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Hypogammaglobulinemia

Hypogammaglobulinemias

Hypogammaglobulinemia is a term describing insufficient levels of gamma globulins, which may occur from malignant, genetic or iatrogenic diseases. Recurrent infections of the respiratory tract and the ear are the main clinical manifestations and infections are one of the most important complications. The diagnosis is made through laboratory and imaging studies, whereas intravenous immunoglobulins coupled with long-term antibiotic prophylaxis are main therapeutic measures.

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Presentation

In patients with X-linked agammaglobulinemia, different clinical phenomena may be observed depending on age [2]. In children between 6 months and 5 years, paralysis after oral polio immunization is considered as a hallmark, whereas deterioration of dermatomyositis and chronic echo-virus encephalitis are seen in in children older than 5 years [2]. In the vast majority of patients, however, recurrent otitis is one of the most prevalent symptoms [13], while pneumonia, sinusitis and other types of infections are readily observed. Physicians may encounter decreased or even absent cervical lymph nodes or tonsils, suggesting hypoplasia of lymphoid tissue [13]. Recurrent infections are clinical hallmarks of CVID as well [12].

Recurrent Infection
  • Recurrent infections of the respiratory tract and the ear are the main clinical manifestations and infections are one of the most important complications.[symptoma.com]
  • Incidence of Hypogammaglobulinemia in Patients Receiving Rituximab and the Use of Intravenous Immunoglobulin for Recurrent Infections. Clin Lymphoma Myeloma Leuk. 2012 Dec 28. [Medline].[emedicine.com]
  • The case emphasizes the importance of including hypogammaglobulinemia in the differential diagnosis for children presenting with a history of recurrent infections.[ncbi.nlm.nih.gov]
Weight Loss
  • We present a 67-year-old patient with chronic lymphocytic leukemia (CLL) who presented with weight loss of 40 pounds, severe diarrhea, hypoalbuminemia and hypokalemia.[ncbi.nlm.nih.gov]
  • More than half of patients present with diarrhea and 10% develop idiopathic malabsorption associated with weight loss.[medcraveonline.com]
  • loss, intermittent fever, right loin pain, intermittent abdominal pain, and small volume diarrhea of 3–4 episodes/day for 7–8 months with weight loss of 8 kg over 8 months.[ijccm.org]
Recurrent Otitis Media
  • Case description: A 41-year-old female with TS, hypothyroidism, and recurrent otitis media as a child presents with severe vitamin deficiencies including: iron, vitamin B12 and vitamin D.[eposters.net]
  • otitis media and meningitis, asthma 6.2 2 0.8 48 F Chronic HCV infection, cirrhosis, chronic kidney disease 3 67 M Remote ovarian cancer and meningioma, depression, seizures 2.5 0.6 0.1 Serum reference ranges: IgG 6 g/L, IgA 0.7 g/L, IgM 0.5 g/L [8].[academic.oup.com]
  • Hearing loss is seen in nearly half of patients, some of which is no doubt due to recurrent otitis media but CT radiography has demonstrated dysplastic morphology of inner ear structures and the petrous bone.[disorders.eyes.arizona.edu]
  • Children with THI typically begin to experience increasingly frequent and recurrent otitis media, sinusitis, and bronchial infections.[clinicaladvisor.com]
Recurrent Upper Respiratory Infection
  • High incidence of recurrent upper respiratory infections but usually not severe infections and doesn't require immunoglobulin therapy. Bruton's X-linked hypogammaglobulinaemia : usually presents at age 7-10 months.[patient.info]
  • CVID was considered a likely diagnosis, since it is often made during the second or third decade of life, however it is usually associated with a history of recurrent upper respiratory infections [ 6 ], not noted here.[journals.plos.org]
Recurrent Bronchitis
  • Over 98% of patients present with recurrent bronchitis, sinusitis, otitis and pneumonia, and chronic pulmonary damage is the major complication.[orpha.net]
  • Infections are usually localized in the respiratory tract and a majority of patients have recurrent bronchitis, sinusitis, or otitis (which is more common in childhood-onset CVID), and have had one or more episodes of pneumonia. click for large version[the-rheumatologist.org]
Pneumonia
  • After the start of IVIG replacement, there was a decline in the frequency of pneumonia (p Conclusion:: Pulmonary complications were common in this cohort, despite the decrease in the frequency of pneumonia with treatment.[ncbi.nlm.nih.gov]
  • Infections of the lungs (pneumonia), ear (otitis) and sinuses (sinusitis) are most frequently reported.[symptoma.com]
  • Streptococcus pneumoniae is the most common cause of community-acquired pneumonia (CAP) worldwide and accounts for 27.3% of CAP cases [ 1 ].[academic.oup.com]
  • People with hypogammaglobulinemia can more easily catch pneumonia, meningitis, and other infections that a healthy immune system would normally protect against. These infections can damage organs and lead to potentially serious complications.[healthline.com]
  • Dalal et al reported that recurrent upper respiratory tract infections occurred in most patients and recurrent pneumonia occurred in 23% of patients.[clinicaladvisor.com]
Nasal Discharge
  • It is also important to establish whether there is chronic damage related to recurrent infection: shortness of breath, chronic cough, and sputum production may indicate the presence of bronchiectasis; sinus pain, nasal discharge, and postnasal drip may[online.epocrates.com]
  • Sinus pain, nasal discharge, and postnasal drip may indicate the presence of chronic sinusitis.[en.wikipedia.org]
Rales
  • […] and throat abnormalities (eg, tympanic membrane perforation, purulent nasal discharge, cobblestone pattern of pharyngeal mucosa, and nasal exudate) Pulmonary abnormalities suggestive of recurrent infections (eg, bronchiectasis and lung fibrosis with rales[emedicine.com]
Diarrhea
  • We present a 67-year-old patient with chronic lymphocytic leukemia (CLL) who presented with weight loss of 40 pounds, severe diarrhea, hypoalbuminemia and hypokalemia.[ncbi.nlm.nih.gov]
  • More than half of CVID patients present with diarrhea and possible risk of malabsorption and weight loss. Chronic diarrhea presents as one of the most common clinical presentation of CVID [1-4].[medcraveonline.com]
  • Other important presenting symptoms may include failure to thrive in children, chronic diarrhea, and complications after receiving live vaccines.[online.epocrates.com]
  • Immunodeficiency with Thymoma Non Hodgkin's lymphoma B cell malignancy Systemic Disorders Immunodeficiency caused by hypercatabolism of immunoglobulin Immunodeficiency caused by excessive loss of immunoglobulins (nephrosis, severe burns, lymphangiectasia, severe diarrhea[esid.org]
Chronic Diarrhea
  • Chronic diarrhea was the presentation in majority (90.9 %) of patients. Malabsorption was identified in 87.5 % of patients followed by weight loss (59.0 %), abdominal pain (27.2 %), and oral ulcers (4.5 %).[ncbi.nlm.nih.gov]
  • Chronic diarrhea presents as one of the most common clinical presentation of CVID [1-4].[medcraveonline.com]
  • Gastrointestinal symptoms may include chronic diarrhea, persistent vomiting, food allergy and/or intolerance. Neutropenia (low white blood cells) is not uncommon.[primaryimmune.org]
  • Infections that cause chronic diarrhea are also common. Recurrent infections can lead to organ damage.[icdlist.com]
  • Symptoms include frequent episodes of: Bronchitis (airway infection) Chronic diarrhea Conjunctivitis (eye infection) Otitis media (middle ear infection) Pneumonia (lung infection) Sinusitis (sinus infection) Skin infections Upper respiratory tract infections[nlm.nih.gov]
Heart Murmur
  • However, such an examination is necessary to exclude other potential cardiac causes of syncope or cardiac arrest in an otherwise healthy patient (eg, heart murmurs from hypertrophic cardiomyopathy or from a valvular or septal defect).[emedicine.medscape.com]
Eczema
  • Babies with hypogammaglobulinemia often get respiratory tract infections, food allergies, and eczema. Infants can also develop urinary tract and intestinal infections.[healthline.com]
  • The eczema-like patches on upper extremities and eyelids which was reported previously by the patient, were not observed at the time of visit or afterwards.[medcraveonline.com]
Arthritis
  • The clinical presentation of a monoarticular, red, hot, and swollen joint has many possible diagnoses, including septic arthritis, which is 1 of the most devastating.[ncbi.nlm.nih.gov]
  • In many cases, acute septic arthritis may occur after recognized or unrecognized bacteremia.[emedicine.medscape.com]
Arthralgia
  • Musculoskeletal symptoms Arthralgia and monoarticular or oligoarticular arthritis of the large joints with sterile effusions occasionally occur. Ureaplasma urealyticum has been implicated in the pathogenesis of "sterile" arthritis.[emedicine.medscape.com]
  • Arthralgia, monoarticular or oligoarticular arthritis of the large joints with sterile effusions and septic arthritis may occur. Anaphylaxis or other severe reactions following transfusion of blood products may indicate an underlying IgA deficiency.[patient.info]

Workup

Patient history may be one of the most important parts of the diagnostic workup, as signs and symptoms may provide important clues for further evaluation [2]. Additionally, history of prolonged immunosuppression therapy, antiepileptics, sulfasalazine, or rituximab and other immunotherapeutics [4] [8], should prompt the physician to evaluate and iatrogenic etiology, as these two drug groups are known causes of reduced IgG levels [1]. In all patients with suspected hypogammaglobulinemia, a complete blood count (CBC) with determination of lymphocyte subset numbers, as well as their distribution is necessary, most frequently through flow cytometry [4]. In the setting of transient hypogammaglobulinemia, IgG levels below 2 standard deviations for appropriate age and normal B lymphocyte numbers are highly suggestive of the diagnosis [7]. Because of possible renal loss of immunoglobulins, kidney function tests, including urinalysis for protein levels, urea and creatinine should be performed [1]. CT of the chest, abdomen and pelvis is of significant benefit in evaluation of lymph nodes and viscera [11].

Treatment

Antibody replacement therapy through administration of intravenous immunoglobulins (IVIG) is the mainstay of therapy in these patients [4]. A starting dose of 400-600 mg/kg/per month is recommended, but in patients with severe hypogammaglobulinemia (< 2g/L), a loading dose of 1g/kg of body weight may be necessary [4]. The administration of IVIG is carried out once weekly or once every two weeks when subcutaneous routes are used, whereas intravenous administration requires a regimen of once every three to four weeks [4]. The use of IVIG is a topic of significant debate for transient hypogammaglobulineia of infancy, but its use has proved to be beneficial in severe forms of the disease [11]. Antibiotic prophylaxis is considered to be equally important in long-term management of patients with hypogammaglobulinemia, primarily because infections are the most important causes of morbidity. Amoxicillin, amoxicillin-clavulanate, trimethoprim-sulfamethoxazole, azithromycin or clarithromycin are used in various regimens and depending on the source of infection [4].

Prognosis

The prognosis depends on the underlying cause, but recurrent infections are present regardless of the disease and are established as most important complications [11]. In addition, numerous diseases may appear in patients with hypogammaglobulinemia. 10% of patients suffering from CVID will develop gastric carcinoma or lymphoma, autoimmune diseases including SLE, Addison's disease, thyroiditis, rheumatoid arthritis and several other have shown increased rates in these patients [2] [12]. Bronchiectasis, one of the forms of chronic obstructive pulmonary disease were also seen in higher rates in patients who suffer from hypogammaglobulinemia [2]. Infections, however, are the most important causes of morbidity in these patient, the most important pathogens being Streptococcus pneumoniae and Haemophilus influenzae. [6]. 20-years Survival rates for CVID are estimated at 64% and 67% for males and females, respectively, indicating that this form of immunodeficiency poses great risk, especially if not diagnosed on time[5]. Transient hypogammaglobulinemia of infancy may spontaneously resolve within a few years.

Etiology

Most important causes of hypogammaglobulinemia are:

  • X-linked agammaglobulinemia, caused by deficiency of tyrosine kinase BTK enzyme characterized by the appearance of infections during infancy, as well as neutropenia and lymphoid hypoplasia [3].
  • Common variable immunodeficiency (CVID), a multifactorial disease belonging to the group of primary immunodeficiencies that results in inability of antibody production by B cells that for some reason do not proliferate into plasma B cells [3]., presents in mid-adulthood with typical symptoms [5].
  • Transient hypogammaglobulinemia of infancy (THI) is considered to be a prolongation of the period during infancy (3-6 months) when IgG levels are physiologically low, presumably due to delayed B and T cell maturation and involvement of various inflammatory cytokines that render Ig production [3].
  • Good syndrome, associated with the presence of both benign or malignant thymoma and recurrent infections in middle aged adults (around 40 years), is also a recognized cause of hypogammaglobulinemia [1] [7].
  • Drug induced hypogammaglobulinemia has been diagnosed in patients on prolonged immunosuppressive, antiepileptic, or antimalarial therapy [1] [4]. Rituximab, an anti-CD20 monoclonal antibody used for various lymphoproliferative diseases, is particularly known for its deleterious effects through destruction of B cells and consequent hypogammaglobulinemia [8].
  • Hematologic malignancies - Non-hodgkin lymphoma, chronic lymphocytic leukemia (CLL) and multiple myeloma are some of the most important lymphoproliferative disorders responsible for reduced gamma-globulin production [9]., In about 15% of patients suffering non-Hodgkin lymphoma and 25% of patients with CLL, hypogammaglobulinemia occurs as a result of progressive reduction in antibody production, thus predisposing patients to various forms of infections [2] [10].
  • Renal loss - Nephrotic syndrome, severe burns and protein-losing enteropathy are conditions in which excessive loss of proteins, including gamma globulins occur through renal excretion [9].
  • Post-transplantation hypogammaglobulinemia has also been described [9].

Epidemiology

Transient hypogammaglobulinemia of infancy is considered to be one of the most common forms of primary immunodeficiency and isolated epidemiological reports show a prevalence rate of 7 per 100,000 individuals [11]. X-linked agammaglobulinemia, on the other hand, has an estimated prevalence rate of 1 per 190,000 male births in the United States [4]. Age and onset of symptoms is an important factor in distinguishing between diseases that cause reduced IgG production. XLA is symptomatic in 90% of patients by the age of 5 [4]., whereas certain reports have determined that CVID is most commonly diagnosed at the end of third and the beginning of fourth decade of life [5]. Moreover, Good's syndrome is almost exclusively seen in patients around 40 years [1].

Sex distribution
Age distribution

Pathophysiology

In almost all diseases (except renal loss of gamma globulins), impaired B cell function is the main pathophysiological event, but various forms of B-cell damage have been established. The pathogenesis model for THI is incompletely formed, but most likely includes abnormal secretion of interleukin 10 (IL-10) and two tumor necrosis factors - TNF-α and TNF-β, leading to an excessive Th1-T cell subtype activation that causes abnormalities in B-cell development [3]. Additionally, the role of CD19/CD21 co-receptor complex in regulating the B cell response has been well-documented and deficiencies of CD19 or CD21 were shown to be crucial in poor B cell response to antigens and low antibody production [3]. In X-linked agammaglobulinemia, mutations of the tyrosine kinase BTK enzyme lead to inability of B cells to proliferate from the bone marrow [4]., whereas rituximab is known for its role of marked B-cell suppression [8]. In hematologic diseases, a combination of immune-mediated mechanism triggered by malignant alteration and the effects of chemotherapy has been proposed as the pathogenic mechanism [9].

Prevention

Certain studies have determined that 5-6 years pass from the onset of symptoms to the diagnosis [5]., suggesting that physicians need to consider this condition when evaluating patients with recurrent infections and other signs that may suggest an impaired immune function. Drug-induced hypogammaglobulinemia can be prevented in some patients through regular follow-ups and monitoring of B-cell function through various laboratory tests, whereas long-term management of the underlying cause (when possible) might be one of the most important preventive strategy.

Summary

Hypogammaglobulinemia a rare clinical condition defined as plasma levels of immunoglobulin G under 5g/L [1]. Numerous diseases have been described as potential causes that either impair normal antibody production or provoke their loss from the body. Hematologic malignancies such as chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma and multiple myeloma, primary immune deficits including common variable immunodeficiency (CVID), renal diseases that trigger excretion of proteins (nephrotic syndrome and protein-losing enteropathy), but also various drugs (immunosuppessants, antiepileptics and immunotherapeutics) are all established causes of hypogammaglobulinemia [2]. Additionally, this condition may appear in the setting of transient hypogammaglobulinemia of infancy (THI), where the physiological period of 3-6 months of age in which low IgG levels are normally observed is prolonged [3]. The pathogenesis model significantly varies from one condition to another, but the end-result is insufficient production of gamma globulins from B cells. The diagnosis can be made in patients in patients of various ages and their respective clinical appearance should be taken into consideration in the differential diagnosis [4] [5]. Clinical presentation invariably includes recurrent infections - pneumonia, otitis and sinusitis, most frequently caused by Streptococcus pneumoniae and Haemophilus influenzae [6]., which are the most significant complications seen in hypogammaglobulinemia. To make the diagnosis, it is necessary to obtain a thorough patient history and conduct a meticulous physical examination, while various laboratory and imaging findings may be used to support the obtained findings. A complete blood counts (CBC) with determination of lymphocyte numbers and their distribution, renal function tests and computed tomography (CT) of the chest, abdomen and pelvis are recommended [1] [4]. Long-term antibiotic prophylaxis and replacement of antibodies through intravenous immunoglobulins (IVIG) are the two main forms of therapy that have shown marked success when administered carefully and appropriately [4]. The prognosis of patients with hypogammaglobulinemia depend on several factors, such as the underlying cause and its management, level of long-term care and the promptness of the diagnosis, as studies have determined that several years may pass from the onset of the disease to its diagnosis [5]. For these reasons, a high clinical suspicion is necessary in children and younger adults who report recurrent infectious without an identifiable cause.

Patient Information

Hypogammaglobulinemia is a rare clinical condition that is defined as reduced levels of a specific subset of antibodies (gamma globulins or IgG) in the circulation. Numerous conditions are described as potential causes:

  • Hematologic malignancies, including non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL) and multiple myeloma.
  • X-linked agammaglobulinemia, in which mutations of enzymes responsible for maturation of cells that should normally produce these antibodies (B cells) are observed, are one of the most important causes of hypogammaglobulinemia in early childhood.
  • Various drugs, such as rituximab, used for blood cancers and causes destruction of B cells, is one of the most important drugs that trigger impaired antibody production, while antiepileptics and immunosuppressant have also been described in literature.
  • Common variable immunodeficiency, a disorder of B and T cells, causes various abnormalities of the immune system, including hypogammaglobulinemia. Symptoms appear at the beginning of the third decade, but the diagnosis is most often made several years after their appearance.
  • Good's syndrome, a disease associated with both benign and malignant tumors of the thymus gland (thymoma) is diagnosed in middle-aged adults in most cases because of a somewhat late onset.
  • Transient hypogammaglobulinemia of infancy (THI) is considered to be a prolongation of the physiological period of low IgG levels between 3-6 months of age, most likely as a result of activation of various pro-inflammatory cytokines and deficiency of molecules that serve as receptors found on B cells, but the exact cause remains unknown.

In virtually all conditions, the end-result is impaired activity of B cells, except in the setting of renal diseases such as nephrotic syndrome and protein-losing enteropathy, in which increased excretion of proteins through urine consequently reduces the levels of gamma globulins in the circulation. The main clinical symptom (and the most important complication) is the presence of recurrent infections that occur due to the inability of the immune system to defend against various microorganisms, most important pathogens being Streptococcus pneumoniae and Haemophilus influenzae. Infections of the lungs (pneumonia), ear (otitis) and sinuses (sinusitis) are most frequently reported. Having in mind the age of onset and typical symptoms, the physician should carefully evaluate these patients through a detailed patient history and a proper physical examination, whereas laboratory and imaging studies should be used in order to confirm the diagnosis and the underlying cause. The focus of treatment is aimed at prevention of recurrent infections through long-term antibiotic prophylaxis together with administration of intravenous immunoglobulins (IVIG) to replace the depleted stores of IgG. In addition to recurrent infections, patients are exposed to numerous autoimmune diseases and malignancies (approximately 10% of patients develop gastric carcinoma or lymphoma), which is why high clinical suspicion and an early diagnosis is necessary in these patients.

References

Article

  1. Samson M, Audia S, Lakomy D, et al. Diagnostic strategy for patients with hypogammaglobulinemia in rheumatology. Joint Bone Spine. 2011;78(3):241-245
  2. Porter RS, Kaplan JL. Merck Manual of Diagnosis and Therapy. 19th Edition. Merck Sharp & Dohme Corp. Whitehouse Station:N.J; 2011.
  3. Artac H, Kara R, Gokturk B, et al. Reduced CD19 expression and decreased memory B cell numbers in transient hypogammaglobulinemia of infancy. Clin Exp Med. 2013;13(4):257-263.
  4. Fried AJ, Bonilla FA. Pathogenesis, Diagnosis, and Management of Primary Antibody Deficiencies and Infections. Clin Microbiol Rev. 2009;22(3):396-414.
  5. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92(1):34-48.
  6. Fieschi C, Malphettes M, Galicier L, et al. Adult-onset primary hypogammaglobulinemia. [Article in French] Presse Med. 2006;35(5 Pt 2):887-894.
  7. Agarwal S, Cunningham-Rundles C. Assessment and clinical interpretation of reduced IgG values. Ann Allergy Asthma Immunol. 2007;99(3):281-283.
  8. Filanovsky K, Miller EB, Sigler E, et al. Incidence of Profound Hypogammaglobulinemia and Infection Rate in Lymphoma Patients Following the Combination of Chemotherapy and Rituximab. Recent Pat Anticancer Drug Discov. 2016;11(2):228-235.
  9. Compagno N, Malipiero G, Cinetto F, et al.Immunoglobulin Replacement Therapy in Secondary Hypogammaglobulinemia. Front Immunol. 2014;5:626.
  10. Parikh SA, Leis JF, Chaffee KG, et al. Hypogammaglobulinemia in newly diagnosed chronic lymphocytic leukemia: Natural history, clinical correlates, and outcomes. Cancer. 2015;121(17):2883-2891
  11. Memmedova L, Azarsiz E, Edeer Karaca N, et al. Does intravenous immunoglobulin therapy prolong immunodeficiency in transient hypogammaglobulinemia of infancy?. Pediatr Rep. September 2013;5(3):e14.
  12. Sneller MC. Common variable immunodeficiency. Am J Med Sci. 2001;321(1):42-48.
  13. Conley ME, Howard V. Clinical findings leading to the diagnosis of X-linked agammaglobulinemia. J Pediatr. 2002;141(4):566-571.

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Last updated: 2019-07-11 20:55