• Sign Up

Use coupon code EXTENDEDHOLIDAY2020 at checkout for 20% off

Hypogammaglobulinemia


Hypogammaglobulinemia

Article Author:
Madiha Huq
Article Author:
Nayan Kishori Bhatnagar
Article Editor:
Robert Hostoffer
Updated:
10/7/2020 2:06:27 PM
For CME on this topic:
Hypogammaglobulinemia CME
PubMed Link:
Hypogammaglobulinemia

Introduction

Hypogammaglobulinemia is a disorder caused by low serum immunoglobulin or antibody levels. Immunoglobulins are the main components of the humoral immune system and are able to recognize antigens to trigger a biological response and eradicate the infectious source. Hypogammaglobulinemia is the most common primary immunodeficiency and encompasses a majority of immune-compromised patients.[1] It can be diagnosed in childhood or adulthood. Onset is usually around the second to the third decade in life; however clinical signs of primary hypogammaglobulinemia can occur at any age. Bimodal distribution has been noted in the past with frequent diagnoses between the ages of 6 and 10 and ages 20 to the 40s. Clinical manifestations are rare but have been reported in patients above 50 years old.[2]

This condition predisposes children and adults to recurrent infections, allergies, neoplasms, and autoimmunity. Previous clinical findings suggested these disorders develop in childhood, however, this is now increasingly seen in adult medicine.[3] Common variable immunodeficiency (CVID) is often the cause of hypogammaglobulinemia in adults and X-linked agammaglobulinemia (XLA) is the most common in the pediatric population.[4]

Etiology

Hypogammaglobulinemia can be of primary or secondary origin. Primary immunodeficiencies result from genetic disorders and/or chromosomal anomalies during the development of the immune system. Secondary causes are usually induced by an external or acquired factor such as a corticosteroid or immunosuppressant drug, nutritional disorders, infections, chemotherapy, malignancy, nephrotic syndrome, other metabolic diseases, and hazardous environmental conditions.[5] It is important that physicians distinguish between primary and secondary causes of hypogammaglobulinemia to provide appropriate treatment.[6]

Categories of primary humoral Iimmunodeficiencies include X-linked Agammaglobulinemia, CVID, Hyper IgM syndrome, selective/Isolated Ig deficiency, and Transient hypogammaglobulinemia of Infancy.

X-linked Agammaglobulinemia (XLA) or Bruton Agammaglobulinemia

It is the first primary immune deficiency disease with a genetic cause identified. Mutation noted in the Bruton tyrosine kinase gene (Btk) is an important component for the maturation of pre-B cells. This leads to a lack of plasma cells with low levels of Ig and therefor no humoral response.[7][8] Inheritance of primary agammaglobulinemia is X-linked, with most mutations being familial with few autosomal recessive forms.[9]

Common Variable Immunodeficiency (CVID, Variable Pan-hypogammaglobulinemia)

It is defined by immune dysfunction of B-cells, T-cells, and dendritic cells due to a defect in the ability of B-cells to differentiate into plasma cells decreasing the secretion of immunoglobulins. Approximately 25 to 50% of CVID patients have a single gene defect which can lead to molecular deficiencies, epigenetic changes affecting gene expression, immune cell abnormalities such as increased B-cell apoptosis, and impaired antibody production. Genetic defects involve mutations in either the nucleus, cytoplasm or cell surface and can be autosomal dominant or recessive.[10][11] Intrinsic B-cell defect can play a role by involving mutations in CD 19 at 16p11.2 leading to CD 19 deficiency. Another gene identified is the transmembrane activator calcium-modulator and cyclophilin ligand interactor (TACI) which impacts B cell maturation. TACI deficient CVID involving the TACI gene at 17p11.2 is another well-known mutation. Tumor necrosis factor (TNF) receptor gene defects have been studied and also are involved.[12][13] Other T-cell defects with mutations in ICOS, 2q33 (ICOS-deficient CVID) SH2DIA (responsible for X-linked lymphoproliferative disease [XLP]), CD19, CD20, CD21, CD81, BAFF-R (B-cell–activating factor of the tumor necrosis factor family receptors) and 2 genes that encode DNA methyltransferase (DNMT3B and ZBTB24) have been reported. Patients with CVID and IgA deficiency have a common genetic basis. CVID is common in patients with 1st degree relative with IgA deficiency, and some patients with IgA deficiency may later become panhypogammaglobulinemic.[14]

Transient Hypogammaglobulinemia of Infancy (THI)

It is characterized by hypogammaglobulinemia with adequate antibody response. It is observed during the first three to six months of life secondary to prolongation of the physiologic nadir of immunoglobulin levels. Ig levels normalize by three years of age in most children (age range 2-6 years).[15] The cause is unknown but some theories have been proposed including failure of T-cells to stimulate the synthesis of B -cells and antibodies, IgG production suppression by maternal IgG, low levels of critical cytokines, and familial genetic variations.[16]

Selective IgA Deficiency

Decreased levels or complete absence of IgA in both serum and secretory forms (IgA <10mg/dl). B-cells are phenotypically normal. Selective IgA deficiency has autosomal dominant inheritance with variable expressivity. Chromosomal abnormalities and mutations in JAK3, TACI, RAG1, RAG2, STAT1 have been reported as a potential cause of selective IgA deficiency. Patients treated with drugs like phenytoin, gold, D-penicillamine who developed CVID, were found to have secondary IgA deficiency. It is also seen in conditions like ataxia-telangiectasia. Infections like CMV, EBV, Rubella, and Toxoplasmosis may also cause transient IgA deficiency.[17]

Hyper-IgM Syndrome

It is a rare primary immunodeficiency disorder characterized by normal to elevated IgM levels with decreased levels of IgG, IgA, and IgE immunoglobulins caused by mutations in genes on the X-chromosome and autosomal chromosomes which are responsible for the B-cell class switch from IgM to other classes of antibodies.[18][19] On the X chromosome, the CD40 ligand (hyper-IgM syndrome type 1 [HIGM1]) and NEMO (nuclear factor κB essential modulator, XHM-ED) genes play an active role. Autosomal chromosomal involvement is seen with 3 genes including the activation-induced cytidine deaminase (AID) gene (hyper-IgM type 2 [HIGM2]) on chromosome 12, the uracil DNA glycosylase gene (UNG, hyper-IgM type 5 [HIGM5]) on chromosome 12, and the CD40 gene (hyper-IgM type 3 [HIGM3]) on chromosome 20.[14]

Epidemiology

For X-Linked Agammaglobulinemia, prevalence is approximately 1 in 379,000 live births (1 in 190,000 male births) reported from a United States registry.[8]

Of the primary immunodeficiencies, Common Variable Immunodeficiency is the most common after selective IgA deficiency and is noted to have a high prevalence of 1 in every 10000 to 50000 live births. CVID affects 1 in 25.000 individuals with some evidence of higher prevalence in those from northern Europe.[20][21][22] CVID in pediatric age groups presents mostly after puberty, but in all patients with CVID, about 25% present in childhood or adolescence with a peak age of diagnosis at 8 years of age.[23][24] The male to female ratio is approximately 5 to 3.[5]

THI is usually diagnosed retrospectively, predominant in males with a male to female ratio of 2 to 1. The cause is unknown.[15]

Pathophysiology

The immune system has the potential to produce several species of antibodies to remove a variety of different antigens. Immunoglobulins are glycoproteins produced by plasma cells known as antibodies that are present in extracellular fluid and serum. Different classes exist for Ig such as IgG with subtypes 1-4, IgA with subtypes 1-2, IgM, IgD, and IgE. Function and longevity of the subclasses differ with some living for weeks and others for hours. Anti-infectious immunity is primarily regulated by IgG, IgA, and IgM.[25] 

Ig heavy chain class switching takes place rapidly after the activation of mature naïve B cells. This results in a switch from expression of IgM and IgD to IgG, IgA, or IgE. This isotype switching of the antibody then enhances the immune reaction by adequate removal of the pathogen that initially induced the humoral response.[26] Different mechanisms exist for anti-infectious immunity such as antigen neutralization, activation of the classical complement pathway with bactericidal effect, Ab-dependent cytotoxicity, and opsonization with phagocytosis. On serum protein electrophoresis, Ig travels primarily in the region of gamma globulins and normal values are determined based on the age of the individual. Different categories and their pathophysiology are described below.

X-linked Agammaglobulinemia (XLA) or Bruton Agammaglobulinemia

Bruton tyrosine kinase gene (Btk) is essential for the development of mature B-cells. Mutations in this gene will cause low levels of plasma cells and immunoglobulins resulting in little to no humoral response.[26][8] This may cause immunoglobulin deficiency (hypogammaglobulinemia) or a complete absence of immunoglobulins (agammaglobulinemia).[18]

Common Variable Immunodeficiency (CVID)

Defected B-cells lead to low levels of plasma cells and therefore low immunoglobulins. Defects in T cells and dendritic cells are present causing both humoral and cell-mediated immune response disturbance. CVID is defined based on age-specific levels of serum Ig, response to immunization (poor vs absent), absence of profound T-cell immunodeficiency, and any other immunodeficiency states.[27][28][29]

Transient Hypogammaglobulinemia of Infancy (THI)

Seen in 3-6 months of life with low levels of immunoglobulins due to the presence of maternal antibodies crossing the placenta. This indirectly causes immunosuppression for the infant. In addition to IgG, IgM and IgA can also be suppressed during this stage. Ig levels normalize by 3 years of age in most children.[15] Patients with THI may present with recurrent infections or be asymptomatic. The diagnosis can be incidental when evaluated for other reasons.

Selective IgA Deficiency

The main defect consists of immunoglobulin class switching. IgA bearing B lymphocyte cannot convert into an IgA secreting plasma cell.[17] Deficient T helper cells, impaired B-cell signaling, and cytokine disturbance can play a role in defective antibody production. Infectious etiologies and drug-induced deficiency are some secondary causes.

Hyper-IgM Syndrome

This is a rare primary immunodeficiency disorder with normal to elevated IgM levels and decreased levels of IgG, IgA, and IgE immunoglobulins.[30] 

History and Physical

Physical examination may be normal or patients may exhibit signs and symptoms of chronic illnesses.[23]

Some common clinical manifestations are listed below:

1. Infections

  • Recurrent infections of the sino-pulmonary tract with encapsulated pyogenic bacteria (Streptococcus pneumoniae, Hemophilus influenzae type B, Streptococcus pyogenes, Pseudomonas species, and some atypical species).[14] Bacterial infections may be present both before with recurrent otitis media being the most common and after the diagnosis with pneumonia, acute or chronic sinusitis.[7][8][31][32] Patients requiring several rounds of antibiotics to eradicate infections is a common finding.
  • Tympanic membrane scarring from recurrent otitis can be noted on the physical exam.
  • In XLA by 2 years of age, more than 50% of patients have had serious infections with encapsulated bacteria, and virals including coxsackievirus, enterovirus, and echovirus infections are also common.[33][34]
  • In CVID, sinopulmonary infections and complications like bronchiectasis and bronchial wall thickening being common in all age groups. History of at least one episode of bacterial pneumonia is present in almost 75% of the patients prior to diagnosis.[22]
  • Urogenital infections by mycoplasma, gastrointestinal infections by Giardia lamblia (common in IgA deficiency), and Campylobacter jejuni have also been reported in CVID and XLA patients. CNS involvement with intracranial granulomas manifesting as seizures, ataxia, weakness, headaches, vision loss, and coma has been seen in children with CVID.[35]
  • Opportunistic infections are common in Hyper-IgM syndrome. Congenital rubella syndrome may also cause elevated IgM levels.[36]

2. Autoimmune Manifestation

  •  Cytopenias, polyarthritis, and other immune dysfunctions. Autoimmune cytopenias are more common in children with CVID compared to adults. 
  •  Vitiligo, Psoriasis, ITP, Hyper/Hypothyroidism, SLE, JIA, IBD can be the presenting disorder in patients with CVID.[37][38][39] Hematologic disorders are common manifestations of autoimmunity in CVID.[40]
  •  Antibodies to IgA are reported in almost 44% of patients with selective IgA deficiency with an increased incidence of autoimmune diseases and malignancies.

3. Hepatomegaly, Splenomegaly, and Peripheral Lymphadenopathy

  • Physical exam findings in children and adults seen in hypogammaglobulinemia.[22]

4. Allergic Symptoms

  • Allergic diseases such as asthma, eczema, urticaria, and allergic rhinitis have been reported in children with CVID.
  • Children with IgA deficiency have higher rates of atopy and food and drug allergies.[41]

5. Growth Retardation or Developmental Abnormalities

  • Failure to thrive, poor oral intake, GI symptoms like diarrhea, and abdominal pain seen as common findings.
  • With XLA, the absence of tonsils and adenoids can be present in adulthood from prophylaxis treatment with antimicrobials in childhood.
  • In CVID,  GI involvement presenting with diarrhea, weight loss and malabsorption in children and adults are common.
  • In IgA deficiency, children and adults may present with the celiac-like syndrome, recurrent diarrhea with blunting of villi on jejunal biopsy leading to growth retardation in children.[25]

6. ENT Abnormalities and Cardiovascular Abnormalities such as Digeorge or CHARGE Syndromes in Pediatric Patients

  • Tympanic membrane perforation, scarring, and possible hearing loss found on examination.
  • Cobblestoning pattern of mucosa in the pharynx with the absence or underdevelopment of tonsillar tissue, nasal exudates.[42]

7. Malignancies in the Older Population

  • Approximately 25% of patients diagnosed with chronic lymphocytic leukemia (CLL) developed hypogammaglobulinemia long term, this was demonstrated in a study conducted at the Mayo Clinic in the 2000s. IgG levels were subsequently lower during the course of the disease when compared to initial levels during diagnosis.[25][5][43] 
  • Patients with CVID and XLA may also present with colorectal cancer, lymphoreticular malignancies, and non-Hodgkins lymphoma.[44][45]
  • Adults with IgA deficiency may develop complications like adenocarcinoma of stomach and lymphoma.[41]

Evaluation

Diagnostic criteria for hypogammaglobulinemia by the European Society of immunodeficiency (ESID) require a substantial decrease in IgG concentration defined by at least two standard deviations below the average for the age group. The range for healthy adults is from 8 to 12 g/L. In this group, hypogammaglobulinemia is diagnosed by 2 standard deviations below the average with levels less than 5g/L.[25] 

Reduced IgA and IgM isotypes are also commonly seen with low IgG levels. IgM is the main immunoglobulin which is abundant during the primary immune response but is contained in the intravascular compartment. IgG is the most numerous in both vascular and extravascular compartments and interacts with different Fc fragments on immune cells to activate the complement pathway. Measurement of IgG is key in diagnosing Hypogammaglobulinemia. 

Evaluation should consist of:

1. Measuring the serum Immunoglobulin levels (IgM, IgG, IgA):

  • Laboratory tests: CBC with differential, Quantitative serum immunoglobulin levels, Antibody titers in response to immunization (tetanus, diphtheria vaccines), or infections. If the results of the tests are suggestive of XLA, then do flow cytometry to determine the lymphocyte subsets to rule out combined immunodeficiencies.
  • In adults and children with CVID, IgE and allergen-specific IgE may be undetectable or absent. For diagnosing CVID, decreased IgG in association with low levels of IgM and/or IgA is needed using age-specific values for pediatric patients.
  • The level of IgG is at least two standard deviations below the expected controls in patients with THI.[46] Infants with THI make normal antibodies in response to diphtheria, tetanus, hepatitis A & B vaccines, MMR, and conjugated H.influenza. If there is a lack of response, then a complete immunological evaluation is warranted.[47][48][49][50]
  • Hypogammaglobulinemia is the primary lab finding of CVID. It is important to exclude secondary causes and physiologic causes, before considering primary immunodeficiencies. Selective IgA deficiency has normal levels of other Immunoglobulins, with usually elevated IgM levels.[14] Hyper-IgM presents with normal to elevated levels of serum IgM and reduced levels of IgG, IgA, and IgE

2. Functional Antibody production (Isohemagglutinins, IgG antibodies level, post-immunization/post-exposure):

  • Testing for B-cell function can be determined by the presence and titer of isohemagglutinins, and natural antibodies to type A and B red blood cell polysaccharide antigens. It measures IgM antibodies predominantly. The absence of Isohemagglutinins is normal in the 1st two years of life, and are always absent in patients with blood group AB.[14] In addition to the isohemagglutinins, the antibodies produced in response to the antigens during the routine vaccination are abnormally low in XLA but are normal in THI.
  • Adequate antibody response in young children demonstrated by vaccination history, antibody titers to Diphtheria, tetanus, H.influenza excludes the diagnosis of CVID.

3. Flow cytometry for Immunophenotyping of B- cells and T-cell/B-cell evaluation:

  • Conditions of B-cell deficiency mimic each other, hence to differentiate XLA from CVID, hyper–IgM syndrome, and THI flow cytometry is a critical test to demonstrate the absence of circulating B cells which is characteristic of XLA, and presence of B-cells in CVID, IgA deficiency, and hyper-IgM syndromes.[51][52]

4. Genetic testing:

  • A genetic test to identify the mutation in the BTK gene once the decreased Ig and B-cells have been found is needed for confirmation. In the absence of family history, molecular testing is indicated for other B-cell defects and XLA to help with genetic counseling.[14] Genetic testing is usually not required for the diagnosis of CVID but is helpful in understanding the inheritance pattern.
  • Combined immunodeficiencies involving cellular and innate immunity must be excluded in addition to secondary causes of humoral immunodeficiency.

5. Miscellaneous:

  • Additional blood tests (CRP, ESR) and antinuclear antibody testing may be obtained in patients with active infections, and symptoms suggestive of autoimmune conditions respectively. Lymph node biopsy and bone marrow biopsy can be considered if there is a suspicion of lymphoma or myelodysplasia.[53]

Treatment / Management

1. Avoiding infections by practicing hand hygiene, drinking treated water, and having adequate respiratory protection.

2. IV Immunoglobulin replacement therapy has limitations as it only replaces IgG but not IgM or IgA. Immunoglobulin levels need to monitor every 6 months, and the dose should be adjusted based on the patient’s IgG production and weight. Immunoglobulin therapy is not indicated in THI or conditions with normal B cells but specific antibody impairment. Patients with high IgG and mild impairment in response to vaccination can be followed closely. Side effects with IVIG administration may range from inflammatory reactions to rarely anaphylaxis. Headache, AKI, hemolytic anemia, and neutropenia can also be seen. Patients receiving IVIG should be screened for anti-IgA antibodies to prevent anaphylactic reactions caused by a patient’s IgE antibodies to the IgA in the IVIG preparation in patients with CVID or IgA deficiency. Patients with IgA deficiency make IgG antibodies normally and therefore do not need IVIG with >99% IgG. Administration of IVIG with IgA deficient patients may cause anaphylaxis.[54]

3. Antibiotics for active infections or prophylaxis and monitoring for chronic lung problems due to recurrent pneumonia.[55]

4. Systemic glucocorticoids can be used for cytopenias, high dose IVIG, and rituximab as a steroid-sparing adjunctive agent have also shown benefits.[56]

5. Hematopoietic stem cell transplant can also be done when weighing for cost and IVIG availability. In cases with no response to the above treatment, a splenectomy can be considered.[57]

6. Vaccination recommendations: seasonal influenza vaccine for high-risk patients. The recommendations vary according to the severity of antibody deficiency. In severe deficiency, live attenuated vaccines are not recommended but routine vaccination with inactivated vaccines like Influenza, HPV, Anthrax, and Rabies can be given. The vaccination schedule for inactivated or subunit vaccines is the same as the general population in mild antibody deficiency but its important to weigh the benefit and possible harm in administering live-attenuated vaccines to this population.[58]

7. Allergy testing/ PFT  in children with continued sinopulmonary symptoms. They may need allergy testing to rule out asthma or allergic triggers contributing to these symptoms.

8. Repeated ear infections may lead to sensorineural hearing loss and need audio examinations for concerns of impaired hearing or poor school performance.[59]

Differential Diagnosis

Differential diagnosis includes:

  • Drug-induced secondary causes such as antimalarial agents, Phenytoin, Penicillamine, Glucocorticoids. Stopping offending drug and rechecking immunoglobulins is warranted if patients are demonstrating an immunocompromised state.[17]
  • Genetic disorders as mentioned above including but not limited to Hyper IGM immunodeficiency, X-linked agammaglobulinemia, X-linked SCID, Trisomy 18, and 21, ataxia-telangiectasia can be mistaken for hypogammaglobulinemia. A genetic evaluation would be the next step to distinguish any chromosomal involvement or defect.[14]
  • Infectious etiologies such as CMV, EBV, HIV, Rubella, and congenital Toxoplasma gondii. Rule out by PCR is indicated if suspicion is high. Certain viruses and bacterial infections can cause low serum immunoglobulins and must be ruled out. Repeat Serum immunoglobulins once the infection is treated.[17]
  • Malignancies like Chronic lymphocytic leukemia, Non-Hodgkins lymphoma, B cell malignancy can present similar to hypogammaglobulinemia. Oncological evaluation with proper tissue biopsies will be beneficial in certain cases if malignancy is high on the differential. 
  • Systemic disorders such as severe burns, nephrotic syndromes, severe diarrhea, and malnutrition can also be causes of low immunoglobulins. Proper history and examination are essential for adequate evaluation and assessment.[40]

Pertinent Studies and Ongoing Trials

Role of B-cells in COVID-19

In a study involving seven patients with COVID-19 infection and underlying primary immunodeficiencies, it was found that patients with agammaglobulinemia had mild symptoms of COVID-19 as compared to patients with CVID who presented with severe symptoms needing antiretroviral drugs, IL-6 blocking drug therapy, and mechanical ventilation. There were significant changes in high-resolution chest CT noted in response to treatment in these two conditions.
This was attributed to a possible role of B-cells in the inflammation caused by SARS-CoV-2. Also, the reason why children contain the SARS-CoV-2 better in the early infection phase because of the ability of the B-lymphocytes to produce natural antibodies in a timely manner in children when compared to the adults.[60][61][62]

Prognosis

Pulmonary complications and malignancy mainly determine the prognosis. Antibiotics usage and IVIG therapy have decreased the mortality from bacterial infections.[38] Timely intervention can delay or prevent these complications but the range of IgG replacement to prevent the complications is not clear.[63]

Patients with THI with low IgM and IgA levels were found to have a slow recovery, whereas those who breastfed for longer duration had an early recovery. In patients with Hyper-IgM syndrome, mortality is secondary to opportunistic infections, malignancies, and liver/biliary tract disease.[64]

Complications

Pulmonary complications can lead to shorter life expectancy even in early detection of hypogammaglobulinemia. The main complication involved is the development of bronchiectasis which is seen in approximately 20% of patients with a history of recurrent infections. This may cause worsening respiratory symptoms with increased bronchospasms presenting like an obstructive and/or restrictive pulmonary disease.

A high-resolution CT scan is recommended periodically to monitor pulmonary status. Another long term complication is malignancy that is usually seen in the fourth to fifth decades of life, for which close follow up is advised. High dose IVIG started early in the disease course can promote a healthier outcome with decreased pulmonary complications.[65]

Deterrence and Patient Education

It is imperative to educate parents and adult patients about the warning signs such as recurrent sinopulmonary infections, allergic diseases, and prolonged fevers as clues for the diagnosis of hypogammaglobulinemia. The severity of allergic diseases also warrants an investigation by an immunologist for an immunological workup. Patients with CVID whose family members have frequent infections should be evaluated, as they may have increased frequency of selective IgA deficiency and CVID.[14] 

Proper hand hygiene, sanitation, detection of infection in its early stages, and compliance to treatment can improve symptoms and long term outcomes. Medications and certain underlying diseases can be the cause of hypogammaglobulinemia, speaking to a physician regarding long term drugs like glucocorticoids, unintentional weight loss, malnutrition, or a strong family history of early deaths to infections or malignancy need to be discussed for proper assessment and management of the patient.[65]

Pearls and Other Issues

Hypogammaglobulinemias may be primary or secondary and secondary causes need to be excluded prior to the diagnosis of primary immunodeficiencies.

Patients with secondary immunodeficiencies often produce antibodies normally even though the serum IgG is low. Hence it is important to determine the antibody titers to specific antigens before treating with IV immunoglobulins to differentiate between inadequate production vs. protein loss. High serum concentrations of 1 or more Ig classes point towards HIV infection, chronic granulomatous disease, chronic inflammation, or autoimmune lymphoproliferative syndrome.

Children with congenital immunodeficiency present with chronic diarrhea and failure to thrive secondary to malabsorption, also complicated by micronutrient deficiencies including vitamin A, E, B12, calcium, zinc, & iron.

Viral infections are handled well because of intact T-cell function with few exceptions suggesting the role of secretory IgA in host defense against viruses especially the enteroviruses and hepatitis viruses.[14]

Enhancing Healthcare Team Outcomes

It is important to differentiate THI and CVID especially in children younger than 6 years of age because patients with CVID have defective vaccine responses whereas patients with THI produce an adequate response to vaccines and infections. Early recognition of the condition can avoid prolonged delays between symptom onset and immunoglobulin replacement therapy. Prognosis depends on the clinical manifestation of the disease.

Comorbid mental health conditions like depression, anxiety, social withdrawal, and somatization were also associated with pediatric-onset CVID and need to be identified and treated.

Management of immunodeficiencies is complex and needs a multidisciplinary approach involving the immunologist, allergist, infectious disease specialist, pediatrician, pharmacist, and a primary care physician for identification, monitoring, and timely intervention.

Educating the parents about the possible causes, identifying warning signs, evaluating family members with frequent infections, genetic counseling, and compliance with the treatment plan play a crucial role in the management of hypogammaglobulinemias.[66]


References

[1] Yong PF,Chee R,Grimbacher B, Hypogammaglobulinaemia. Immunology and allergy clinics of North America. 2008 Nov;     [PubMed PMID: 18940570]
[2] Carvalho-Neves Forte W,Morad H,Oliveira É,Reis A,Mosca T,Leite L,Santos de-Menezes MC, [Clinical manifestations and late diagnosis of common variable immunodeficiency]. Revista alergia Mexico (Tecamachalco, Puebla, Mexico : 1993). 2019 Oct-Dec;     [PubMed PMID: 32105430]
[3] Litzman J, Primary immunodeficiencies in adults. Vnitrni lekarstvi. 2019 Winter;     [PubMed PMID: 30909700]
[4] Hsu J,Opoka R,Lund TC, Hypogammaglobulinemia in sub-Saharan Africa: a case report and review of the literature. African health sciences. 2015 Mar;     [PubMed PMID: 25834564]
[5] Pimenta FMCA,Palma SMU,Constantino-Silva RN,Grumach AS, Hypogammaglobulinemia: a diagnosis that must not be overlooked. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas. 2019;     [PubMed PMID: 31618370]
[6] Fieschi C,Malphettes M,Galicier L,Oksenhendler E, [Adult-onset primary hypogammaglobulinemia]. Presse medicale (Paris, France : 1983). 2006 May;     [PubMed PMID: 16710162]
[7] Ochs HD,Smith CI, X-linked agammaglobulinemia. A clinical and molecular analysis. Medicine. 1996 Nov;     [PubMed PMID: 8982147]
[8] Winkelstein JA,Marino MC,Lederman HM,Jones SM,Sullivan K,Burks AW,Conley ME,Cunningham-Rundles C,Ochs HD, X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine. 2006 Jul;     [PubMed PMID: 16862044]
[9] Tsukada S,Saffran DC,Rawlings DJ,Parolini O,Allen RC,Klisak I,Sparkes RS,Kubagawa H,Mohandas T,Quan S, Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell. 1993 Jan 29;     [PubMed PMID: 8425221]
[10] Vorechovský I,Cullen M,Carrington M,Hammarström L,Webster AD, Fine mapping of IGAD1 in IgA deficiency and common variable immunodeficiency: identification and characterization of haplotypes shared by affected members of 101 multiple-case families. Journal of immunology (Baltimore, Md. : 1950). 2000 Apr 15;     [PubMed PMID: 10754342]
[11] Fuchs HB,Slater L,Novey H,Ong K,Gupta S, Immunological analysis in familial common variable immunodeficiency. Clinical and experimental immunology. 1984 Apr;     [PubMed PMID: 6609034]
[12] Ahn S,Cunningham-Rundles C, Role of B cells in common variable immune deficiency. Expert review of clinical immunology. 2009 Sep;     [PubMed PMID: 20477641]
[13] Yazdani R,Habibi S,Sharifi L,Azizi G,Abolhassani H,Olbrich P,Aghamohammadi A, Common Variable Immunodeficiency: Epidemiology, Pathogenesis, Clinical Manifestations, Diagnosis, Classification, and Management. Journal of investigational allergology     [PubMed PMID: 30741636]
[14] Pomerance HH, Nelson Textbook of Pediatrics. Archives of pediatrics     [PubMed PMID: 22604661]
[15] GITLIN D,JANEWAY CA, Agammaglobulinemia, congenital, acquired and transient forms. Progress in hematology. 1956;     [PubMed PMID: 13359516]
[16] Whelan MA,Hwan WH,Beausoleil J,Hauck WW,McGeady SJ, Infants presenting with recurrent infections and low immunoglobulins: characteristics and analysis of normalization. Journal of clinical immunology. 2006 Jan;     [PubMed PMID: 16418798]
[17] Abolhassani H,Aghamohammadi A,Hammarström L, Monogenic mutations associated with IgA deficiency. Expert review of clinical immunology. 2016 Dec;     [PubMed PMID: 27266541]
[18] Justiz Vaillant AA,Qurie A, Immunodeficiency 2020 Jan;     [PubMed PMID: 29763203]
[19] Bazregari S,Azizi G,Tavakol M,Asgardoon MH,Kiaee F,Tavakolinia N,Valizadeh A,Abolhassani H,Aghamohammadi A, Evaluation of infectious and non-infectious complications in patients with primary immunodeficiency. Central-European journal of immunology. 2017;     [PubMed PMID: 29479289]
[20] Hammarström L,Vorechovsky I,Webster D, Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clinical and experimental immunology. 2000 May;     [PubMed PMID: 10792368]
[21] Gathmann B,Mahlaoui N,Gérard L,Oksenhendler E,Warnatz K,Schulze I,Kindle G,Kuijpers TW,van Beem RT,Guzman D,Workman S,Soler-Palacín P,De Gracia J,Witte T,Schmidt RE,Litzman J,Hlavackova E,Thon V,Borte M,Borte S,Kumararatne D,Feighery C,Longhurst H,Helbert M,Szaflarska A,Sediva A,Belohradsky BH,Jones A,Baumann U,Meyts I,Kutukculer N,Wågström P,Galal NM,Roesler J,Farmaki E,Zinovieva N,Ciznar P,Papadopoulou-Alataki E,Bienemann K,Velbri S,Panahloo Z,Grimbacher B, Clinical picture and treatment of 2212 patients with common variable immunodeficiency. The Journal of allergy and clinical immunology. 2014 Jul;     [PubMed PMID: 24582312]
[22] Oksenhendler E,Gérard L,Fieschi C,Malphettes M,Mouillot G,Jaussaud R,Viallard JF,Gardembas M,Galicier L,Schleinitz N,Suarez F,Soulas-Sprauel P,Hachulla E,Jaccard A,Gardeur A,Théodorou I,Rabian C,Debré P, Infections in 252 patients with common variable immunodeficiency. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2008 May 15;     [PubMed PMID: 18419489]
[23] Urschel S,Kayikci L,Wintergerst U,Notheis G,Jansson A,Belohradsky BH, Common variable immunodeficiency disorders in children: delayed diagnosis despite typical clinical presentation. The Journal of pediatrics. 2009 Jun;     [PubMed PMID: 19230900]
[24] Yong PL,Orange JS,Sullivan KE, Pediatric common variable immunodeficiency: immunologic and phenotypic associations with switched memory B cells. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2010 Aug;     [PubMed PMID: 20337966]
[25] Samson M,Audia S,Lakomy D,Bonnotte B,Tavernier C,Ornetti P, Diagnostic strategy for patients with hypogammaglobulinemia in rheumatology. Joint bone spine. 2011 May;     [PubMed PMID: 21036646]
[26] Stavnezer J,Schrader CE, IgH chain class switch recombination: mechanism and regulation. Journal of immunology (Baltimore, Md. : 1950). 2014 Dec 1;     [PubMed PMID: 25411432]
[27] Picard C,Bobby Gaspar H,Al-Herz W,Bousfiha A,Casanova JL,Chatila T,Crow YJ,Cunningham-Rundles C,Etzioni A,Franco JL,Holland SM,Klein C,Morio T,Ochs HD,Oksenhendler E,Puck J,Tang MLK,Tangye SG,Torgerson TR,Sullivan KE, International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity. Journal of clinical immunology. 2018 Jan;     [PubMed PMID: 29226302]
[28] Bonilla FA,Barlan I,Chapel H,Costa-Carvalho BT,Cunningham-Rundles C,de la Morena MT,Espinosa-Rosales FJ,Hammarström L,Nonoyama S,Quinti I,Routes JM,Tang ML,Warnatz K, International Consensus Document (ICON): Common Variable Immunodeficiency Disorders. The journal of allergy and clinical immunology. In practice. 2016 Jan-Feb;     [PubMed PMID: 26563668]
[29] Seidel MG,Kindle G,Gathmann B,Quinti I,Buckland M,van Montfrans J,Scheible R,Rusch S,Gasteiger LM,Grimbacher B,Mahlaoui N,Ehl S, The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity. The journal of allergy and clinical immunology. In practice. 2019 Jul - Aug;     [PubMed PMID: 30776527]
[30] Moazzami B,Yazdani R,Azizi G,Kiaei F,Tafakori M,Modaresi M,Shirzadi R,Mahdaviani SA,Sohani M,Abolhassani H,Aghamohammadi A, Respiratory Complications in Patients with Hyper IgM Syndrome. Journal of clinical immunology. 2019 Aug;     [PubMed PMID: 31183658]
[31] Lederman HM,Winkelstein JA, X-linked agammaglobulinemia: an analysis of 96 patients. Medicine. 1985 May;     [PubMed PMID: 2581110]
[32] Plebani A,Soresina A,Rondelli R,Amato GM,Azzari C,Cardinale F,Cazzola G,Consolini R,De Mattia D,Dell'Erba G,Duse M,Fiorini M,Martino S,Martire B,Masi M,Monafo V,Moschese V,Notarangelo LD,Orlandi P,Panei P,Pession A,Pietrogrande MC,Pignata C,Quinti I,Ragno V,Rossi P,Sciotto A,Stabile A, Clinical, immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study. Clinical immunology (Orlando, Fla.). 2002 Sep;     [PubMed PMID: 12217331]
[33] Wilfert CM,Buckley RH,Mohanakumar T,Griffith JF,Katz SL,Whisnant JK,Eggleston PA,Moore M,Treadwell E,Oxman MN,Rosen FS, Persistent and fatal central-nervous-system ECHOvirus infections in patients with agammaglobulinemia. The New England journal of medicine. 1977 Jun 30;     [PubMed PMID: 301244]
[34] Halliday E,Winkelstein J,Webster AD, Enteroviral infections in primary immunodeficiency (PID): a survey of morbidity and mortality. The Journal of infection. 2003 Jan;     [PubMed PMID: 12504601]
[35] Touw CM,van de Ven AA,de Jong PA,Terheggen-Lagro S,Beek E,Sanders EA,van Montfrans JM, Detection of pulmonary complications in common variable immunodeficiency. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2010 Aug;     [PubMed PMID: 19912551]
[36] Ameratunga R,Woon ST,Koopmans W,French J, Cellular and molecular characterisation of the hyper immunoglobulin M syndrome associated with congenital rubella infection. Journal of clinical immunology. 2009 Jan;     [PubMed PMID: 18663564]
[37] Cunningham-Rundles C,Bodian C, Common variable immunodeficiency: clinical and immunological features of 248 patients. Clinical immunology (Orlando, Fla.). 1999 Jul;     [PubMed PMID: 10413651]
[38] Resnick ES,Moshier EL,Godbold JH,Cunningham-Rundles C, Morbidity and mortality in common variable immune deficiency over 4 decades. Blood. 2012 Feb 16;     [PubMed PMID: 22180439]
[39] Agarwal S,Cunningham-Rundles C, Autoimmunity in common variable immunodeficiency. Annals of allergy, asthma     [PubMed PMID: 31349011]
[40] Wang J,Cunningham-Rundles C, Treatment and outcome of autoimmune hematologic disease in common variable immunodeficiency (CVID). Journal of autoimmunity. 2005 Aug;     [PubMed PMID: 15994061]
[41] Yazdani R,Azizi G,Abolhassani H,Aghamohammadi A, Selective IgA Deficiency: Epidemiology, Pathogenesis, Clinical Phenotype, Diagnosis, Prognosis and Management. Scandinavian journal of immunology. 2017 Jan;     [PubMed PMID: 27763681]
[42] Schilder AG,Chonmaitree T,Cripps AW,Rosenfeld RM,Casselbrant ML,Haggard MP,Venekamp RP, Otitis media. Nature reviews. Disease primers. 2016 Sep 8;     [PubMed PMID: 27604644]
[43] Parikh SA,Leis JF,Chaffee KG,Call TG,Hanson CA,Ding W,Chanan-Khan AA,Bowen D,Conte M,Schwager S,Slager SL,Van Dyke DL,Jelinek DF,Kay NE,Shanafelt TD, Hypogammaglobulinemia in newly diagnosed chronic lymphocytic leukemia: Natural history, clinical correlates, and outcomes. Cancer. 2015 Sep 1;     [PubMed PMID: 25931291]
[44] Lavilla P,Gil A,Rodríguez MC,Dupla ML,Pintado V,Fontán G, X-linked agammaglobulinemia and gastric adenocarcinoma. Cancer. 1993 Sep 1;     [PubMed PMID: 8348486]
[45] van der Meer JW,Weening RS,Schellekens PT,van Munster IP,Nagengast FM, Colorectal cancer in patients with X-linked agammaglobulinaemia. Lancet (London, England). 1993 Jun 5;     [PubMed PMID: 8099142]
[46] Dalal I,Reid B,Nisbet-Brown E,Roifman CM, The outcome of patients with hypogammaglobulinemia in infancy and early childhood. The Journal of pediatrics. 1998 Jul;     [PubMed PMID: 9672529]
[47] Wang HC,Whelan MA,McGeady SJ,Yousef E, A 5-month-old boy with recurrent respiratory infections, failure to thrive, and borderline elevated sweat chloride levels. Allergy and asthma proceedings. 2006 May-Jun;     [PubMed PMID: 16913275]
[48] Eroglu FK,Aerts Kaya F,Cagdas D,Özgür TT,Yılmaz T,Tezcan İ,Sanal Ö, B lymphocyte subsets and outcomes in patients with an initial diagnosis of transient hypogammaglobulinemia of infancy. Scandinavian journal of immunology. 2018 Oct;     [PubMed PMID: 30152873]
[49] Rutkowska M,Trzyna E,Lenart M,Szaflarska A,Pituch-Noworolska A,Kobylarz K,Siedlar M, The elevated number of circulating regulatory T cells in patients with transient hypogammaglobulinemia of infancy is not associated with any abnormalities in the genes encoding the TGF-β receptors. Clinical immunology (Orlando, Fla.). 2013 Oct;     [PubMed PMID: 23899993]
[50] Karaca NE,Aksu G,Gulez N,Yildiz B,Azarsiz E,Kutukculer N, New laboratory findings in Turkish patients with transient hypogammaglobulinemia of infancy. Iranian journal of allergy, asthma, and immunology. 2010 Dec;     [PubMed PMID: 21131704]
[51] Argyropoulos KV,Palomba ML, First-Generation and Second-Generation Bruton Tyrosine Kinase Inhibitors in Waldenström Macroglobulinemia. Hematology/oncology clinics of North America. 2018 Oct;     [PubMed PMID: 30190023]
[52] Wu J,Zhang M,Liu D, Bruton tyrosine kinase inhibitor ONO/GS-4059: from bench to bedside. Oncotarget. 2017 Jan 24;     [PubMed PMID: 27776353]
[53] Salzer U,Warnatz K,Peter HH, Common variable immunodeficiency: an update. Arthritis research     [PubMed PMID: 23043756]
[54] Tillman BF,Pauff JM,Satyanarayana G,Talbott M,Warner JL, Systematic review of infectious events with the Bruton tyrosine kinase inhibitor ibrutinib in the treatment of hematologic malignancies. European journal of haematology. 2018 Apr;     [PubMed PMID: 29285806]
[55] El-Shanawany TM,Williams PE,Jolles S, Response of refractory immune thrombocytopenic purpura in a patient with common variable immunodeficiency to treatment with rituximab. Journal of clinical pathology. 2007 Jun;     [PubMed PMID: 17483248]
[56] Mahévas M,Le Page L,Salle V,Cevallos R,Smail A,Duhaut P,Ducroix JP, Efficiency of rituximab in the treatment of autoimmune thrombocytopenic purpura associated with common variable immunodeficiency. American journal of hematology. 2006 Aug;     [PubMed PMID: 16823831]
[57] Sève P,Bourdillon L,Sarrot-Reynauld F,Ruivard M,Jaussaud R,Bouhour D,Bonotte B,Gardembas M,Poindron V,Thiercelin MF,Broussolle C,Oksenhendler E, Autoimmune hemolytic anemia and common variable immunodeficiency: a case-control study of 18 patients. Medicine. 2008 May;     [PubMed PMID: 18520327]
[58] Sobh A,Bonilla FA, Vaccination in Primary Immunodeficiency Disorders. The journal of allergy and clinical immunology. In practice. 2016 Nov - Dec;     [PubMed PMID: 27836056]
[59] Berlucchi M,Soresina A,Redaelli De Zinis LO,Valetti L,Valotti R,Lougaris V,Meini A,Salsi D,Nicolai P,Plebani A, Sensorineural hearing loss in primary antibody deficiency disorders. The Journal of pediatrics. 2008 Aug;     [PubMed PMID: 18639734]
[60] Quinti I,Lougaris V,Milito C,Cinetto F,Pecoraro A,Mezzaroma I,Mastroianni CM,Turriziani O,Bondioni MP,Filippini M,Soresina A,Spadaro G,Agostini C,Carsetti R,Plebani A, A possible role for B cells in COVID-19? Lesson from patients with agammaglobulinemia. The Journal of allergy and clinical immunology. 2020 Jul;     [PubMed PMID: 32333914]
[61] Grimsholm O,Piano Mortari E,Davydov AN,Shugay M,Obraztsova AS,Bocci C,Marasco E,Marcellini V,Aranburu A,Farroni C,Silvestris DA,Cristofoletti C,Giorda E,Scarsella M,Cascioli S,Barresi S,Lougaris V,Plebani A,Cancrini C,Finocchi A,Moschese V,Valentini D,Vallone C,Signore F,de Vincentiis G,Zaffina S,Russo G,Gallo A,Locatelli F,Tozzi AE,Tartaglia M,Chudakov DM,Carsetti R, The Interplay between CD27{sup}dull{/sup} and CD27{sup}bright{/sup} B Cells Ensures the Flexibility, Stability, and Resilience of Human B Cell Memory. Cell reports. 2020 Mar 3;     [PubMed PMID: 32130900]
[62] De Schryver S,Mazer B,Clarke AE,St Pierre Y,Lejtenyi D,Langlois A,Torabi B,Zhao WW,Chan ES,Baerg I,Ben-Shoshan M, Adverse Events in Oral Immunotherapy for the Desensitization of Cow's Milk Allergy in Children: A Randomized Controlled Trial. The journal of allergy and clinical immunology. In practice. 2019 Jul - Aug;     [PubMed PMID: 30776522]
[63] Gregersen S,Aaløkken TM,Mynarek G,Fevang B,Holm AM,Ueland T,Aukrust P,Kongerud J,Johansen B,Frøland SS, Development of pulmonary abnormalities in patients with common variable immunodeficiency: associations with clinical and immunologic factors. Annals of allergy, asthma     [PubMed PMID: 20568383]
[64] de la Morena MT,Leonard D,Torgerson TR,Cabral-Marques O,Slatter M,Aghamohammadi A,Chandra S,Murguia-Favela L,Bonilla FA,Kanariou M,Damrongwatanasuk R,Kuo CY,Dvorak CC,Meyts I,Chen K,Kobrynski L,Kapoor N,Richter D,DiGiovanni D,Dhalla F,Farmaki E,Speckmann C,Español T,Shcherbina A,Hanson IC,Litzman J,Routes JM,Wong M,Fuleihan R,Seneviratne SL,Small TN,Janda A,Bezrodnik L,Seger R,Raccio AG,Edgar JD,Chou J,Abbott JK,van Montfrans J,González-Granado LI,Bunin N,Kutukculer N,Gray P,Seminario G,Pasic S,Aquino V,Wysocki C,Abolhassani H,Dorsey M,Cunningham-Rundles C,Knutsen AP,Sleasman J,Costa Carvalho BT,Condino-Neto A,Grunebaum E,Chapel H,Ochs HD,Filipovich A,Cowan M,Gennery A,Cant A,Notarangelo LD,Roifman CM, Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation. The Journal of allergy and clinical immunology. 2017 Apr;     [PubMed PMID: 27697500]
[65] Wang LJ,Yang YH,Lin YT,Chiang BL, Immunological and clinical features of pediatric patients with primary hypogammaglobulinemia in Taiwan. Asian Pacific journal of allergy and immunology. 2004 Mar;     [PubMed PMID: 15366655]
[66] Baloh C,Reddy A,Henson M,Prince K,Buckley R,Lugar P, 30-Year Review of Pediatric- and Adult-Onset CVID: Clinical Correlates and Prognostic Indicators. Journal of clinical immunology. 2019 Oct;     [PubMed PMID: 31377970]