Chronic granulomatous disease

* Both an enlarged thymus (with normal results on histologic examination) and an increase in the percentage of peripheral CD4+CD45RA+ (naive) T lymphocytes developed in a child with chronic granulomatous disease receiving long-term interferon gamma therapy. The thymic regrowth may be secondary to interferon gamma therapy or to overstimulation of his compromised immune system by recurrent infections. To our knowledge, an association between enlargement of the thymus and either chronic granulomatous disease or interferon gamma has not been previously reported.

(Arch Pathol Lab Med. 1998;122:562-565)

Chronic granulomatous disease (CGD) is an inherited immunodeficiency disorder characterized by defective respiratory burst in stimulated phagocytes.l Several heterogeneous genetic defects can give rise to the same disease phenotype via deficient neutrophil cytochrome b558. Interferon gamma (IFN-y) has been shown to decrease the frequency of infection in patients with CGD.2 Its mechanism of action is elusive, but it exerts a pleiad of immunomodulatory effects on various cell types. We report a case of thymic regrowth in a 7-year-old patient with X chromosome-linked CGD who is receiving long-term IFN-y therapy.

CASE REPORT

A 7-year-old boy with X chromosome-linked CGD presented to the hospital with cough, central chest pain, and fever. Upon presentation he was tachypneic and had decreased breath sounds in the lung bases and a pericardial rub. His temperature was 38.8C, and he appeared moderately ill.

Three years before this admission he was treated with amphotericin B for Aspergillus pneumonia involving the right upper and lower lobes. Since that time he had continued taking itraconazole prophylaxis. His medical history was notable for perirectal abscess at 6 months of age, Staphylococcus aureus cervical adenitis at 9 months, and Escherichia coli osteomyelitis of the forearm and Klebsiella psoas abscess at 11 months. The diagnosis of CGD was made at that time on the basis of abnormal results on a nitroblue tetrazolium test and a complete absence of cytochrome b558. He continued to have recurrent infections such as cervical and inguinal adenitis and tibial osteomyelitis. Therapy with IFN-y was started at 4 years of age.

At admission, laboratory tests revealed a white blood cell count of 4.4 x 109/L (4400 cells/mm3) (23% neutrophils, 66% lymphocytes, 2% monocytes, and 4% eosinophils); hemoglobin, 110 g/L (11 g/dL); platelets, 350 x 109/L; and erythrocyte sedimentation rate, 48 mm/h. A chest radiogram revealed consolidations in the right upper and middle lobes and increased interstitial markings bilaterally. He had cardiomegaly and a widened mediastinum; both of these findings were not present in older films (Fig 1, A and B). Levels of immunoglobulin G and M were normal for his age, but the level of immunoglobulin A was increased (3.26 g/L [326 mg/dL]). Flow cytometric analysis of his peripheral blood lymphocyte subpopulations showed an increase in CD4+CD45RA+ T lymphocytes. The results and normal reference ranges for his age, are given in the Table.

Therapy with vancomycin, amikacin, and amphotericin B was started. Bronchoscopy with bronchoalveolar lavage was performed, and all the cultures and stains yielded negative results for bacterial, fungal, mycobacterial, or Pneumocystis carinii infection, except for an immunofluorescence test for influenza A, which yielded positive results. Amantadine was added to his therapeutic regimen. An echocardiogram showed mild pericardial thickening with a 10-mm pericardial effusion. A computed tomographic scan of the chest demonstrated an area of dense, homogeneous soft tissue occupying the anterior mediastinal and prevascular spaces as well as the middle mediastinum, extending inferiorly below the carina (Fig 1, C).

An open biopsy of the anterior mediastinum was performed. A large thymus was seen at the site of the dense, soft tissue on the computed tomographic scan. A specimen of the thymus was sent for frozen-section analysis, which showed a normal thymus. Histologic examination showed normal thymic architecture with no evidence of malignant changes or follicular hyperplasia (Fig 2). Histologic sections of the patient's thymus, together with sections of thymus from an age-matched control and a 5-month-old infant control, were immunostained with a monoclonal antibody (MIB-1, BioGenex, San Ramon, Calif) to Ki-67, a proliferating antigen that detects cells that have entered the cell cycle. The patienf's thymus had a proliferative index of more than 90%, similar to that of both control individuals.

Over the next few days he defervesced, with considerable improvement of his symptoms. The pericardial rub disappeared, and the cardiac silhouette decreased in size on x-ray; however, the mediastinum remained widened over the following 18 months. Results on all cultures remained negative. He completed a 7-day course of amantadine, vancomycin, and amikacin and continued taking amphotericin B for presumed relapse of Aspergillus pneumonia for 8 weeks, after which he resumed his prophylactic regimen of itraconazole.

COMMENT

The mechanisms by which IFN-y exerts its protective effects against infection in patients with CGD are not clearly understood, because these patients usually experience little or no enhancement of respiratory burst function.l2 The most common side effects of IFN-y therapy are headache, fever, rash, chills, and myalgi as which are usually alleviated by pretreatment with acetaminophen.

Interferon gamma is produced by activated THl lymphocytes and natural killer cells and exerts antiviral and immunomodulatory effects. The role of IFN-y on the thymus is not known, but several lines of evidence suggest that it may have a regulatory function on thymocyte growth and differentiation: IFN-y-inducible protein 10, a peptide thought to mediate the effects of IFN-y, was found to be constitutively expressed at high levels by thymic epithelial and stromal cells in mice.4 Interferon gamma has been shown to increase major histocompatibility complex class II expression on thymic epithelial cells.56 This suggests a role for IFN-y in the interactions between thymocytes and major histocompatibility complex ligands on thymic epithelial cells, a critical interaction for normal T cell development.

There is increasing evidence that cytokines are present in the thymus and play a role in the regulation of immature thymocyte differentiation. It was shown that IFN-y reverses interleukin-4-induced inhibition of fetal mouse thymic cell growth.67 In vivo, it has been observed that C57B1/6 mice, which express predominantly TH1 cell responses (interleukin-2 and IFN-y), have a faster rate of thymic development than BALB/c mice, which express a predominance of TH2 cell responses (interleukin-4, -5, and -6).7

Thymic rebound has been shown after chemotherapy mainly in children.8,9 The CD4+ recovery correlates with the appearance of CD4+CD45RA+ (naive) T lymphocytes in the blood and with thymic enlargement as assessed by computed tomography or Gallium scanning.8 Thymic hyperplasia without a predisposing factor has also been described in infants and young children.l,ll In these cases, it presents diagnostic and therapeutic challenge, often requiring thoracotomy for definive diagnosis and exclusion of malignancy. Thymic enlargement has not been previously reported in association with CGD or exogenous IFNgamma administration.

Thymic growth may also be influenced by additional factors, such as infection and age. Generally, severe acute infections and increasing age cause thymic involution; however, the role of chronic infection as a stimulus for thymic activity has not been examined. We believe that in this patient thymic regrowth was triggered by a combination of factors, including exogenous administration of IFN-y and chronic infection.

To our knowledge, CGD has not been associated with an increase in peripheral CD4+CD45RA+ (naive) T lymphocytes, although a decrease in the number of CD4+CD29+ (memory) T cells has been reported.lz Our patient had an increase in the percentage of CD4+CD45RA+ lymphocytes without a concomitant decrease in CD4+CD29+ cells, suggesting an increase in production of these cells de novo (Table). He also had an increase of CD19+ (B) cells, possibly as a result of stimulation by recurrent infections; the extent to which IFN-y might contribute is unknown.

In summary, an enlarged thymus and an increase in the percentage of peripheral CD4+CD45RA+ (naive) lymphocytes developed in a 7-year-old boy with CGD who was receiving IFN-y. Thymic regrowth may be a side effect of long-term therapy with IFN-y.

References

1. Curnutte J. Recent advances in chronic granulomatous disease. Curr Opin Pediatr. 1990;2:907-915.

2. Ezekowitz R. Chronic granulomatous disease: an update and a paradigm for the use of interferon-y as adjunct immunotherapy in infectious diseases. Curr Top MicrobiolImmunol. 1992;181:283-292.

3. Ibegbu C, Spira T, Nesheim S, et al. Subpopulations of T and B cells in perinatally HIV-infected and noninfected age-matched children compared with those in adults. Clin Immunol Immunopathol. 1994;71:27-32.

4. Gattass C, King L, Luster A, et al. Constitutive expression of interferon-y inducible protein 10 in lymphoid organs and inducible expression inT cells and thymocytes. J Exp Med. 1994;179:1373-1378.

5. Murphy M, Hyun W, Hunte B, et al. A role for tumor necrosis factor-a and interferon-y in the regulation of interleukin-4-induced human thymocyte proliferation in vitro: heightened sensitivity in the Down syndrome (trisomy 21 ) thymus. PediarRes. 1992;32:269-276.

6. Ransom J, Fisher M, Mosmann T, et al. Interferon-y is produced by activated immature mouse thymocytes and inhibits interleukin 4-inducing proliferation of immature thymocytes. I Immunol. 1987139:102-107.

7. Plum J, DeSmedt M, Billiau A, et al. IFN-gammareverses IL-4 inhibition of fetal thymus growth in organ culture. J Immunol. 1991;147:50-54. 8. Mackall C, Fleisher T, Brown M, et al. Age, thymopoiesis, and CD4^sup +^ T

lymphocyte regeneration after intensive chemotherapy. N Engl J Med. 1995;332: 143-149.

9. Choyke P, Zeman R, GootenbergJ, et al. Thymic atrophy and regrowth in response to chemotherapy: CT evaluation. AJR Am J Roentgenol.1987;149:269272.

10. Sauter E, Arensman R, Falterman K. Thymic enlargement in children. Am Surg. 1991;57:21-23.

11. Li Odell ), Fennell K, Taniuchi 5, et al. Massive thymic hyperplasia. Ann ThorT) cells in patients with chronic granulomatous disease. I /nf Dis. 1993;55:1197-1201.

12. Hasui M, Hattori K, Taniuchi S, et al. Decreased CD4^sup +^ CD29^sup +^ (memory T) cells in patients with chronic granulomatous disease. J Inf Dis.1993;167:8385.

13. Hulstaert F, Han net ,Deneys V et al. Age-related changes in human blood lymphocyte subpopulations. Clin Immunol Immunopathol. 1994;70:152-158.

Accepted for publication January 15, 1998. From the Division of Pediatric Infectious Diseases, Epidemiology, and Immunology (Drs Kourtis and Ibegbu), the Department of Pathology (Dr Abramowsky), and the Division of Pediatric Allergy, Immunology, and Rheumatology (Dr Kobrynski), Department of Pediatrics, Emory University School of Medicine, Atlanta, Ga.

Reprint requests to Division of Infectious Diseases, Epidemiology, and Immunology, Department of Pediatrics, Emory University School of Medicine, 69 Armstrong St SE, Atlanta, GA 30303 (Dr Kourtis).

Copyright College of American Pathologists Jun 1998
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