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Internal Medicine

Common variable immunodeficiency (CVID)

Heterogeneous group of disorders that are characterized by hypogammaglobulinaemia predisposing to recurrent bacterial infections that mainly affect the respiratory and gastrointestinal tracts

  • M/C primary immunodeficiency

Aetiology

Genetic defects:

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Genes associated with monogenic forms of CVID: summary of genetic, clinical and immunological features | Bogaert, D. J. A., Dullaers, M., Lambrecht, B. N., Vermaelen, K. Y., De Baere, E., & Haerynck, F. (2016). Genes associated with common variable immunodeficiency: one diagnosis to rule them all? Journal of Medical Genetics, 53(9), 575 LP-590. Retrieved from http://jmg.bmj.com/content/53/9/575.abstract

Clinical features

Range of clinical manifestations is broad, including acute and chronic infections, inflammatory and autoimmune diseases, and an increased incidence of cancer and lymphoma.

Hypogammaglobulinemia

Chronic/recurrent infections:

Recurrent respiratory tract infections (M/C organ system involved):

  • Pathogens: Encapsulated (Haemophylus influenzae, Streptococcus pneumoniae) or atypical (Mycoplasma spp.) bacteria
  • Chronic sinusitis (90%)
  • Recurrent otitis media (70%)
    • Hearing loss (tympanic membrane perforation)
  • Bronchiectasis
  • Pneumonia (75–85%)

GI tract involvement (2nd M/C, 10–40%):

  • Giardia lamblia → Giardiasis (M/C)
  • H. pylori → Chronic active gastritis, achlorhydria, gastric adenocarcinoma and gastric lymphoma
  • Other pathogens: Campylobacter jejuni, Salmonella spp., Cryptosporidium parvum, CMV, Clostridium difficile, Helicobacter pylori, HBV, HCV, etc

Other manifestations:

  • CNS: Meningoencephalitis (Enterovirus spp.)
  • Joints, bones (Mycoplasma spp.)
  • Skin and eyes
  • Recurrent urinary tract infections (UTI) (Ureaplasma urealyticum) Fibrotic bladder
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Oligoarthritis due to Mycoplasma salivarius as an early manifestation of common variable immunodeficiency: A male aged 36 years was healthy until he developed recurrent upper respiratory tract infections and a first bout of pneumonia 18 months prior to these images being taken. Five months later he presented with refractory right-sided gonarthritis to an orthopedic surgeon. Despite multiple sterile knee taps, arthroscopy and a Baker cyst resection, joint inflammation continued and extended to the right shoulder and the right ankle. He was referred to the Division of Rheumatology and Clinical Immunology at Freiburg University Hospital for further diagnosis and treatment of ‘multifocal osteomyelitis and oligoarthritis of unknown origin’. On admission he presented with three tender and swollen joints (right knee, shoulder, ankle), moderately elevated C-reactive protein (CRP) levels (5 to 29 mg/dl) and severe hypogammaglobulinemia: IgG 1.7 g/L, IgA <0.6 g/L, IgM <0.3 g/L. Diagnosis of CVID was established and the patient was started on monthly intravenous immunoglobulin infusions (500 mg/kg) plus various ineffective antibiotic regimens (initially cefuroxime plus neomycin, then clarithromycin and metronidazol). A diagnostic puncture of the right shoulder eventually revealed Mycoplasma salivarius by multiplex PCR diagnostics. From that point on the patient was put on doxicycline (200 mg/daily orally) and the inflammatory process rapidly improved. Doxicycline was stopped after 4 weeks, whereas monthly intravenous immunoglobulin was continued. As of today, the patient has been back to work for 7 years and is clinically doing well. Magnetic resonance imaging follow-up (T2, TIRM sequences of the right knee) and laboratory parameters at three time points (A, B, C) nicely show the improvement of the severe arthritis and osteomyelitis of the right knee. | Salzer, U., Warnatz, K., & Peter, H. H. (2012). Common variable immunodeficiency: an update. Arthritis research & therapy, 14(5), 223. doi:10.1186/ar4032

Case study:


Complications

Pulmonary complications (M/C):

Recurrent pulmonary infections → permanent pulmonary disorders

  • Bronchiectasis (obstructive and restrictive) (M/C, 33%)
    • Subsequent to recurrent pneumonia 
  • Air-trapping
  • Ground-glass attenuation
  • Parenchymal opacification
  • Reticular fibrosis
  • Bronchial wall thickening
  • Atelectasis
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(A) High-resolution computed tomography (HRCT) scans showing bronchiectasis related to CVID in the context of a normal chest radiograph (not shown). (B) HRCT scans showing granulomatous lymphocytic interstitial lung disease (GLILD) related to CVID in the context of a normal chest radiograph (not shown). | Tam, J. S., & Routes, J. M. (2013). Common variable immunodeficiency. American journal of rhinology & allergy, 27(4), 260–265. doi:10.2500/ajra.2013.27.3899

Polyclonal lymphocytic infiltrative complications (10–25%):

  • Pulmonary granulomatous diseases (present with shortness of breath and persistent cough):
    • Granulomatous lymphocytic interstitial lung disease (GLILD)
    • Lymphoid interstitial pneumonitis (LIP)

Autoimmune-associated disorders (20–25%):

D/t immune dysregulation due to failed or circumvented specific autoreactivity checkpoints during the B-cell development process

  • M/C disorders (5–8%):
    • Autoimmune thrombocytopenic purpura (ITP)
    • Autoimmune hemolytic anaemia (AIHA)
  • Other autoimmune disorders:
    • Presence of anti-IgA antibodies, autoimmune neutropenia, pernicious anaemia, juvenile rheumatoid arthritis (JRA), systemic lupus erythematosus (SLE), psoriasis, autoimmune thyroiditis, autoimmune hepatitis, primary biliary cirrhosis, insulin-dependent diabetes, sicca syndrome, vitiligo and vasculitis
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Autoimmunity in CVID: Of 473 patients with CVID, 134 (28.6%) had autoimmunity. The main autoimmune diseases are shown here. In the category “other” are included neutropenia, pernicious anemia, anticardiolipin Ab, antiphospholipid syndrome, diabetes mellitus, juvenile rheumatoid arthritis, uveitis, multiple sclerosis, systemic lupus erythematosus, autoimmune thyroid disease, lichen planus, vasculitis, vitiligo, and psoriasis. | ITP indicates immune thrombocytopenia; AIHA, autoimmune hemolytic anemia; RA, rheumatoid arthritis. | Cunningham-Rundles C. (2012). The many faces of common variable immunodeficiency. Hematology. American Society of Hematology. Education Program, 2012, 301–305. doi:10.1182/asheducation-2012.1.301

GI complications & enteropathy:

  • Diarrhea (60%)
  • Digestive complications (10%)
  • Inflammatory GI disorders (20%):
    • Celiac (gluten-sensitive) disease (rare)
    • CVID-related enteropathy
    • Inflammatory bowel disease (ulcerative colitis, ulcerative proctitis or Crohn’s disease)
  • Intestinal lymphangiectasia, nodular lymphoid hyperplasia and nonspecific malabsorption
  • Liver dysfunctions (10%):
    • Unexplained liver disease + portal hypertension (5–10%)

Diagnosis

ESID (European Society for Immunodeficiencies) and PAGID (Pan-American Group for Immunodeficiency) (1999) criteria:

  • Marked decrease (≥ 2 SD below mean for age) of IgG + IgM/IgA isotypes
  • Onset of immunodeficiency > 2 years age
  • Absence of isohemagglutinins and/or poor response to vaccines
  • Exclusion of other causes of hypogammaglobulinemia

Differential diagnosis

X-linked lymphoproliferative disease (XLP):

  • Reduced B cells in lymphoid tissues (vs normal B cell count in CVID)

Management

Immunoglobulin replacement therapy:

  • Intravenously (IVIg)
  • Subcutaneously (SCIg)
  • Intramuscularly (IMIg)

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