10 levels, or IL-18 levels are supportive evidence for diagnosis.
Treatment: Steroids, mycophenolate mofetil, sirolimus.

Message: Chronic lymphadenopathy/splenomegaly + high vitamin B₁₂—think of ALPS.

CASE II

Master M, a 7-year-old boy, a product of a remotely consanguineous marriage, presented with recurrent submental and cervical lymphadenopathy from 1 year of age. On multiple occasions, hepatosplenomegaly was recorded. Along with chronic LP, he also had seven to eight episodes of pneumonia, requiring oxygen support on various occasions. On examination, he had grade II clubbing and bilateral crepitations.

Investigations

Complete blood count (CBC) Hb 10.1 gm/dL, TC 10,500 cells/cu mm (N₅₃/L ₃₈) PC 320,000/cu mm.
Erythrocyte sedimentation rate 40 mm/hour, CRP 55 mg/L.
Human immunodeficiency virus (HIV) I and II: Negative.

Immunological Workup

Immunoglobulin G (IgG) 46 mg/dL (608–1,572), IgA 26 mg/dL (33–236), IgM 18 mg/dL (43–207).
CD3 77% (3,090), CD19 21% (861), CD56 1% (38), CD4 42.6% (1,707), CD8 33% (1,323)
Dihydrorhodamine (DHR) test: Normal (ruling out chronic granulomatous disease)

Genetic Testing

Whole-exome sequencing (WES): Hemizygous pathogenic mutation [c.163C>T (p.Arg55*)] in SH2D1A gene.

Diagnosis

X-linked lymphoproliferative disease (XLP) type 1:

X-linked lymphoproliferative disease type 1 (XLP1) is caused due to inactivating mutations in the SH2D1A gene.
Triad of EBV-induced HLH, B cell lymphoma, and hypo- or dysgammaglobulinemia.
Autoimmunity also known in XLP patients.
X-linked lymphoproliferative disease type 2 (XLP2) caused by pathogenic variants in the X-linked inhibitor of apoptosis gene.
Present with milder HLH, hypo or dysgammaglobulinemia and hemorrhagic colitis.

Message: In male patients with LP and hypogammaglobulinemia, XLP is a possibility.

CASE III

A 7-year-old male, the product of a third-degree consanguineous marriage, presented with recurrent cervical lymphadenopathy from 3 years of age. He had adenotonsillar hypertrophy since 4 years of age, for which he had undergone tonsillectomy. He also had ongoing complaints of cough with expectoration for the past 3 years, with no response to multiple courses of antibiotics and empirical antitubercular therapy. On examination, he had hepatosplenomegaly.

Investigations

Hemoglobin (Hb) 10 gm/dL, TC 8,800 cells/cu mm (N₅₀/L₄₀), PC 400,000/cu mm.
Epstein–Barr virus (EBV) polymerase chain reaction (PCR): Positive (27,520 copies/mL).
Human immunodeficiency virus (HIV) I/II: Nonreactive.
Dihydrorhodamine (DHR): Normal.
Cluster of differentiation (CD) 3 67.2% (1,927), CD19 3.6% (104), CD56 28.9% (829), CD4 17.8% (512), CD8 40.4% (1,160), CD4:CD8 ratio: 0.44.
Immunoglobulin G (IgG) 1,830 mg/dL (range 608–1,572), IgA 138 mg/dL (33–236), IgM 233 mg/dL (43–207), IgE 41.6 IU/L.
Whole-exome sequencing (WES): Heterozygous pathogenic missense mutation (c.1573G > A p.Glu525Lys) in PIK3CD gene.

Diagnosis: APDS

Activated PI3 kinase δ syndrome (APDS) is a type of combined Immunodeficiency.
Present with pulmonary infections, autoimmune manifestations, and LP.
Activated PI3 kinase δ syndrome type 1 (APDS1) caused by gain of function (GOF) mutation in PIK3CD gene encoding for p110δ catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ).
Increased predisposition to EBV infection.
Sirolimus is useful for LP.
Definitive treatment: Hematopoietic stem cell transplantation (HSCT).

Message: In patients with chronic lymphadenopathy and recurrent infections, IEI must be thought of.

CASE IV

Master E, a 6.6-year-old boy, a product of a remotely consanguineous marriage, was unwell from 10 months of age. He had jaundice, abdominal distension, and recurrent diarrhea. He was diagnosed with autoimmune hepatitis, which was treated with steroids and azathioprine. The family history was significant as the father was diagnosed with immune thrombocytopenic purpura, and his brother passed away at 30 years due to chronic liver disease. On examination, his weight and height were less than a third centile, and per abdomen examination showed hepatosplenomegaly.

Investigations

Complete blood count (CBC): Hb 10.6 gm/dL, TC 9,300 cells/cu mm (N₄₀/L ₅₁), PC 300,000/cu mm.
Total bilirubin: 4.4 mg/dL, direct bilirubin: 2.3 mg/dL.
Serum glutamic-oxaloacetic transaminase/serum glutamic-pyruvic transaminase: 506/527 IU/L.
Alkaline phosphatase (ALP): 763, prothrombin time/international normalized ratio: 20/1.8.
Anti-liver kidney microsomal antibody: Positive (1/320).
Hepatitis A virus, hepatitis B surface antigen, hepatitis C virus, HIV: Negative
Immunoglobulin G (IgG) 1,746 mg/dL.
Antinuclear antibody by immunofluorescence: Negative.
Cytomegalovirus IgG: Negative.
Liver biopsy: Liver parenchyma preserved architecture. Mild lobular and portal inflammation. Random foci of bile ductular proliferation. An occasional focus of portal tract fibrosis.
Gastrointestinal endoscopy: Grade II esophageal varices.
Whole exome sequencing (WES): Heterozygous pathogenic missense mutation in Exon 2 (c.151 C>T) of cytotoxic T-lymphocyte associated protein 4 (CTLA4) gene.

Diagnosis: CTLA4 Haploinsufficiency

Cytotoxic T-lymphocyte associated protein 4 (CTLA4) haploinsufficiency is a novel IEI associated with prominent autoimmunity and immune dysregulation.
Associated with regulatory T cells (T_reg) dysfunction.
Hypogammaglobulinemia in 80% of patients.
Patients have B and CD4 T-cell lymphopenia and increased but impaired T_reg cells.
Abatacept, a CTLA-4-Ig fusion protein-specific treatment.
Definitive treatment: HSCT.

Message: Think of IEI in LP with coexisting autoimmunity and positive family history.

CONCLUSION

Lymphoproliferation (LP) can be a presenting manifestation or may evolve during the course of an IEI.
Among the different groups, disorders of immune dysregulation characteristically predispose to LP.
Epstein–Barr virus (EBV) testing is fundamental in all patients with LP.

REFERENCES

1. Natkunam Y, Gratzinger D, Chadburn A, et al. Immunodeficiency-associated lymphoproliferative disorders: time for reappraisal? Blood 2018;132(18):1871–1878. DOI: 10.1182/blood-2018-04-842559

2. Sharma S, Pilania RK, Anjani G, et al. Lymphoproliferation in inborn errors of immunity: the eye does not see what the mind does not know. Front Immunol 2022;13:856601. DOI: 10.3389/fimmu.2022.856601

3. Migliavacca M, Assanelli A, Ponzoni M, et al. First occurrence of plasmablastic lymphoma in adenosine deaminase-deficient severe combined immunodeficiency disease patient and review of the literature. Front Immunol 2018;9:113. DOI: 10.3389/fimmu.2018.00113

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