Nine-Year-Old Girl With Lymphangiectasia and Chest Pain

A 9-year-old girl, known to have lym-phangiectasia of the intestine and left upper extremity, presented with a 2-month history of night sweats, a 1.5-kg weight loss, a 3-week history of left posterolateral chest pain, a 2-week history of fever and intermittent headaches. She had no shortness of breath and no infectious contacts or contacts with birds or other animals. The past medical history was significant for the development of left arm edema, abdominal distention, poor weight gain and persistent loose stools in the first weeks of life. These symptoms fluctuated until age 2 years when development of generalized edema with ascites, diarrhea and abdominal pain led to a diagnosis of intestinal lymphangiectasia by intestinal biopsy. This condition was managed with dietary changes, including elemental formula in infancy, and now a diet low in long chain fatty acids, high in medium chain fatty acids and high in protein. Consumption of excess long chain fatty acids leads to diarrhea and left arm swelling. Growth and development have been normal. Immunizations were administered according to recommended schedules and included BCG (given while the patient was in China), diphtheria-pertussis-tetanus toxoids, live polio virus vaccine, measles-mumps-rubella and hepatitis B vaccines, with no adverse effects. There was no history of thrush, pneumonia or severe viral infections. She had an uncomplicated course with chickenpox at age 2 years. On physical examination, she appeared well and in no distress. Her height was on the 5th percentile and weight on the 25th percentile. Vital signs were normal and she was afebrile. She was in no respiratory distress and had normal chest expansion. On auscultation, she had good air entry, with only some faint crackles in the peripheral lung fields. The rest of the physical examination was normal except that her left arm was several centimeters greater in diameter than her right. Laboratory investigations revealed a normal total white blood cell count of 10.95 × 109 cells/L with a low lymphocyte count at 1.040 × 109 cells/L. The hemoglobin value and platelet count were normal. Serum albumin and total protein concentrations were low at 28 and 55 g/L, respectively. Chest radiograph and chest computed tomography demonstrated multiple pulmonary masses bilaterally. On computed tomography, the largest mass was in the left apex, measuring 3.7 × 3.8 cm, and multiple other nodules measuring 1–2 cm were present throughout both lungs. Low attenuation was suggestive of necrosis. She was referred to surgery for a lung biopsy. For denouement, see p. 663. Denouement Continued from p. 659 The open lung biopsy revealed necrotizing pneumonitis and the presence of spherical structures consistent with Cryptococcus on hematoxylin and eosin stain, Gram stain, and periodic acid-Schiff stain. Mucicarmine stain demonstrated prominent hyaline staining of the walls of the spheroidal structures. Despite the strong histologic evidence of the presence of Cryptococcus in the lung parenchyma of this case, cultures were negative. We attribute this to a delay in set-up of the culture after referral to a reference laboratory (specimen remained at room temperature for 48 hours before inoculation). All other cultures for virus and bacteria were negative. Based on these findings, our patient was treated with a 2-week course of amphotericin B, 1 mg/kg/d, and flucytosine, 100 mg/kg/d, followed by fluconazole for 6 months. During these 6 months, her clinical complaints of chest pain and night sweats gradually resolved and she resumed normal activity and gained weight. Radiologically the lung lesions cleared. Two weeks after initiation of therapy, a repeat chest radiograph demonstrated a decrease in lesion size. Ten weeks later, a repeat computed tomography scan showed a decrease in the largest lesions from 3.8 to 3.3 cm in diameter. The slow radiographic changes were considered to be related to the extensive necrosis of the lung tissue. Because cryptococcal infection is seen predominantly in those with impaired cellular immunity, further studies of this child's immune function were undertaken. Lymphocyte phenotyping by fluorescence-activated cell sorting (Beckman-Coulter) with monoclonal antibodies directed against lymphocyte antigens for B (CD19) and T (CD3, CD4+, CD8+) cells (Beckman-Coulter) revealed profound T lymphocyte deficiency as follows: CD3+ cells, 22%; absolute count, 180 × 109/L (normal, >700); CD4+ cells, 8%; absolute count, 70 × 109/L (normal, >300); and CD8+ cells, 8%; absolute count, 70 × 109/L (normal >300 × 109/L). B lymphocyte numbers were normal at 510 × 109/L (normal, 200–1600 × 109/L). Serum immunoglobulins showed normal IgM, IgA and IgE values and low IgG concentrations of 4.94 g/L (normal, 6.98–16.00 g/L). Specific antibodies were detected against varicella-zoster virus and against pathogens for which the patient had been immunized including measles, rubella and hepatitis B. Human immunodeficiency virus antibody studies were negative. Mitogen-induced lymphocyte stimulation studies were determined by [3H]thymidine incorporation of 5 × 104 cells after 4 days in culture with the mitogens phytohemagglutinin (PHA) or pokeweed mitogen and 105 cells with Staphylococcus aureus Cowan A strain antigen (SAC); or after 7 days in culture with microbial antigens including cytomegalovirus, herpes simplex, varicella-zoster, measles, mumps, rubella and Candida. Compared with age-matched controls, the patient showed reduced PHA responses and low normal pokeweed mitogen and SAC responses. Positive antigen-specific cellular immune responses were present to mumps, measles and cytomegalovirus and negative to varicella-zoster virus, Candida and herpes simplex. In brief, results showed profound T cell deficiency, but the ability to make specific antibodies and maintain cellular immune responses against some pathogens. Cellular immunity was not detected against varicella-zoster despite past history of chickenpox. Primary intestinal lymphangiectasia is a congenital disorder of lymphatic development with presentation in the first 2 years of life. Intestinal lymphangiectasia is characterized by dilated enteric lymphatic vessels, which rupture and result in the loss of protein-rich lymph and lymphocytes into the gastrointestinal tract, leading to hypogammaglobulinemia and lymphopenia. Definitive diagnosis is made by intestinal biopsy. Loss of lymphocyte-rich lymphatic fluid into the bowel lumen is unique to intestinal lymphangiectasia, and accounts for the distinguishing finding of lymphopenia in intestinal lymphangiectasia compared with other protein-losing enteropathies. Fuss et al1 determined that the loss of lymphocytes primarily affects naive CD4+ T cells and, to a lesser extent, B lymphocytes, natural killer cells and CD8+ T cells. Further cell typing that they conducted showed that the residual circulating CD4+ cells from intestinal lymphangiectasia patients were highly differentiated and previously sensitized. In functional experiments, these cells proliferated poorly and produced cytokines reflective of highly differentiated cells. These findings extend previous reports by others2–4 of cellular immune deficiency in intestinal lymphangiectasia where patients had skin anergy, impaired allograft rejection and deficient mitogen-induced in vitro lymphocyte proliferation. Immunoglobulins and other proteins are deficient in intestinal lymphangiectasia. All proteins are lost into the intestine at the same rate, but proteins with long half-lives, such as albumin and IgG, are depressed more profoundly than IgA and IgM. Despite the usual strikingly abnormal immunologic parameters, there are few reports of the clinical consequences of immunodeficiency associated with primary intestinal lymphangiectasia. There are isolated reports of development of malignancy in adulthood5 Cutaneous warts are a principal infectious complication,5 although we found reports of 2 patients who developed cryptococcal cellulitis.6,7 To our knowledge, our case is the first report of cryptococcal pulmonary disease in primary lymphangiectasia. In conclusion, intestinal lymphangiectasia predisposes to cellular and humoral immunodeficiencies, which put these patients at potential risk for opportunistic infections. It is important to have a high index of suspicion for these complications in a patient with intestinal lymphangiectasia and also to suspect a diagnosis of intestinal lymphangiectasia in a patient with clinical or laboratory evidence of lymphopenia and protein-losing enteropathy.

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