Epidemiology:

• Prevalence of PID- 1 in 10,000 to 50,000 live births
• Most follow Mendelian inheritance

Classification:

• B Lymphocyte deficiency/ dysfunction
  • X linked agammaglobulinemia of Bruton
  • IgM deficiency
  • IgG deficiency
  • IgAdeficiency
  • Hyper IgE syndrome
  • Hyper IgM syndrome
  • X Linked immunoproliferative disease
  • Common variable immunodeficiency
• T Lymphocyte deficiency/ dysfunction
  • Cartilage hair hypoplasia
  • CD4 lymphopenia
  • De George syndrome
  • Nezelof syndrome
  • Wiskott Aldrich syndrome
  • ZAP-70 deficiency
  • Coronin 1A deficiency
  • APECED syndrome
  • Omenn’s syndrome
  • Autoimmune lymphoproliferative syndrome
• Combined B and T Lymphocyte deficiency/ dysfunction
  • Severe combined immunodeficiency
  • MHC class II deficiency
  • Omenn syndrome
  • WHIM syndrome
  • Nijmegen breakage syndrome
• NK cell deficiency/ dysfunction
  • Chronic NK cell lymphocytosis

Clinical Features: Depends on immune defect

• Recurrent infections
  • Including
    • Upper and lower respiratory tract infections- Otitis media, sinusitis, pneumonia
    • Invasive bacterial infection with sepsis
    • Purulent lymphadenitis
    • Skin and deep abscesses
    • Meningitis
  • Organisms:
    • Complement deficiency- Capsulated organisms such as Neisseriameningitidis
    • Antibody deficiency- Giardia, enterococcus, streptococcus, staphylococci, Hemophilus, enteroviral encephalitis
    • T cell defect- CMV, EBV, severe varicella, candida, Pneumocystisjirovici
    • Combined deficiency- Pneumocystisjirovici, CMV, mycobacteria, cryptosporidium
• Persistent and recurrent candidiasis
• Increased susceptibility to malignancies

Indications for investigating for functional neutrophil disorders

• Two or more systemic bacterial infections in a relatively short period of time
• Frequent, serious respiratory infections such as pneumonia, sinusitis, otitis media, lymphadenitis etc
• Infections in unusual sites, such as liver or brain abscess
• Infections associated with unusual pathogens such as aspergillus, Serratiamarcescens, Nocardia, Burkholderiacepacia
• Family history of recurrent infections
• Infections in absence of neutrophilic infiltration
• Organomegaly/ lymphadenopathy

Investigations:

• Hemogram
• S. Immunoglobulin levels
• T, B and NK cell enumeration by flow cytometry
• Neutrophil function studies
• S. Complement levels
• HIV testing
• Delayed hypersensitivity skin tests- Tetanus toxoid
• C3, C4, CH50 levels
• Neutrophil function evaluation
  • Nitrobluetetrazolium test
  • CD18/ CD11b by FACS
  • CD15a by FACS
  • Bombay blood group

General principles of treatment:

• Antimicrobial prophylaxis- Co-trimoxazole
• Aggressive treatment of infections
• Avoid giving live vaccines
• Regular IVIg substitution- 400-600mg/kg- every 4 weeks
• Allogeneic stem cell transplantation
• Gene therapy
• Enzyme replacement therapy

Individual Disorders:

DiGeorge Syndrome

• Developmental anomaly of 3^rd and 4^th pharyngeal pouch
• Causes
  • Hemizygous deletion of chromosome 22q11
  • CHARGE syndrome- Coloboma of eye, heart defects, atresia of nasal choanae, retardation of growth, genito-urinary abnormalities and deafness. Occurs due to 10p deletion.
• Clinical features
  • Thymichypoplasia resulting in decreased number of T cells- Causes oral thrush, recurrent infections, autoimmune diseases
  • Hypoparathyroidism- Hypocalcemic seizures
  • Conotruncal heart malformations- Interrupted aortic arch (type B), truncusarteriosus
  • Facial dysmorphism- Micrognathia, hypertelorism, antimangoloid slant of eyes, cleft palate, ear abnormalities
• Investigations:
  • FISH for 22q11
  • T lymphocyte subset analysis
• Treatment
  • Correction of severe heart defects
  • Supplementation of calcium and Vitamin D for hypocalcemia
  • Thymic transplantation in quadriceps muscles- Thymus is obtained from infants undergoing cardiac surgery, during which thymus is usually discarded.
  • BMT is useful in patients with partial DiGeorge syndrome
• Variant disorder
  • FOXN1 deficiency- Athymia, profound T cell lymphopenia, alopecia totalis, nail dystrophy

X linked agammaglobulinemia of Bruton

• It is failure of maturation of pre-B cells into B cells
• Cause
  • Mutation in Bruton tyrosine kinase gene
  • Located on chromosome Xq21.22
• Features (manifests at 6 months when maternal antibodies are depleted)
  • Infections
• Investigations:
  • S. Immunoglobulin levels- Decreased
  • Circulating B cells- Decreased
  • Intestinal mucosal biopsy- No B cells
  • NGS for BTK gene
• Treatment
  • Replacement of immunoglobulins

Common variable immunodeficiency

• Presence of hypogammaglobulinemia (IgG/IgA/IgM) and lack of specific antibody response in individuals with onset of symptoms after 2 years of age and other causes of humoral deficiency are ruled out.
• In this, B cells are unable to transform into plasma cells, which results in hypogammaglobulinemia.
• Features
  • Recurrent sinopulmonary infections
  • Autoimmune diseases- RA, dermatomyositis, scleroderma, AIHA, ITP, AI neutropenia, chronic active hepatitis
  • Lymphadenopathy
  • Splenomegaly
  • Caseatinggranulomas in lung, liver, spleen, skin and other tissues (Cause of this is not known)
• Treatment
  • IVIg substitution
  • Prophylactic antibiotics
  • Immunosuppression for autoimmune manifestations
  • HSCT- If there is associated lymphoid malignancies

Isolated IgA deficiency

• It is a condition in which naïve B cells do not differentiate into IgA producing cells resulting in IgA levels <5mg/L
• Causes
  • Familial
  • Acquired- Toxoplasmosis, measles
• Features
  • Usually asymptomatic
  • Infections of mucosal surfaces is common
  • Allergic manifestations: Food allergy (common), allergic conjunctivitis, rhinitis, eczema
  • Autoimmune diseases- RA, SLE, thyroiditis, myasthenia gravis, ulcerative colitis
  • Many have anti IgA antibodies in serum- They can have severe reactions when exposed to blood products or IgA containing IVIg.
• Treatment
  • No specific treatment needed
  • Intermittent or continuous prophylactic antibiotics

Hyper IgM syndrome

• Mutations affecting CD40 molecule, prevents interaction of T cells with activated helper T cells. This results in failure of switching of IgM to other immunoglobulins.
• Gene is mapped on chromosome Xq26
• Features
  • Recurrent sino-pulmonary infections
  • Cryptosporidiosis
• Treatment
  • Prophylactic antibiotivs and IVIg
  • Hematopoietic stem cell transplantation

Severe combined immunodeficiency (SCID)

• It is a condition in which both cellular and humoral immunity are deficient.
• Causes
  • X linked recessive- Mutation in common gamma chain subunit of cytokine receptors. This transmembrane protein is a part of signal transducing components of receptors for IL-2, IL4, IL7, IL9, IL11, IL15
  • Autosomal recessive
    • Deficiency of adenosine deaminase enzyme- This leads to accumulation of deoxyadenosine, which is toxic to immature lymphocytes
    • Mutation in recombinase activating gene
    • Mutations impairing expression of class II MHC molecules (Bare lymphocyte syndrome)
    • Mutations involving intracellular JAK kinase
    • Purine nucleoside phosphorylase deficiency
  • Immunological subtypes
    • T-B+NK- (Most common type)
    • T-B+NK+
    • T-B-NK+
    • T-B-NK-
  • Features (Present at age of 6 months)
    • Severe recurrent infections
    • Dermatitis
    • Failure to thrive
    • GVHD- Due to T cell engraftment from maternal transplacentally derived cells
  • Investigations:
    • Absolute lymphocyte count- <2000/cmm
    • Chest X Ray- No thymic shadow
    • Flow cytometry- Absence of circulating T cells
    • Hemogram- Anemia, Eosinophilia, neutropenia, thrombocytopenia
    • S. Immunoglobulin- IgE- Increased. Rest- Decreased
    • PCR- For specific gene defects
    • ADA enzyme levels in RBCs
  • Differential diagnosis
    • AIDS
    • Congenital rubella and CMV infection
    • Severe malnutrition
    • Marrow failure syndromes
    • Defects in B12 and folate metabolism
  • Prognosis
    • Generally fatal by 1 year of age
  • Treatment
    • Aggressive treatment of infections
    • IV Cotrimoxazole, Ganciclovir
    • IVIg
    • Parenteral nutrition, if there is chronic diarrhea
    • Enzyme replacement therapy for ADA deficiency
    • Immunosuppression if there are signs of GVHD
    • Allogeneic stem cell transplantation
      • If there is matched sibling donor, bone marrow can be infused without requirement for conditioning or GVHD prophylaxis
      • For matched related donor and matched unrelated donor, conditioning (Flu+Bu) and GvHD prophylaxis have to be given.
      • Less toxic conditioning must be used if there is radiosensitive SCID (DNA ligase 4 deficiency, Cernunnos deficiency, DNA-PKcs deficiency)
      • Doing haploidentical transplant is justified if no matched donor is available.
      • Only T cells of donor develop and myeloid and erythroid cells remain of recipient origin
      • Majority achieve humoral reconstitution despite lack of donor B cells
      • Factors influencing the outcome include
        • Type of donor- Better results with MSD
        • Type of SCID- Poor outcome with TB forms
        • Preceding infections/ malnutrition adversely affect the outcome
        • Age at transplant- Better results at age of <6 months.
    • Always give only irradiated blood products
    • Avoid BCG
    • Gene therapy- SCID is the first human disease for which gene therapy has shown unequivocal benefits.
  • Variant disorder
    • Ommen syndrome
      • SCID associated with triad of erythroderma, hepatosplenomegaly and lymphadenopathy
      • Hypoproteinemia
      • Marked eosinophilia
      • Mutations in RAG1 and RAG2
    • ZAP 70 deficiency
      • Autosomal recessive
      • ZAP-70 is necessary for intracellular signaling in T lymphocytes
      • CD8+ cells are markedly decreased
    • Calcium entry channel deficiency
      • SCID with non-progressive myopathy, ectodermal dysplasia, hepatosplenomegaly, hemolytic anemia and thrombocytopenia.

X Linked anhidroticectodermal dysplasia with immunodeficiency caused by mutations of NEMO

• Characterized by decreased or absent sweat glands, sparse hair growth, abnormal dentition and low IgG levels
• Mutations in IKBKG gene
• Treated with prophylactic IVIg and antibiotics.

CD40 ligand deficiency

• CD40 is expressed on activated CD4+ cells
• Chromosome- Xq26
• Decreased immunoglobulin levels
• Treatment- IVIg infusions on regular basis

MHC class I deficiency

• CD8+ cell count is markedly decreased

MHC class II deficiency

• CD4+ cell count is markedly decreased

Coronin-1a deficiency

• Coronin is involved in trafficking of naïve T lymphocytes to secondary lymphoid organs
• T lymphocyte count is markedly decreased
• Hypogammaglobulinemia

Wiskott Aldrich syndrome

• Refer to congenital thrombocytopenia chapter

Immunodeficiency disorders presenting as autoimmune diseases

• IPEX syndrome
  • Immune dysregulation
  • Polyendocrinopathy
  • Enteropathy
  • X Linked
  • Mutation of FOXP3 gene on X chromosome
  • Presents with diarrhea (autoimmune enteropathy), multiple endocrinopathy (Insulin dependent diabetes, thyroiditis, adrenal insufficiency), lymphadenopathy, autoimmune disorders (AIHA, ITP, autoimmune neutropenia), eczema
  • Poor prognosis with death within 1 year of life
  • Treatment: Immunosuppressive agents, HSCT
• APCED syndrome
  • Autoimmune polyendocrinopathy (parathyroid and adrenal)
  • Candidiasis
  • Ectodermal dysplasia (Dystrophic dental enamel and finger nails)
  • Mutation in AIRE gene

Autoimmune lymphoproliferative syndrome

• It is condition in which there is defect in apoptosis of T cells, leading to their continued survival and proliferation
• Cause: Mutation in genes that regulate apoptosis- FAS (70% cases), CASP-10, FAS LG etc.
• 400 cases have been reported worldwide
• Features
  • Lymphadenopathy- Which persists for >6months (Must for diagnosis)
  • Hepatosplenomegaly
  • Autoimmune diseases- ITP, AIHA, Autoimmune neutropenia, Rarely hepatitis, nephritis, colitis etc.
  • Malignancy (10-20% higher risk)- Leukemia, lymphoma, solid tumors
• Investigations:
  • T Cell analysis by flow cytometry- Presence of TCR-alpha-beta positive double T negative (CD4- and CD8-) cells. Presence of >1.5% of such cells is significant.
  • S. Protein electrophoresis and immunoglobulin levels- Polyclonal hypergammaglobulinemia
  • Anti cardiolipin antibody- Positive in 50% patients
  • ANA, RA Factor- Usually positive
  • Serum levels of IL10, IL18, Vitamin B12, sFasL- Increased
  • Hemogram- Lymphocytosis
  • Anemia- Due to AIHA, hypersplenism, iron deficiency
  • FAS mutation analysis
  • Lymphocyte apoptosis assay
  • CT chest and abdomen- To note lymph node involvement.
• Criteria for diagnosis (Definitive diagnosis: Both required criteria and any one primary accessary criteria. Probable diagnosis: Both required criteria and any 1 secondary accessary criteria)
  • Required criteria
    • Lymphadenopathy and/ or splenomegaly for > 6months
    • DNT cells- >1.5% of total lymphocytes or >2.5% of CD3+ lymphocytes
  • Primary accessary criteria
    • Defective lymphocyte apoptosis
    • Mutation of any genes involved
  • Secondary accessary criteria
    • Elevated sFASL/IL-10/ Vitamin B12
    • Typical IHC findings
    • Autoimmune cytopenia
    • Family history of noninfectious/ nonmalignant lymphadenopathy
• Treatment
  • Only lymphadenopathy- Wait and watch
  • Only autoimmune symptoms- Short course of steroids +/- Rituximab
  • Severe hypersplenism- Splenectomy
  • Other autoimmune manifestations- MMF, Sirolimus
  • If unresponsive of any treatment- HSCT

Hyper IgE syndrome (Job’s syndrome)

• 2 forms- 
  • Autosomal dominant- Mutation in transcription factor STAT-3
  • Autosomal recessive- Mutation of DOCK8 gene, additionally have neurological complications
• Features
  • Eczema
  • Recurrent Staphylococcal skin abscesses due to chemotactic defect in neutrophil function
  • Skeletal anomalies- Coarse facial features, hyperextensive joints, pathological fractures, scoliosis, craniosynostosis, retained primary teeth
• Investigations:
  • S. IgE levels- >2000IU/ml
  • Hemogram- Eosinophilia
  • Neutrophil chemotaxis- Impaired
  • Th-17 cells- Markedly decreased
• Treatment
  • Prophylactic antibiotics and cotrimoxazole
  • Antifungal prophylaxis for candidiasis
  • Surgery and antibiotics for abscesses
  • Topical steroids and PO antihistaminics for pruritus
  • IVIg to decrease the number of infections
  • Bathing in diluted bleach- To decrease staphylococcal colonization
  • HSCT- Doubtful benefit

Immuno-osseous dysplasias

• Cartilage hair hypoplasia
  • Autosomal recessive
  • Mutation of gene encoding untranslated RNA component of the ribonuclease mitochondrial RNA processing complex
  • Characterized by short limbed dwarfism, light colored hypoplastic hair, bone marrow dysplasia, increased susceptibility to malignancy, Hirschsprung disease, defects in spermatogenesis, immunodeficiency
  • Treatment- HSCT is useful in some cases
• Schimke syndrome
  • Autosomal recessive
  • Mutation in SMARCAL1 gene which encodes chromatin remodeling protein
  • Characterized by dwarfism, progressive renal failure, facial dysmorphism, lentigines, immunodeficiency, bone marrow failure
• WHIM Syndrome
  • Characterized by warts, hypogammaglobulinemia, infections, myelokathexis/ neutropenia
  • Occurs due to mutation in CXCL-12 gene
  • Treatment:
    • Immunoglobulin replacement
    • Antibiotic prophylaxis
    • G-CSF to increase neutrophil count
    • Local therapy for warts

Chromosomal instability syndromes associated with immunodeficiency

• Ataxia Telangiectasia
  • Both cellular and humoral immunodeficiency
  • Progressive neurological impairment
  • Ocular and cutaneoustelangiectasia
  • High alpha feto protein levels
  • Increased incidence of NHL, leukemias and solid tumors
• Fanconi anemia Refer to “Inherited bone marrow failure” chapter
• Nijmegen breakage syndrome
  • Short stature
  • Microcephaly
  • Bird like face
  • Both cellular and humoral immunodeficiency
  • Increased radiosensitivity
  • High incidence of malignancies such as- NHL, ALL, HL, AML, solid tumors
• Bloom syndrome
  • Short stature
  • Hypersensitivity to sunlight
  • Both cellular and humoral immunodeficiency
  • High incidence of malignancies- Leukemias, NHL, solid organ malignancies

X Linked lymphoproliferative disease (Duncan syndrome)

• Mutation of SH2D1A gene which encodes SLAM protein involved in T and NK cell signaling
• Presents with
  • Fulminant infectious mononucleosis- Rapid increase in liver enzymes, impaired coagulation, hepatic encephalopathy, HLH
  • EBV related lymphoma- Burkitt lymphoma in 50% cases
  • Vasculitis
  • Marrow aplasia secondary to HLH
• Treatment
  • HSCT
  • IVIg infusions

Other immunodeficiencies:

• Deficiency of complement system
  • Deficiency of C2 is common. But in this there is no increased risk of infection
  • Deficiency of alternate pathway components leads to increased susceptibility to infection with capsulated organisms
• IL-12 RP40 deficiency
  • Only genetically determined cytokine deficiency known in humans
  • Associated with increased susceptibility to infections with BCG, salmonella, Nocardia, M. Tuberculosis

Recent advances:

Sequential Stem Cell–Kidney Transplantation in Schimke Immuno-osseous Dysplasia 

Schimke immunoosseous dysplasia is characterized by spondyloepiphyseal dysplasia (SED) resulting in short stature, nephropathy, and T-cell deficiency.  Hematopoietic stem-cell transplantation (HSCT) and kidney transplantation from the mother was done successfully in a 5-year-old patient with SIOD.

https://doi.org/10.1056/NEJMc2209527

Lentiviral Gene Therapy for Artemis-Deficient SCID

The DNA-repair enzyme Artemis is essential for rearrangement of T- and B-cell receptors. Mutations in DCLRE1C, which encodes Artemis, cause Artemis-deficient severe combined immunodeficiency (ART-SCID), which is poorly responsive to allogeneic hematopoietic-cell transplantation.In the present study autologous CD34+ cells, transfected with a lentiviral vector containing DCLRE1C, were transfused, in 10 infants with newly diagnosed ART-SCID. Five of 6 patients who were followed for at least 24 months had T-cell immune reconstitution at a median of 12 months. 

https://doi.org/10.1056/NEJMoa2206575

Allogeneic stem cell transplantation compared to conservative management in adults with inborn errors of immunity

Allogeneic hematopoietic stem cell transplantation is curative for severe inborn errors of immunity. Present study compared outcomes of transplanted vs matched nontransplanted adults with severe IEIs. Nontransplanted patients had an ongoing risk of severe events, with an increased mean cumulative number of recurrent events compared with transplanted patients. AlloSCT prevents progressive morbidity associated with IEIs in adults, which may outweigh the negative impact of transplant-related mortality.

https://doi.org/10.1182/blood.2022015482

Leniolisib for activated PI3Kδ syndrome 

Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an inborn error of immunity with clinical manifestations including infections, lymphoproliferation, autoimmunity, enteropathy, bronchiectasis, increased risk of lymphoma, and early mortality. Hyperactive PI3Kδ signaling causes APDS and is selectively targeted with leniolisib, an oral, small molecule inhibitor of PI3Kδ. In present study, 31 patients with APDS aged ≥12 years were enrolled. Leniolisib reduced spleen volume compared with placeboand improved key immune cell subsets. 

https://doi.org/10.1182/blood.2022018546 

Idiopathic CD4 Lymphocytopenia

Idiopathic CD4 lymphocytopenia (ICL) is a clinical syndrome that is defined by CD4 lymphopenia of less than 300 cells per cubic millimeter in the absence of any primary or acquired cause of immunodeficiency. Present study evaluated the clinical, genetic, immunologic, and prognostic characteristics of 108 patients who were enrolled during an 11-year period. Whole-exome and targeted gene sequencing were performed to identify genetic causes of lymphopenia. The most prevalent opportunistic infections were diseases related to human papillomavirus (in 29%), cryptococcosis (in 24%), molluscum contagiosum (in 9%), and nontuberculous mycobacterial diseases (in 5%). A reduced CD4 count (<100 cells per cubic millimeter) was associated with a higher risk of opportunistic infection and invasive cancer  and a lower risk of autoimmunity. 

https://doi.org/10.1056/NEJMoa2202348

Mavorixafor, a CXCR4 antagonist, for WHIM syndrome

This phase 3 trial assessed mavorixafor, an oral CXCR4 antagonist, in participants with WHIM syndrome, a rare immunodeficiency. Over 52 weeks, mavorixafor significantly increased the time above absolute neutrophil and lymphocyte count thresholds, reduced infection rates by 60%, and lowered infection severity and duration compared to placebo. The treatment was well tolerated, with no serious treatment-related adverse events or discontinuations due to adverse events.

https://doi.org/10.1182/blood.2023022658