Enlarged Tonsils Marker for Post-Transplant Lymphoproliferative Disorder

One of the recent great advancements in pediatric care is surgical transplantation. New techniques now allow children to receive a needed organ that will result in a long and healthy life. According to the United Network for Organ Sharing (UNOS), the following number of transplants were performed on American children, younger than 18, in 2000: heart (217); heart and lung (7); kidney (453); liver (427), and lung (39).

Transplantation results in some physiological changes to the body, the consequences of which are not all known at this time. For example, the prevalence of enlarged tonsils and adenoids in the pediatric post-transplant population, relative to the general pediatric population, remains unknown. Adenotonsillar enlargement in the healthy pediatric population has been attributed to recurrent upper respiratory tract infections, allergy-related upper respiratory tract inflammation, and upper airway obstruction. Adenotonsillar enlargement in the post-transplant population may be a result of the same processes. However, the childhood disorder may also be indicative of post-transplant lymphoproliferative disorder (PTLD).

Post-transplant lymphoproliferative disorder is defined as an abnormal proliferation of lymphocytes, with symptoms, which may include fever, poor appetite, weight loss, irritability and generalized malaise. Conversely, the patient may be asymptomatic of this disorder and present solely with enlarged tonsils and adenoids. PTLD has been attributed to Epstein-Barr virus (EBV) in up to 80 percent of cases. EBV, a ubiquitous herpes virus, infects and immortalizes B-lymphocytes. The immunocompetent host mounts a T-lymphocyte response to control the proliferation of B cells. The anti-T-cell specific immunosuppressant agents used following solid organ transplantation limit the T-lymphocyte response, allowing uncontrolled proliferation of B-lymphocytes. In the setting of PTLD, reduction of immunosuppressant medication to treat the lymphoma puts the patient at risk for organ rejection. A rapid onset of post-transplant lymphoproliferative disorder has been associated with mortality rates of up to 60 percent.

Patients with post-transplant lymphoproliferative disorder may present with adenotonsillar enlargement with or without systemic symptoms. Adenotonsillar enlargement may also represent EBV hyperplasia. The epithelial cells of Waldeyer's ring may be a primary site for EBV replication. EBV hyperplasia may represent an earlier stage in the spectrum of PTLD. Adenotonsillar enlargement may be more prevalent in the post-transplant pediatric population, secondary to EBV infections in the setting of immunosuppression.

Using the Obstructive Sleep Apnea Syndrome -- 18 item questionnaire (OSA-18) and a physical examination to identify children with adenotonsillar enlargement, researchers compared the prevalence of signs and symptoms of adenotonsillar enlargement between solid organ transplant recipients, children with chronic illness, and healthy subjects. Leukemia patients were studied to examine the effect of chronic/life-threatening illness on OSA-18 scores and act as a control group.

The authors of "Comparison of Obstructive Sleep Apnea across Three Pediatric Populations" are Ali Strocker MD, Alexandra Carrer, Melanie Landay, Andrew Martin, and Nina Shapiro MD, all from the Department of Surgery, Division of Head and Neck Surgery, University of California Los Angeles Medical School, Los Angeles, CA. Their findings are being presented at the annual meeting of the American Society of Pediatric Otolaryngology http://www.aspo.us/ being held May 4-5, 2003, at the Gaylord Opryland Hotel, Nashville, TN.

The goal of their effort was to recognize adenotonsillar enlargement in those children at risk for PTLD, thus allowing for earlier diagnosis and treatment of this organ-threatening and life-threatening disorder.

Methodology: The subjects were pediatric patients at the Mattel-UCLA Children's Hospital. Three subgroups were studied; pediatric solid organ transplant recipients, children with leukemia, and healthy children. Abstraction of the medical records allowed for relevant past medical history to be obtained for each subject. For the transplantation recipients this included type of transplant, age at transplantation, Epstein-Barr virus (EBV) serology of donor and recipient, immunosuppressant medications, and history of organ rejection. For the children with leukemia, this included type of chemotherapeutic agent, time of last cycle, and history of bone marrow transplantation. For the healthy children, history of mononucleosis and any medical problems were recorded.

All kidney and liver transplant recipients under 21 years of age were invited to participate. Exclusion criterion included prior adenotonsillectomy. Children with leukemia, on chemotherapy, and who had not undergone a adenoidectomy/tonsillectomy, were included in the study. For the healthy population, all children under 21 years of age were eligible. Exclusion criteria included those children with prior adenotonsillectomy, current respiratory infection, chronic heart disease and chronic lung disease, including asthma, bronchopulmonary dysplasia, or cystic fibrosis.

During the patients' scheduled outpatient clinic visit, the parent or guardian was invited to participate in the study. The Obstructive Sleep Apnea Syndrome -- 18 item questionnaire (OSA-18) was administered and a brief physical examination of the nasal and oral cavities was performed. The questionnaire assessed sleep disturbance, physical symptoms, emotional symptoms, daytime function, and care giver concerns. The physical examination focused on quiet respiration through the mouth or nose, examination and grading the size of the tonsils, and examination of the inferior turbinate size, and nasal discharge as an indicator of adenoid-related nasal airway obstruction.

Results: Two hundred and six children participated in this study from January to August of 2002. Forty-six were kidney transplant recipients, fifty-nine were liver transplant recipients, thirty-four were patients with leukemia, and sixty-seven were healthy children. Liver and kidney transplant recipients were considered separately, as the risk for PTLD is higher in liver transplant recipients.

The healthy children had a mean age of 4.3 years. The mean ages for the kidney transplant recipients and liver transplant recipients were 14.5 years and 10.4 years, respectively. The children with leukemia had a mean age of 9.7 years. When the mean ages of the groups were compared, there were statistically significant differences between all groups, except between the children with leukemia and the liver transplant recipients. However, no correlation existed between age and physical examination scores or OSA-18 scores, in any group or for the study participants as a whole.

The mean OSA-18 score for the healthy children was 29.52, out of a maximum of 126. The mean score for kidney transplant recipients was 32.98, and 34.03 for liver transplant recipients. Children with leukemia had a mean score of 33.79. No statistically significant differences were noted between the groups in the categories of sleep disturbance, physical symptoms, or caregiver concern. However, both the mean and median score for emotional symptoms were significantly higher for liver transplant recipients when compared to healthy children. A statistically significant difference existed in the median scores in daytime function of both kidney and liver transplant recipients when compared to healthy children. A difference, although not statistically significant, also existed in daytime function between children with leukemia and healthy children.

The mean physical examination score for healthy children was 2.40 out of a maximum of 8. Kidney transplant recipients had a mean physical examination score of 2.87 and liver transplant recipients had a mean score of 2.86. The mean score of the children with leukemia was 1.88. While no difference in physical examination scores between healthy children and children who had received solid organ transplants, a statistically significant difference existed when children treated for leukemia were compared to both the healthy population and the organ transplant recipients. Both the mean and median physical examination scores were significantly higher for liver transplant recipients and for kidney transplant recipients. Healthy children also had significantly higher median physical examination scores relative to children treated for leukemia.

Conclusions: Adenotonsillar enlargement in the post-transplant population appears to have greater significance, as a marker for EBV hyperplasia and PTLD. When identified either by symptoms or physical exam, plans for adenotonsillectomy should be emphasized. Unlike healthy children who may be observed for regression, pathologic examination of adenotonsillar tissue is necessary to identify early lymphoproliferative disorders.

The utility of the OSA-18 as a screening tool for identifying adenotonsillar enlargement in the post-transplant population has yet to be determined. Health care professionals caring for pediatric recipients of solid organ transplants should have continued vigilance in identifying the early signs and symptoms of adenotonsillar enlargement and post-transplant lymphoproliferative disorder.