eMedicine Specialties > Hematology > Disorders of Lymphocytic Function

Pure B-Cell Disorders: Follow-up

Author: Issam Makhoul, MD, Associate Professor, Department of Medicine, Division of Hematology/Oncology, University of Arkansas for Medical Sciences
Coauthor(s): David Claxton, MD, Assistant Professor, Department of Internal Medicine, Section of Hematology-Oncology, Hershey Medical Center, Pennsylvania State University; Witold Rybka, MD, Professor of Medicine and Pathology, Penn State Hershey College of Medicine, Director, Bone Marrow Transplant Program, Penn State Hershey Medical Center; Hanan Makhoul, MD, Staff Physician, Department of Internal Medicine, University of Arkansas School of Medicine
Contributor Information and Disclosures

Updated: Nov 4, 2009

Follow-up

Further Outpatient Care

• Regular follow-up monitoring of the following parameters is necessary:
  • Growth and development
  • Chest radiographs and, if pulmonary abnormalities are suggested, HRCT scans
  • Pulmonary function tests
  • Immunoglobulin trough level
    • Levels higher than or equal to 400 mg/dL are considered satisfactory.
    • Occasionally, levels higher than 500 mg/dL are required to clear certain viral infections such as enteroviral meningoencephalitis.
  • Liver function tests and, if abnormalities are identified, imaging studies of the liver and biliary tree
    • These studies are necessary to exclude malignancies or sclerosing cholangitis.
    • Sclerosing cholangitis is observed in persons with XHM.

Deterrence/Prevention

• Prophylactic antibiotics are recommended for patients who continue to experience frequent infections despite good immunoglobulin levels.

Complications

• X-linked agammaglobulinemia
  • In patients with XLA, attenuated live poliovirus vaccine may cause vaccine-associated poliomyelitis.
  • Chronic disseminated enteroviral infection may be associated with vasculitis, pneumonitis, and hepatitis.
  • Dermatomyositislike syndrome, a constellation of edema of subcutaneous tissue, skin rash, and muscle weakness, is unusual.
  • Chronic pulmonary disease (50% of patients) and chronic enteroviral meningoencephalitis remain the major complications of this disease. Very high doses of immunoglobulin (0.4 mg/kg q48h to 1g/kg/d for 3-12 mo) have been used by Quartier et al in the treatment of 3 patients with enteroviral meningoencephalitis.⁹ Trough levels as high as 3100-6300 mg/dL were achieved. Two patients survived, and clinical and cerebrospinal fluid abnormalities resolved. Hearing loss due to chronic otitis media or meningoencephalitis may affect up to a third of these patients.¹⁰
  • Infectious complications cause death by age 20 years in approximately 15% of patients.
• Common variable immunodeficiency
  • Spruelike syndrome with malabsorption is observed in 10% of patients with CVID. Histologically, this resembles gluten-sensitive enteropathy (except for the absence of plasma cells). Infectious enteritis may imitate ulcerative colitis or Crohn disease, and both seem to occur more commonly in these patients.
  • Most patients with CVID and primary hypogammaglobulinemia develop pulmonary complications after several years of recurrent infections, sometimes despite appropriate IVIG therapy.
    • Although chest radiographs are useful, the criterion standard remains HRCT scans.
    • Using HRCT scans, 95% of patients studied by Kainulainen et al showed abnormalities.¹¹ The most common findings were fibrosis (81%), bronchiectasis (73%), parenchymal scarring (45%), pleural thickening (36%), and, less commonly, emphysema or parenchymal nodules. Pulmonary function tests showed obstruction in 33% of patients. Follow-up using HRCT scans and pulmonary function tests revealed silent and asymptomatic deterioration despite appropriate IVIG therapy.
    • Cor pulmonale may ultimately result from chronic/recurrent lower respiratory tract infections.
  • Autoimmune diseases occur in 10-20% of patients. The most common disorders are Coombs-positive hemolytic anemia and idiopathic thrombocytopenic purpura. Neutropenia is observed less frequently. Pernicious anemia occurs in 10% of patients with CVID and is characterized by younger age of onset and an absence of antiparietal cell antibodies. Other less common autoimmune disorders have been reported, including thyroid diseases, Addison disease, diabetes mellitus, biliary cirrhosis, alopecia totalis, rheumatoid arthritis, systemic lupus erythematosus, polymyositis, sicca syndrome, and Guillain-Barré syndrome.
  • Granulomatous disease has been reported in 5.4-10% of patients with CVID.
    • Noncaseating granulomas can be localized in any organ, with the lungs, liver, and lymph nodes being the most frequent localizations, followed by the bone marrow and skin. Lung involvement led to restrictive lung disease and death in 4 of 17 patients studied by Mechanic et al.¹² This entity should be differentiated from mycobacterial and fungal infections and from sarcoidosis.
    • The major distinguishing feature from idiopathic sarcoidosis is the level of immunoglobulins, which is increased in person with sarcoidosis and decreased in those with CVID. The Kveim test is not helpful because it returns a positive finding in up to 40-50% of CVID patients. ACE levels, a marker of macrophage activity, is elevated in approximately a third of these patients.
    • In vitro T-cell dysfunction in CVID patients with granulomatous disease may explain the higher risk of autoimmune diseases in these patients than in the rest of the group. In the small subset of patients with aggressive disease, corticosteroids are the treatment of choice.
  • The risk of cancer in CVID patients is 5-fold higher than in matched controls. A 47-fold increase in gastric cancer and a 30-fold increase in lymphoma have been reported; however, benign lymphoproliferative disorders are much more common, affecting up to 30% of patients and manifesting as splenomegaly with or without diffuse lymphadenopathy. They are distinguished from lymphomas by the presence of a mixture of B and T lymphocytes and by the absence of clonal B- and T-cell receptor rearrangement.
• IgA deficiency
  • Malabsorption, celiac disease, giardiasis, nodular lymphoid hyperplasia, pernicious anemia, primary biliary cirrhosis, and chronic hepatitis are observed.
  • The incidence of gastric and colon cancer is increased.
  • Patients have anaphylactic reactions to blood products containing IgA.
• Hypogammaglobulinemia: Encephalitis is a rare complication in hypogammaglobulinemic patients. It is frequently related to Enterovirus or coxsackievirus infection and, less commonly, to measles and papovavirus.
• Complications related to IVIG therapy
  • Complications include increased serum viscosity and more frequent thromboembolic events. The risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-5 d postinfusion to 30 d) is also increased.
  • The most common adverse reactions are nonanaphylactic and are characterized by back and abdominal pain, nausea, vomiting, chills, fever, and myalgias. The infusion should be discontinued until the symptoms subside, and then it should be restarted at a slower rate.
  • True anaphylactic reactions are rare and occur seconds to hours after the infusion is started. Typical symptoms consist of flushing, facial swelling, dyspnea, and hypotension. The infusion should be stopped, and the patient should receive epinephrine, steroids, and antihistamines together.
  • The risk of renal tubular necrosis is increased in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease.
  • Hepatitis C virus (HCV) infection transmission is much less common now than in the past. Most of HCV RNA–positive patients contracted their infection in the 1980s, when serologic testing of blood donors was not available for this infection. Chronic liver disease in HCV RNA–positive patients is characterized by a severe clinical course, particularly in CVID patients. Hepatitis B and G viruses seem to play minor roles in the pathogenesis of chronic liver disease in these patients. A milder form of chronic liver disease with negative serology findings for HCV, hepatitis B virus (HBV), and hepatitis G virus (HGV) infections has been described in these patients. This form occurs an average of 36 months after the beginning of IVIG therapy and is thought to be related to immune phenomena or to an as yet undescribed viral infection. A small subset of patients without HCV, HBV, or HGV infection has a particularly severe course; in most, granulomatous disease of the liver has been identified.

Prognosis

• Before the immunoglobulin era, patients with XLA died at an early age because of the complications of infections with encapsulated bacteria. The advent of intramuscular immunoglobulin brought some clinical improvement, with only partial control of upper and lower respiratory tract infections, but patients still died before age 25 years. The introduction of IVIGs in the early 1980s resulted in significant improvement of infection control with prolonged survival.
• Most patients with XHM die in the first and second decades of life. The actuarial survival rate at 25 years is only 25%, and 80% of these patients develop liver disease by age 20 years.

Miscellaneous

Medicolegal Pitfalls

• Failure to carefully screen patients before the administration of live attenuated vaccines
• Failure to perform prenatal screening for inherited disorders in patients with a family history of these disorders in order to discuss the indications of therapeutic discontinuation of pregnancy

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