Hypogammaglobulinemia with Facial Edema

Knight and colleagues discuss the diagnosis and management of a 35-year-old man with a past history of recurrent cellulitis and otitis media and a two-year history of facial swelling.


D E S C R I P T I O N o f C A S E
A 35-year-old man came to the offi ce with right-sided facial swelling, which he had noted over the last two years. The swelling was worse in the mornings and decreased through the day; however there were no symptom-free days. He had not experienced fevers, chills, or changes in his vision. He had experienced multiple episodes of lower extremity cellulitis, left more frequent than right leg, beginning in childhood. Although most instances were treated with oral antibiotics, he required hospitalization for intravenous antibiotics at least four times. Previous evaluation had confi rmed lymphedema by radionucleotide clearance. In addition, he had symptoms of allergic rhinitis and two episodes of otitis media as an adult, but he had no history of pneumonia or other signifi cant respiratory or gastrointestinal infections.
On physical examination he had no evidence of wasting or malnutrition. He had normal tonsils and no cervical lymphadenopathy; there was mild right facial swelling with induration and trace erythema from the eye to mid-cheek. The right facial skin was slightly warmer than the left, but it was non-tender to palpation. Tympanic membranes and chest examination were normal. His legs were moderately swollen, left greater than right, with a "woody" or indurated texture to the left leg; there were no rashes or other skin lesions. He had no hepatosplenomegaly.

What Investigations Are Indicated in This Patient?
Frequent infections raise the possibility of immunodefi ciency. A targeted immunologic evaluation should be guided by the clinical symptoms as well as the relative frequency of known immunodefi ciencies.
Immune defects in the humoral system are most common and screening can be performed with tests for serum immunoglobulin levels and titers of specifi c antibody. A suggestion of immunoglobulin defi ciency arises if there is a low total protein on standard chemistry panels, as the immunoglobulins make up a considerable portion of serum proteins. Clinical symptoms of immunoglobulin defi ciency include increased frequency or severity of sino-pulmonary and other bacterial infections.
Cellular immune defi ciencies are suggested by opportunistic and viral infections. An initial step in the evaluation of these is a complete blood count (a low lymphocyte number can be missed if only total white cells are counted) followed by a lymphocyte panel enumerating CD4 and CD8 T cells as well as B cells and natural killer cells. It is important to obtain the lymphocyte evaluation with a standard complete blood count to allow for the calculation of absolute numbers of cells and not just percentages, since normal relative percentages may be preserved despite very low cell numbers. More subtle defects in T cell function may be investigated by examining lymphocyte proliferative responses to mitogens and soluble antigens.

What Is the Differential Diagnosis?
Decreased immunoglobulin levels can result from reduced production or increased loss (Table 1). Primary causes of hypogammaglobulinemia are the genetic B or T cell defects. Secondary causes of reduced immunoglobulin production can be malignancy (lymphoma, thymoma, leukemia, multiple myeloma), selected medications (carbazepine [1], oxcarbazepine [2], immunosuppressive agents [3], and others), or infections such as Epstein-Barr virus, perinatally acquired HIV, or starvation. Increased nonselective loss of immunoglobulin can occur in rare states of high catabolism or with protein loss through protein-losing enteropathy ( Table 2), drainage of ascites, or chylothorax (lymph fl uid in the pleural space).
Lymphedema may predispose to recurrent cellulitis in affected limbs, however, given the signifi cant hypogammaglobulinemia found here, an intrinsic defect in the immune system leading to an inability to eliminate infections should be investigated.

What Additional Laboratory Data or Investigations Would Be Helpful in Making a Diagnosis in This Patient?
The ability to make specifi c antibody after vaccination challenge can assist in differentiating between decreased production and increased loss of immunoglobulins. Defects in specifi c IgG antibody production are characteristic of primary immune defects such as X-linked agammaglobulinemia, hyper-IgM syndrome(s), and common variable immunodefi ciency (CVID). Patients with hypogammaglobulinemia due to protein loss would be expected to respond normally to vaccinations in generating plasma B cells producing specifi c IgG antibody, though there may be lower serum immunoglobulin levels due to the general loss of proteins including IgG antibodies.
This man was fi rst assumed to have a primary immune defi ciency such as CVID, a syndrome most often associated with sino-pulmonary infections. The diagnosis of CVID is made by documenting decreased serum IgG, and IgA and/or IgM and poor specifi c antibody production [4]. Signifi cant improvement in infections is expected when IgG is replaced by immunoglobulin therapy [5]. 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.   However, other genetic immune defects and secondary causes, such as drug-induced, malignancy-associated hypogammaglobulinemia, or immunoglobulin loss, must be excluded. X-linked agammaglobulinemia and hyper-IgM were considered improbable due to the patient's age, mild clinical history, normal numbers of B cells, normal serum IgA, and normal tonsillar tissue.
Specifi c IgG antibody titers to varicella, rubella, and tetanus were found to be in a range considered to be protective, though the patient lacked suffi cient antibody to measles, mumps, and 12 serotypes of pneumococci. After vaccination with measles, mumps, and rubella (MMR) and pneumococcal vaccine, he developed protective specifi c antibody titers to measles and mumps and nine out of 14 pneumococcal serotypes. The preserved specifi c antibody production in response to pneumococcal, measles, and mumps vaccination, with the protective titers of antibody to varicella, rubella, and tetanus demonstrated normal B cell function, and excluded CVID.

How Did We Investigate the Possibility of a Protein-Losing Enteropathy?
Normal B cell function, low albumin, and the intermittent history of signifi cant lymphedema suggested the possibility of protein loss as the explanation for the hypogammaglobulinemia [7]. Normal urinalysis and renal functions eliminated nephrotic loss, which would have been an extremely unusual etiology for this degree of hypogammaglobulinemia.
To evaluate gastrointestinal protein loss, stool alpha-1 antitrypsin was determined and found to be elevated at 625 mg/dl (normal <55 mg/dl). This result suggested the presence of a protein-losing enteropathy such as intestinal lymphangiectasia. Intestinal lymphangiectasia may also be associated with the loss of T cells through the lymphatic channels. Although we did not evaluate this in our patient, in general naïve T cells are preferentially lost over memory T cells due to their traffi cking patterns though the lymphatic system [8,9]. However, the remaining T cells are generally able to prevent opportunistic infections. Intestinal lymphangiectasia was thus consistent with the patient's reduced numbers of T cells and low levels of serum immunoglobulins.

What Was the Original Diagnosis?
Based on the presence of excess alpha-1 antitrypsin in the stool, the patient was diagnosed with proteinlosing enteropathy. Conditions leading to protein-losing enteropathy can be congenital or acquired. Our patient has had symptoms suggestive of lymphatic dilatation since childhood and congenital lymphangiectasia was considered as a leading diagnosis. The most likely type of congenital lymphangiectasia would be hereditary lymphedema type I (Milroy disease) ( Table 3). Hereditary lymphedema type I is the result of a defect in the FLT4 gene, encoding vascular endothelial growth factor receptor-3 [10]. This is an autosomal dominant mutation with variable penetrance and expression in affected members of a family. Although our patient has no known affected family members, relatively mild disease may have been overlooked. However, the degree of facial swelling our patient experienced is not generally seen in this condition.
Targeted evaluation for secondary causes of intestinal lymphangiectasia was conducted. Cardiac history and echocardiography were unremarkable in our patient, excluding cardiac disease as a secondary cause of his proteinlosing enteropathy. Upper and lower endoscopies by his local gastroenterologist did not reveal any visible anomalies indicative of Crohn disease, ulcerative colitis, or other lesions, suggesting that our patient's protein loss was likely due to either a diffuse process or one occurring in the non-visualized small bowel.

How Is Lymphangiectasia Treated?
Treatment for intestinal lymphangiectasia includes treatment of the underlying pathology if a secondary cause is present (Table 4). Our patient's history is not consistent with any of the secondary causes of protein-losing enteropathy and he has chronic lymphedema of the face and extremities as well. Congenital intestinal lymphangiectasia can be surgically resected if there is an isolated segment of affected bowel. Most often there is diffuse intestinal involvement precluding resection. Other modalities have been used, including an extremely low fat diet to reduce the lymph fl ow to the intestinal mucosa, dietary medium chain triglycerides, or medications including heparin and octreotide [11][12][13][14]. However, our patient's normal intestinal biopsy (no dilated lymphatics characteristic of lymphangiectasia) suggested these treatments were unlikely to be effective.

What Was the Final Diagnosis?
Since his history and biopsy fi ndings were not consistent with congenital or acquired lymphangiectasia, an infl ammatory etiology was considered; thus a diagnostic trial of topical oral steroids (budesonide) was given. After several weeks of use,  the patient experienced a signifi cant decrease in facial and extremity lymphedema. Laboratory evaluation also revealed a decrease in stool protein loss with decreased stool alpha-1 antitrypsin levels ( Figure 1) suggesting an infl ammatory component to his protein-losing enteropathy. Based upon the response to steroids, an infl ammatory gastrointestinal process was considered to be the underlying cause of his proteinlosing enteropathy and subsequent hypogammaglobulinemia, but no specifi c etiology was identifi ed.
With good specifi c antibody production to vaccination challenge and no history of serious infections, replacement immunoglobulin therapy with intravenous immunoglobulin is not indicated. Continued close surveillance and a low threshold for the use of antibiotics would be prudent as he is at higher risk of recurrent cellulitis due to his lymphedema.

Conclusion
The differential diagnosis of hypogammaglobulinemia includes evaluation for both primary and secondary causes, since the treatment for these conditions is different. Proteinlosing conditions can lead to hypogammaglobulinemia and loss of T cells, but immune function is generally preserved and immunoglobulin replacement therapy is not usually required.