Which clinical history findings are characteristic of agammaglobulinemia (hypogammaglobulinemia)?

Updated: Jul 08, 2019
  • Author: Donald A Person, MD, FAAP, FACR; Chief Editor: Harumi Jyonouchi, MD  more...
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History in patients with agammaglobulinemia, or hypogammaglobulinemia, is similar to that for Bruton agammaglobulinemia because the patient is unable to produce functional humoral immunity. Patients may have problems with recurrent upper and/or lower respiratory tract infections or with chronic diarrhea. However, patients with mutations in the μ heavy chain and non-Btk mutations tend to develop symptoms earlier and are more likely to have severe symptoms.

Encapsulated bacteria with Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and pseudomonal species (in that order) cause most infections. Other bacteria, such as Salmonella and Giardia species, may also cause problems. Chronic bacteremia and skin infections by Helicobacter and related species such as Flexispira and Campylobacter in patients with X-linked agammaglobulinemia (XLA) are now appreciated. [19]

Almost three fourths of patients with agammaglobulinemia have infections occurring in the upper respiratory tract with otitis and sinusitis. Lower respiratory tract infections (eg, pneumonia, bronchiolitis), GI tract infections (eg, gastroenteritis), or both occur in more than two thirds of patients. Some have suggested obtaining immunoglobulin levels in all children with community-acquired pneumonia who require hospitalization may be cost effective. [20]

Other bacterial infections, such as pyoderma, sepsis, meningitis, osteomyelitis, and septic arthritis occur less frequently. Lower-grade pathogens, such as Pneumocystis carinii pneumonia, have also been reported. Additionally, sites of infection may be unusual with the encapsulated pyogenic bacteria, such as H influenzae lymphadenopathy or pneumococcal meningitis.

Although patients with agammaglobulinemia are usually able to handle viral infections, they are susceptible to certain viruses that replicate in the GI tract and then spread to the CNS. This indicates the importance of antibody production in limiting the spread of infections by enteroviruses such as poliovirus, echovirus, and coxsackievirus.

Patients may present with vaccine-related poliomyelitis after immunization with the live poliovirus vaccine. [21, 22] Although prolonged secretions of a virus have been described (up to 637 days after vaccination), poliovirus carriers among people with primary immune deficiency appears to be rare, based on 3 separate studies, and may not manifest with disease.

Alternately, echovirus infection of the CNS may cause chronic encephalomyelitis or meningoencephalitis. In 13 patients with primary hypogammaglobulinemia, Rudge et al (1996) described 3 clinical pictures: (1) progressive myelopathy in 1 patient, (2) myelopathy progressing to an encephalopathy in 4 patients, and (3) pure encephalopathy in 8 patients. [23] Enteroviral infection was found in 7 patients by either culture or polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF). However, Katamura et al (2002) described a nonprogressive viral myelitis in a patient and suggested that the prognosis of CNS infections in agammaglobulinemia is not determined by the immunoglobulin (Ig) level alone and that they are not always progressive or fatal. [24]

The use and potential efficacy of interventricular infusion of Ig have been well-documented in these patients. The use of an antiviral agent Pleconaril with intravenous immunoglobulin (IVIG) in these patients has been described. [25]

In addition, rare CNS disorders such as progressive multifocal leukoencephalopathy may present in patients with hypogammaglobulinemia. [26]

GI disorders such as chronic or acute diarrhea, malabsorption, abdominal pain, and inflammatory bowel diseases can all indicate immune deficiency. [27, 28]

Virus-induced autoimmune diseases such as a dermatomyositislike syndromes and chronic arthritis may also occur. These diseases suggest an element of dysregulated antibody production in their pathogenesis. In some cases, enteroviruses have been isolated from skin or joints. Therefore, any joint symptom should be suspected to be caused by various infectious agents in patients with humoral immunodeficiencies. Conversely, noninfectious arthritis may indicate an underlying autoimmune disorders such as lupus or rheumatoid arthritis. [29]

Mycoplasma or Ureaplasma organisms may play a role in other cases of chronic arthritis. In a survey of 358 patients with primary antibody deficiency, mycoplasmal infection was the most common cause of severe chronic erosive arthritis. Patients with mild cases rapidly respond to antimicrobial therapy, such as tetracycline. In more severe cases, arthritis improved following treatment with intravenous Ig. Overall, 7-22% of patients with agammaglobulinemia develop joint manifestations. Reactive arthritis with Campylobacter coli infections is also common. Various types of arthritis such as psoriatic, enthesitis-related, septic, and relapsing polychondritis have all been described. [30, 31]

Always consider that infections may mimic autoimmune arthritis in patients with hypogammaglobulinemia (eg, Mycoplasma). [32]

Enthesitis-related arthritis has also been described in a boy with XLA. [33]

The constellation of symptoms in a family of brothers with leukoencephalopathy, arthritis, colitis, and hypogammaglobulinemia prompted some to label this the LACH syndrome. [34]

Other associated autoimmune disorders most commonly include hematological manifestations (eg, thrombocytopenia, hemolytic anemia, neutropenia), alopecia totalis, glomerulonephritis, protein-losing enteropathy, malabsorption with disaccharidase deficiency, and amyloidosis.

Hypogammaglobulinemia has also been described in the immediate period following transplantation of intestines, kidneys, liver, and lungs. [35, 36, 37] Most likely it is secondary to the immunosuppressive therapy required for transplantation, and restoration of humoral immunity with IVIG decreases the number of infectious complications [38]

Other patients in whom measurements of Ig may be helpful include those with renal dialysis and patients in pediatric ICUs. In the former, IgG and IgG subclass deficiency were found in 8 out of 12 children undergoing continuous ambulatory peritoneal dialysis. [39] Similarly, total IgG levels were below the reference range for age in 14 of 20 patients admitted to a pediatric ICU. [40] However, these studies included a small number of subjects.

A new syndrome has been described warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome. These patients also have neutropenia and a tendency to develop B-cell lymphoma.

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