Infections in Patients with Immunodeficiency with Thymoma (Good Syndrome)

Introduction Abbreviations used in this article: CMV, cytomegalovirus, CVID, common variable immunodeficiency, GS, Good syndrome, HIV, human immunodeficiency virus, HSV, herpes simplex virus, IVIG, intravenous immune globulin. Hypogammaglobulinemia develops in 3%–6% of patients with thymoma (21,46). This association was first reported by Robert Good and colleagues in 1954 (18), and is commonly referred to as Good syndrome (GS) (28,37). GS refers to a rare constellation of thymoma and adult-onset immunodeficiency that is characterized by low or absent B cells in the peripheral blood, hypogammaglobulinemia, and, variably, defects in cell-mediated immunity with CD4+ T lymphopenia and an inverted CD4:CD8+ T-cell ratio (reviewed in reference 1). GS is sometimes regarded as a subset of common variable immunodeficiency (CVID) with thymoma. CVID is a heterogeneous group of primary antibody deficiency syndromes with recurrent infections that is associated with cellular immune defects in up to 60% of patients (9,24,48,56,59a). The reduced number of peripheral blood B cells that is typical of GS is not a feature of CVID, however, even though altered B cell maturation is found in a majority of CVID patients. While a formal diagnostic definition of GS has not been developed, GS is now classified as a diagnostic entity (“immunodeficiency with thymoma”) separate from CVID (48). The pathogenesis of the immunodeficiency in GS remains elusive. A bone marrow defect is suggested by the B and T cell lymphopenia, and the frequent coexistence of eosinopenia (43). Pure red cell aplasia or neutropenia occasionally develops and may respond to treatment with glucocorticosteroids, suggesting an autoimmune pathogenesis. However, the immunologic abnormalities do not correct following either corticosteroid treatment or thymectomy. An increased risk for recurrent infections in GS has been supported by 2 reviews involving 20 patients published in the 1960s (15,28), by 7 cases of GS among referral patients with primary hypogammaglobulinemia in the United Kingdom (1,24), and from individual case reports in the literature. However, a systematic analysis of the infectious complications associated with GS has not been done. Here we report 5 patients with GS and serious infections whom we treated at our 3 institutions from 1983 to 1999. We also review the literature and summarize the information from 46 cases of documented infectious diseases in patients with GS. Methods We searched the English, French, German, Spanish, and Italian literature (1966–1999) using the MEDLINE (National Library of Medicine, Bethesda, MD) database. Keywords used in the search included thymoma, hypogammaglobulinemia, immunodeficiency, infection, infectious disease. Additional cases were identified through bibliographic review of these publications. Reports of potential infectious diseases were included if they occurred in patients with thymoma and hypogammaglobulinemia (the minimal diagnostic criteria for a diagnosis of GS we used here). Infections were considered definite if the case report included the isolation of a pathogen in an appropriate clinical setting. An illness was considered to be of possible infectious nature if the report documented the body site of presumed infection and a clinical course compatible with infection (for example, fever, leukocytosis, localizing signs of infections such as purulent sputum, response to antibiotics, development of bronchiectasis), in the absence of noninfectious causes of the illness. Cases of pneumonia that occurred only in the immediate postoperative course or only as a preterminal event, or that responded to steroids alone without antimicrobial therapy, were excluded. Cases of cough or chronic bronchitis in the setting of dyspnea of uncertain origin, heavy smoking with emphysema, or unknown smoking history, and cases with radiation-associated pulmonary fibrosis, improvement with steroids alone, or insufficient documentation were excluded. Fifteen cases were excluded according to these criteria (12,23,29,31,38,40,42,43,49,50,57,63,67,68). Among 22 reported cases of diarrhea, 17 were excluded because no infectious etiology was documented. The range of pathogens investigated was not recorded in most of these reports (22,26,29–31,41,49,50,53,55,62,63,65,67). Case Reports Case 1 A 54-year-old man was previously healthy when, in 1983, a mediastinal mass was discovered on a chest X-ray. The mass was resected. Pathologic examination revealed a spindle cell thymoma. In April 1986 and May and November 1989, 3 episodes of Campylobacter jejuni diarrhea and bacteremia responded to antibiotic treatment. Colonoscopy, during the second of these 3 episodes, showed multiple mucosal ulcers, and acute and chronic inflammation was seen on histopathologic examination of biopsied tissue. Panhypogammaglobulinemia was first recorded in April 1986, and monthly intravenous immune globulin (IVIG) replacement was given. In February 1990, Escherichia coli bacteremia developed that was attributed to colitis and resolved following treatment with ciprofloxacin. In June 1990 worsening diarrhea, fever, and weight loss were noted. Colonoscopy again showed large ulcers in the descending colon and rectum. Biopsies revealed acute and chronic inflammation, with giant cells, intranuclear, and cytoplasmic inclusions suggestive of cytomegalovirus (CMV) disease. Cultures of the biopsies were negative for CMV. Blood and stool cultures were negative. Peripheral blood B cells were low (<1% of total lymphocytes), and the number of CD4+ T cells was 255 per μL, with a CD4:CD8+ T-cell ratio of 0.3. The patient’s T cells produced no detectable interleukin (IL)-2 and showed a low proliferative response to in vitro stimulation with anti-CD3 monoclonal antibodies (data not shown). Human immunodeficiency virus (HIV) testing by serology and PCR was negative. He was treated with ganciclovir (2.4 mg/kg every 8 hours for 14 days). Despite treatment, he continued to have evidence of active proctosigmoiditis with multiple shallow ulcers seen throughout the colon on repeat colonoscopy. A hemorrhagic, inflammatory exudate was noted to be coming from the ileocecal valve. The colitis did not improve following a second course of ganciclovir, combined with high-dose IVIG (500 mg/kg every other day). Foscarnet (43 mg/kg every 8 hours) was then given for 21 days, with clinical and endoscopic improvement. Foscarnet was continued at 75 mg/kg every 24 hours, and the patient further improved. In April 1991, foscarnet was stopped because of anemia and leukopenia. One month later, foscarnet was given for 8 weeks in addition to monthly IVIG infusions because of recurrent colitis. Colonic biopsies showed acute necrotizing inflammation, CMV inclusions were again seen, and cultures grew CMV. The patient improved, but in January 1992 the CMV colitis again recurred and did not respond to a 5-week course of foscarnet and IVIG. Colonic perforation developed, and the patient died. Comment: Typical features of this case include the initial presentation with an asymptomatic mediastinal mass on chest X-ray and the development of recurrent infections (diarrhea and bacteremia, with C. jejuni and E. coli) several years later. The CMV colitis was ultimately fatal, despite antiviral therapy and high doses of IVIG. Case 2 A 74-year-old previously healthy man presented in March 1986 with a 4-year history of worsening cough with white sputum. Bronchoscopy was done but no pathogen was recovered. He had smoked 40 cigarettes per day for the past 30 years. A chest X-ray showed a mediastinal mass. The mass was resected in April 1986, and on pathologic examination was diagnosed as a spindle cell thymoma. The cough persisted. In January 1987, pneumonia due to Haemophilus influenzae type B was diagnosed, which resolved during treatment with antibiotics. In April 1987, Mycoplasma pneumonia responded only partially to erythromycin. In May 1987 bronchoscopy showed Pneumocystis carinii cysts, and the pneumonia resolved during 2 weeks of treatment with intravenous trimethoprim-sulfamethoxazole. HIV serology was negative. The CD4+ T-cell count was 582 per μL, with a CD8+ T-cell count of 776 per μL, and a CD4:CD8+ T-cell ratio of 0.75. He was hypogammaglobulinemic (IgG, 464 mg/dL; normal >710 mg/dL), with borderline IgA (59 mg/dL; normal >60 mg/dL) and IgM (38 mg/dL; normal >37 mg/dL). He was relatively well for 3 years, but then chronic bronchitis recurred. IVIG was given every 4 weeks starting in May 1990, and he was treated as an outpatient with repeated courses of antibiotics, corticosteroids, and theophylline. In early 1991, diarrhea developed which became persistent. The cause of the diarrhea was not identified. The patient had 6–8 despite and monthly IVIG. He at the of years from a pulmonary Comment: This case a common clinical The patient’s chronic cough was attributed to heavy and to the thymoma. The diagnosis of GS was recurrent pneumonia and, an infection carinii a immunologic typical is the chronic diarrhea for which no cause was identified. Case 3 A with a history of A infection in presented in February with a history of recurrent An mediastinal mass was noted on chest X-ray. The mass was resected in May and histopathologic examination revealed a spindle cell thymoma. in May was for cell with no A 2 was resected from the in February with no In April the patient presented with diarrhea of 1 mg/dL), fever, and was no and no examination suggestive of Blood cultures grew group A to and treatment with was given. the was treated with Hypogammaglobulinemia absent IgM mg/dL; normal mg/dL) was as well as absent B cells and low of cells in the peripheral The CD4+ T-cell count was per with an inverted CD4:CD8+ T-cell ratio of and PCR for HIV were negative. to a cause for the diarrhea, and a showed was of grew cultures were negative. The and diarrhea with IVIG. In June CMV with developed in the CMV was mg/kg every hours) was given for 2 by and of the was continued at mg/kg every 24 hours with further improvement on IVIG was given every weeks to In ganciclovir was the most ganciclovir, no evidence of active CMV was and the CD4+ T-cell count to per Comment: This patient had chronic and developed a a with that responded to IVIG. The of 22 from the was an The of immunologic and the diagnosis of GS. The CMV had a treatment with Case 4 A previously healthy man presented in early with a history of a and an mediastinal mass was seen on chest X-ray. was on January and showed a and thymoma. The patient was hypogammaglobulinemic with low of mg/dL; normal mg/dL) and IgM mg/dL; normal >60 mg/dL), and normal IgA mg/dL; normal mg/dL). 5 February and were and revealed Biopsies showed acute with inclusions and throughout the evidence of infection with was mg/kg every hours) was 14 of continued a repeat was done. was and the of CMV on was CMV grew hours in cell but the was to a the for not be February a low CD4+ T-cell count per was with an inverted CD4:CD8+ T-cell ratio of and low peripheral B cells per normal range per and PCR for HIV and human T-cell virus were negative. Foscarnet mg/kg every 8 hours) was to the ganciclovir for 24 doses of IVIG and 1 of globulin were given. was stopped showed with no inclusions and negative CMV evidence of CMV was The cough thymectomy. Bronchoscopy showed of the and cultures grew influenzae type The cough a course of The patient 1 of IVIG from the examination 30 March the low CD4+ T-cell count and the inverted CD4:CD8+ T-cell ratio per and and peripheral B cells were However, he In he had no further to in the setting of a low normal CD4+ T-cell count per an inverted CD4:CD8+ T-cell ratio and peripheral B Comment: a weeks of this patient developed CMV that to the diagnosis of GS. He was treated with IVIG and antiviral A typical feature of this case is the chronic bronchitis and the of influenzae at Case 5 A man presented in with a history of worsening and frequent He had a 40 history of smoking A mediastinal mass was seen on chest and was diagnosed by chest and was in and histopathologic examination revealed a spindle cell thymoma. In the patient was for pneumonia and cultures grew He responded to antibiotic therapy, but fever, and and cultures again grew He with developed that did not improve with multiple courses of antibiotics, and and was in June The patient was found to be hypogammaglobulinemic at this with low of mg/dL; normal mg/dL), IgA mg/dL; normal mg/dL), and IgM 5 mg/dL; normal mg/dL). The CD4+ T-cell count was per with an inverted CD4:CD8+ T-cell ratio of and peripheral B cells were In vitro stimulation of the patient’s T cells showed a low a normal response to a low normal A and no response to to and showed no response (data not shown). A for HIV was negative. In monthly IVIG infusions were and the patient had a improvement in with episodes, and therapy was stopped and courses of for episodes of or pneumonia were given. In were for recurrent with In May acute developed with abnormalities were at and the In June and were from the during an of worsening and the patient with antibiotics. He did well further was for worsening recurrent Cultures from the were but the patient had been treated with multiple courses of antibiotics. the he was to the with pneumonia and developed and the patient died. was Comment: The typical feature of this case is recurrent was at the GS was diagnosed and IVIG replacement was pathogens for the setting of were from the on the cause of the illness was not identified. A total of patients with GS the of this 5 patients from our institutions and 46 cases reported in the literature that our criteria for were patients and 24 the of a reported case the of the patients was years at the of the first thymoma, or The of the patients was years at the thymoma and hypogammaglobulinemia were documented. The of was 4 years to 8 in our 5 patients and years to in patients from the literature in whom we were to the of The diagnosis of thymoma the diagnosis of hypogammaglobulinemia, infection, or diarrhea in with an of 3 to years was diagnosed the documentation of infection or hypogammaglobulinemia in with an of 3 to 20 years. In 4 the were 2 of and in 2 patients the thymoma was only diagnosed at Infections The infectious diseases and the pathogens from the patients in commonly reported was recurrent infection of the and In cases a pathogen was An 8 cases of recurrent or were documented to be considered of possible infectious but a pathogen was not in these The development of was reported in 7 patients our Case were 2 cases of necrotizing pneumonia with patients developed In of the occurred in the absence of One patient had with E. coli of a that was associated with In the other case the developed chest of a of cases of carinii pneumonia were reported in patients with no therapy our Case In 1 of these patients no of HIV testing were documented and in 1 case were only from at examination diseases and pathogens reported in patients with immunodeficiency with patients had bacteremia and 1 had 1). other infections were 5 patients had and had or infectious were reported in patients and include chronic to herpes simplex virus of 1 with an and One patient had a infection with but were no cases of recurrent One patient had ulcers and 1 had ulcers without the documentation of was reported in 22 of which cases were In only 5 patients were pathogens from the 3 cases of infection with and 2 cases with infections were reported in 4 2 of whom had pathogens from the and E. One of these patients had recurrent with E. on the of were not given. In addition to our 3 CMV infection was reported in on the of compatible in In 2 of these evidence to CMV was presented One patient with had CMV and on a The was not for The patient had lymphopenia with an count of per The case was reported in that the of the HIV and the of and is the only case with evidence of CMV in the literature The other reported in had of 3 CMV inclusions were noted at count or HIV serology was In other cases CMV inclusions were seen at in the of patients with and In these CMV may have been a or in 4 of these patients or were that the inflammatory The patient with and and in the the evidence for presumed CMV was not recorded CMV was also on a from the of a patient with recurrent pneumonia and recurrent CMV without antiviral treatment suggesting CMV CMV with cytomegalovirus infection and from infections with CMV, reported diseases included 4 cases of 3 cases of 1 case of and 1 case of in an was 1 case of 22 infection of from the of our Case but no reports of as have been reported in patients with CVID reported infections in patients with GS in of B and T In of the the number of in the peripheral blood was either as of a white blood cell or by A in either the total number of the CD4+ T-cell or an inverted CD4:CD8+ T-cell ratio was recorded in of these patients on at 1 In of these patients at 1 of these was and found to be the B cells were low or absent in normal in and not in In the patient was treated with the of peripheral B cells increased from to this treatment. to and at 1 was noted in 5 3 other patients had normal and 1 patient had a with negative In vitro were found to be in 5 patients and normal in 3 patients. The T cells of the patient with CMV showed normal in vitro but no response to CMV in vitro in response to stimulation with anti-CD3 monoclonal antibodies was noted in the T cells from 2 patients that were patients had low or absent antibody in response to with In 1 such an antibody response following the of immune globulin and patients during the included in the case 21 were and in 1 the was not Additional included given for or red cell 14 neutropenia and of patients and of 21 patients were had 1 of these The of immune globulin was recorded in 30 patients. In of these 30 a response was seen during the included in the at patients did not immune globulin was used in early and the intravenous (IVIG) were used in reports of patients were treated with responded with of 17 patients IVIG. However, of the 22 had 5 had 1 developed during treatment with IVIG, and in 1 the IVIG was with no of the 7 died. the of CMV immune globulin was documented in only 1 patient Case no of be years on thymoma and hypogammaglobulinemia, the pathogenesis of this primary immunodeficiency syndrome remains We have the on 5 patients with GS and infectious complications whom we treated at our institutions and 46 cases in the literature. and patients were were most in or they developed either thymoma common as the first infectious complications of years of the first the syndrome was characterized by or chronic infections in with or without the development of autoimmune treatment. The most common infectious was recurrent infection, most due to and were but developed in patients. infections in GS most a of the immunity associated with this syndrome, the low of The of infections and pathogens in GS is to that in patients with other hypogammaglobulinemic CVID common in patients with GS was chronic such as or C. were and in 2 cases chronic diarrhea was associated with and in the majority of chronic diarrhea was of to in patients with the other patients with GS to infections do patients with CVID by our 4 the of infections that patients with GS have defects in cell-mediated This is supported by in vitro defects in T in the patients that we 1 and and in reports from the literature. of the GS patients with carinii pneumonia or CMV had been treated with The most infections in patients with GS include herpes carinii and recurrent only 2 cases of infection in with in 1 case and no other infections such as or have been reported in patients with GS, in to other patient with cellular immune to has been the high of serious CMV infection in the patients with GS treated at our We a case of CMV colitis and the first 2 to our of treated CMV and in patients with GS. that CMV was for the and histopathologic of these 2 patients include the of compatible inclusions and CMV cells in with and ulcers, the absence of other potential and the response to antiviral therapy 2 GS cases in the literature with CMV 1 with and 1 with necrotizing of our 3 patients with CMV had CD4+ T lymphopenia and per blood, normal per The patient with CMV and our patient with carinii pneumonia had low but normal CD4+ T-cell and 582 per μL, The lymphopenia in these patients was in with the This CD4+ T-cell defects in GS, and is supported by in vitro in at patients. While CD4+ T lymphopenia may be by acute CMV the documentation in our patients of lymphopenia 3 CMV of CMV and several reports of CD4+ T lymphopenia in GS patients without CMV a association of CD4+ T lymphopenia with GS. In of the cellular immune defects in GS, we that and diagnostic may infections previously CMV and other infections have only been reported in CVID and other This may an of immunodeficiency in GS, in that the hypogammaglobulinemia is associated with cellular immune low or absent peripheral B cell and, in the development of neutropenia or as red cell that treatment. may for the of and that GS is associated with a While in considered is in most patients with in of the potential for and however, most resected found to be the clinical of GS with patients with CVID, to be by the of associated and autoimmune diseases not by the of the thymoma. of this review include to in the in the Methods or documentation of and of in Cases of GS may thymoma is not considered and thymoma may be on chest X-ray in of cases In we have a of the of of the immunodeficiency and the treatment that were used the clinical course of the patients. on of the patients and to be with as this is not a with patients (for example, CVID or GS without infectious immune was on a and reports to the be the range of normal and immunologic reported in our patients and in the literature individual in the nature or of the While they no reference to infectious is that and Good as early as that the of the of GS and to of this these in the we have the following for patient The development of an infectious in a patient with thymoma early and immunologic and and of antimicrobial treatment. the association of thymoma and immunodeficiency is not well may be to in patients with thymoma, in to and at an early the 3%–6% have or GS. In patients with presumed CVID, the development of B cell lymphopenia, CMV or other infections the of a diagnosis of GS. of thymoma, is at the of peripheral B cells, CD4+ and CD8+ T cells by and immunologic may be normal they first in a patient with recurrent infections is diagnosed ultimately as GS, the of repeated immunologic of patients in whom the clinical of GS HIV infection be in the setting of an infection or CD4+ T lymphopenia, HIV infection is associated with In to treatment, be in most patients with to and However, not to to of immune given the absence of reports of of the immunodeficiency in GS that were to be to thymectomy. IVIG be given to GS patients in doses appropriate for the treatment of immunodeficiency (for example, doses to a normal IVIG treatment was associated with clinical at in the majority of GS patients in whom has been This is with other hypogammaglobulinemic the of IVIG has the of with reduced of antibiotics, and, the of chronic and IVIG replacement is by multiple for patients with primary hypogammaglobulinemia (48). for We to cases of infectious diseases in patients with thymoma and to the with thymoma syndrome, is a adult-onset that is characterized by thymoma, hypogammaglobulinemia, and low of peripheral B CD4+ T lymphopenia and an inverted CD4:CD8+ T-cell ratio may be Here we report 5 patients with GS and infectious complications were seen at 3 institutions 1983 and 1999. patients had recurrent 3 had cytomegalovirus (CMV) and 1 had Pneumocystis carinii of the literature identified 46 other reports of infections in GS patients. The infections reported in patients included recurrent infection cases with documented with most Haemophilus influenzae CMV bacteremia or chronic diarrhea cases with documented stool infections carinii pneumonia infection with and other with GS with a of infections and pathogens to common variable immunodeficiency with patients with CVID, CMV carinii and to be common in patients with GS, and patients with GS may have a GS be in patients with thymoma or CVID with intravenous immune globulin is for patients with GS. We to the referred patients with thymoma and immunodeficiency for and treatment to our and to and C. for and review of the