Primary Immunodeficiencies – Clinical Features, Investigations

Classification – There are 2 types of immunity

• Innate immunity 
• Adaptive immunity

Deficiencies In The Innate Immune System

• Complement defects and Phagocyte defects. The important phagocytic defects: Chronic Granulomatous Disease (CGD),Chediak higashi syndrome,Myeloperoxidase deficiency,Leukocyte adhesion defects (LAD),Congenital neutropenia, and other miscellaneous groups

Deficiencies In The Adaptive Immune System

• Humoral immunity/humoral defects
• T-cell defects/cellular defects
• Combined Humoral and T-cell defects.

Humoral Defects

• It is also known as B cell defects. It includes conditions like X-linked agammaglobulinemia, combined variable immunodeficiency, selective IgA deficiency, IgG subclass deficiency and hyper IgM syndrome.

Primarily T Cell Defects

• DiGeorge Syndrome
• APECED Syndrome
• Chronic Mucocutaneous Candidiasis (CMC)

Combined B And T Cell Defects

• They are of severe form and can be divided into two categories: Severe combined immunodeficiency (SCID) can have X-linked and Autosomal forms. Combined defects: Wiskott aldrich syndrome, AT, hyper IgE syndrome(job syndrome) and miscellaneous groups.

Onset

• If a child presents with onset within the first 2-6 months, there could be either T-cell or Phagocyte defects. Onset beyond 6 months will have B-cell defects. Onset anytime is seen in patients with complement defects.

Types Of Organisms

• Viruses, Candida, P.jiroveci and Bacterial infections are potent T-cell defects. Enteroviruses, giardia, cryptosporidium, mycoplasma, and capsulated bacteria are considered B-cell defects. Staph, Pseudomonas, salmonella, Nocardia, candida and Aspergillus indicate phagocytic disease. Graft versus host disease due to non-irradiated blood transfusion, primarily indicating T-cell defects. Association with oculo-cutaneous albinism: Chediak Higashi Syndrome.
• Whenever there is delayed falling of the umbilical cord, there will be Leukocyte Adhesion Defects (LAD) which can be seen in all three forms but are always present in type 1 leukocyte adhesion defects. Eczema will indicate Wiskott Aldrich Syndrome and hyper IgE Syndrome. Patients with erythroderma: Omenn syndrome, and SCID should be there. Inability to kill catalase +ve bacteria is seen in Chronic Granulomatous Disease.The maximum risk of giardiasis is seen in CVID.

Combined Immune Defects

Severe Combined Immunodeficiency(SCID)

• It was previously called Bubble Baby Disease. It is named because of an incident in which a boy named David Vetter, born with severe combined immunodeficiency in Texas in 1971, gained worldwide attention. Vetter spent 12 years inside a specially designed, sterile plastic bubble. It is a life-threatening disease for babies.

There are two forms of Severe Combined Immunodeficiency

• ADA type is associated with increased risk of neonatal PAP. It also produces HMD like illness. Adenyl kinase-2 deficiency: Increased risk of sensorinueral hearing loss.

Approach to Severe Combined Immunodeficiency

Clinical Features

• Most patients present in early life with recurrent bacterial infections. Persistent candidiasis and recurrent viral infection can also be seen. Live vaccines can produce disease. Graft versus host disease with non-irradiated blood transfusion. Tonsils are absent, thymus and LNs are hypoplastic or absent.

Investigation

• Lymphopenia with low T-cells in all forms. Hypogammaglobulinemia is present but may manifest later. Specific cell types such as B-cell and NK may be deficient in specific forms. The absence of significant lymphopenia rules out severe T Cell defects, including SCID.

Treatment

• Hematopoietic stem cell transplant is the therapy of choice for SCID. Gene therapy can also be tried in specific forms. It is a rare but severe morphological manifestation seen in some types of SCID. It is a graft versus host disease-like illness (GVHD-like illness). It arises due to Hypomorphic mutations, mostly missense mutations in SCID genes. Child develops- Erythroderma, Alopecia, Failure to thrive, Hepatosplenomegaly. Blood will show- Eosinophilia, Low B cell counts, Raised T cell counts. Harrison says, "these patients are very fragile, requiring simultaneous anti-infective therapy, nutritional support and immunosuppression". HRCT is curative therapy.

Wiskott Aldrich Syndrome (WAS) 

• It is a disease showing X-linked recessive inheritance with the gene on the short arm of chromosome Xp11.22-23. Gene: WASP gene which codes for a WASP protein. This protein normally binds to CDC42H2 and Rac proteins(Rho-type GTPases). Whenever this WASP gene binds to them, they control actin filament assembly, which is involved in signal transduction in immune cells. The cells affected in Wiskott Aldrich are immune and blood cells such as T-lymphocytes, dendritic cells and platelets.

Clinical Features

• There is a triad comprising three things- Atopic dermatitis or eczema. Recurrent infection. Thrombocytopenia with small platelets producing bleeding manifestations. As per Nelson's 21st edition, the absence of thrombocytopenia rules out the wiskott Aldrich syndrome.

Investigations

• Small platelets with fewer numbers. They have low IgM levels, however, IgA and IgE get elevated. Normal to slightly low IgG levels are there. T cells are mild to moderately decreased. There is a poor humoral response to polysaccharide antigens.

Complications

• There is an increased risk of autoimmune disease due to defective T regulatory cells. For example, cytopenias and a high risk of autoimmune hemolytic anemia (AIHA). There is an increased risk of viral-induced lymphomas with Epstein Barr virus-related lymphomas commonly seen in children with Wiskott-Aldrich syndrome.

Treatment

• HSCT is the therapy of choice.

Ataxia Telangiectasia

• Ataxia telangiectasia shows autosomal recessive inheritance with the gene involved ATM gene present on the long arm of chromosome 11q and it codes for DNA damage sensor. This DNA damage sensor senses defective DNA repair and is also involved in Abnormal isotype switching in Ig production. Defective DNA repair will lead to an increased risk of leukemias and an increased risk of infections.

Clinical Features

• Ataxia, usually cerebellar ataxia, begins between 1-2 years of age, and Purkinje cells of the cerebellum are maximally affected.

Skin telangiectasia 

• In telangiectasia, there are dilated blood vessels, mainly oculo-cutaneous which tend to appear in 3-6 years of age. There are recurrent infections. B cell defects with low IgA and low IgG2. T cell dysfunction associated with hypoplastic thymus with less Hassail's corpuscles in the thymus gland. Increased risk of malignancies occurring due to leukemia and lymphoma.

Nijmegen Breakage Syndrome

• It is another chromosome instability disorder. It shows autosomal recessive inheritance with a protein deficiency known as Nibrin. Recurrent infections occur due to both B and T cell deficiency.

• It has features like: Microcephalym,Bird-like face, High risk of malignancies. Ataxia telangiectasia and Nijmegen breakage syndrome show high sensitivity to ionizing radiation. For example, X-Ray and gamma rays. Xeroderma pigmentosa, which shows increased sensitivity to UV rays.

Also Read: Infections of the Upper Airway- Common Cold and Sinusitis

Hyper IgE Syndrome

• Most common forms show Autosomal Dominant inheritance, also called Job syndrome. Hyper IgE syndrome occurs due to a defect in mutation in the STAT3 gene, which leads to a defect in the helper T cell17 pathway. Due to defective pathways, there are abnormalities in Interleukin-6 and Interleukin-21R signaling to produce recurrent infections.
• There are recurrent skin and lung infections, especially Pneumatoceles, due to staph aureus. Candida albicans is the second most common pathogen.

• Facial dimorphism is also present
  • Broad forehead.
  • Flat nasal bridge and fleshy nasal tip.
  • Deep-set eyes.
  • Coarse facies.
  • Rarely, hemihypertrophy.
• Hyperextensible joints, scoliosis, and osteoporosis.

Blood Investigations

• IgE levels get elevated with more than 2000 IU/ml with raised IgD. Normal IgM, IgG and IgA. Blood and sputum will show the presence of eosinophilia. There will be decreased memory T cells and T helper 17 cells. Treatment is antibiotics, along with IVIG replacement.

Cartilage Hair Hypoplasia Syndrome

• It shows autosomal recessive inheritance, with the gene involved being the RMRP gene.
• Clinical Features:
  • Short-limbed dwarfism.
  • Metaphyseal dysostosis and flaring of the ribs.
  • Sparse hair.
  • Recurrent infections.
  • Increased risk of malignancies.
• The treatment is HSCT.

Dock-8 Deficiency

• It has autosomal recessive inheritance, severe eczema, and recurrent CMV, EBV, and Cryptosporidium infections.

ZAP-70 Deficiency

• In this, the zeta-associated protein 70 is absent. It produces a severe T-cell deficiency with a complete absence of CD8+ T-cells. CD4+ T cells are present but cannot be activated, and humoral response is secondarily affected. Recurrent viral and opportunistic bacterial infections are common.

PNP Deficiency

• Purine nucleosides phosphorylase deficiency causes T-cell dysfunction, mild B-cell dysfunction, and neurological disorders.

Also Read: KEY POINTS AND RECOMMENDATIONS IN PEDIATRIC ADVANCED LIFE SUPPORT

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