J Clin Immunol (2014) 34:283–288 DOI 10.1007/s10875-014-0014-7

ASTUTE CLINICIAN REPORT

Good’s Syndrome and Pure White Cell Aplasia Complicated by Cryptococcus Infection: A Case Report and Review of the Literature K. Akinosoglou & M. Melachrinou & D. Siagris & E. Koletsis & M. Marangos & C. A. Gogos & E. E. Solomou

Received: 3 September 2013 / Accepted: 28 February 2014 / Published online: 14 March 2014 # Springer Science+Business Media New York 2014

Abstract Thymomas can present with a variety of paraneoplastic manifestations, mostly of autoimmune origin, including Good’s syndrome when there is associated hypogammaglobulinemia. Although pure red cell aplasia is a recognised complication of thymoma, selective white cell aplasia is very rare, particularly in Good’s syndrome. Lethal opportunistic infections are a feature of Good’s syndrome, usually occurring in those patients with associated severe T lymphocyte defects. Although the cryptococcus is a recognised fungal pathogen in patients with other causes of CD4+ T cell lymphopenia, surprisingly this complication has not been reported in patients with Good’s syndrome. We now describe a 70 year old man with Good’s syndrome and pure white cell aplasia who presented with disseminated cryptococcosis, and provide an up-to-date review of the relevant literature. Despite meningeal involvement our patient recovered after combined treatment with intravenous globulin, granulocyte stimulating growth, corticosteroids and antifungal therapy. K. Akinosoglou (*) : D. Siagris : C. A. Gogos : E. E. Solomou Department of Internal Medicine, 5th floor, University General Hospital of Patras, 26504 Rio, Greece e-mail: [email protected] M. Melachrinou Department of Pathology, University General Hospital of Patras, 26504 Rio, Greece E. Koletsis Department of Cardiothoracic Surgery, University General Hospital of Patras, 26504 Rio, Greece M. Marangos : C. A. Gogos Department of Infectious Diseases, University General Hospital of Patras, 26504 Rio, Greece E. E. Solomou Department of Haematology, University General Hospital of Patras, 26504 Rio, Greece

Keywords Good’s syndrome . cryptococcus . thymoma . pure white cell aplasia

Case Presentation A 70 year old caucasian woman presented as an emergency with persistent fever (39 °C), rigors and fatigue over the previous 20 days, in the absence of any other symptoms. Her medical history was unremarkable except for obesity and dyslipidemia treated with simvastatin and ezetimibe. She had not travelled abroad or been in close contact with animals, including birds, or had consumed raw or unpasteurized products. On admission she was afebrile, with a pulse rate of 85 bpm and normal blood pressure, and respiratory rate of 14/min. Physical examination was unremarkable. Initial investigations revealed severe leukopenia (WBC: 1.66 K/μl, Poly: 12 %, Lymph: 41 %, Mono: 46 %) with the blood film showing reactive lymphocytes. Electrocardiogram and chest radiography were normal. The patient was given broad spectrum antibiotics (Fig. 1) while waiting for the results of blood, urine and stool cultures. The Mantoux test and serology for viruses including EBV, CMV, HIV, HAV, HBV, HCV, HSV, VZV and Rubella , and other pathogens including Toxoplasma, Borrelia, Salmonella, Rickettsia, Legionella, Leishmania, Leptospira, Brucella were negative. Four days later the patient’s clinical condition remained unchanged although the white cell count had fallen (WBC: 0.9 K/μl, Poly:11 %, Lymph:58 %, Mono:30 %); initial cultures for common pathogens were negative. A bone marrow aspirate showed a block in the differentiation of myeloid progenitors to granulocytes (Fig. 2a); red cell and platelet formation was normal, with no evidence of malignant cells or parvovirus infection. However, some granulomas and yeast-like organisms consistent with cryptococcal infection were present

284 Fig. 1 Schematic presentation of findings and therapeutic regimens during the course of the disease. Horizontal axis represents days post-admission. Grey lines show the time that indicated results were received from the respective diagnostic departments, as shown in boxes. Vertical axis indicates the therapeutic regimens used during hospital admission, and the horizontal red lines the duration of therapies

J Clin Immunol (2014) 34:283–288 Bone marrow aspiration: block of myeloid line maturation CT scan : thymoma

Day of Hospitalization

20

10

30

40

30

40

Methylprednisolone Fluconazole Acyclovir Dexamethasone Immunoglobulin

Amphotericin B Vancomycin Meropenem G-CSF Piperacillin/ Tazobactam

CSF Ag (+) Cryptococcus Blood Ag (+) Cryptococcus

Day of Hospitalization

10

Bone Marrow biopsy (+) for Cryptococcus

20

CSF cultures (+) for Cryptococcus

Blood cultures (-) for Cryptococcus

Marrow cultures (+) for Cryptococcus Blood cultures (+) for Cryptococcus

in the bone marrow (Fig. 2b, c). Immunophenotyping of peripheral blood lymphocytes showed a marked predominance of CD8+ lymphocytes (85.4 %), a reversed CD4/ CD8 ratio (0.016) and absence of CD20+ B cells. The serum γ-globulin fraction was severely reduced at 6.2 % (ref 10.2–18.9 %), with a normal serum IgG (1350 mg/ dl) but low IgA and IgM (31.5 mg/dl and 19.9 mg/dl respectively) (reference range 82–453 mg/dl and 46– 304 mg/dl). A full body CT scan was then performed which showed a large mass in the mediastinum consistent with thymoma, along with two nodules in the left lower lobe of the lung. After the fungal spores in the bone marrow were confirmed as Cryptococcus neoformans (Fig. 2c), a diagnosis

of disseminated cryptococcosis was made and appropriate treatment given (Fig. 1). Meanwhile, the patient started vomiting and complained of blurred vision and headache. Lumbar puncture confirmed cryptococcal meningitis (positive latex agglutination test for cryptococcal antigen and CSF culture). By this time the initial blood culture was also reported positive for Cryptococcus neoformans (Fig. 1). The patient then gradually recovered, and by 20 days after admission the white cell count had risen to 6.06 K/μl (Poly: 87 %, Lymph: 7 %, Mono: 4 %). Following negative blood cultures, she was finally discharged 45 days post-admission on fluconazole and a tapering scheme for methylprednisolone. The thymoma was later surgically removed, the encapsulated

Fig. 2 Bone Marrow biopsy showing: a Severe granulocytic hypoplasia. The immunostain for myeloperoxidase (MPO) reveals immature granulocytes including pro-myelocytes (arrows), scattered and in small groups, among hyperplastic erythroid islands (arrowheads). Mature granulocytes are totally absent. b Bone marrow biopsy shows a poorly

formed granuloma composed of epithelioid macrophages and multinucleated giant cells. Yeast-like organisms are present within the cytoplasm of multinucleated giant cells (arrows). c PAS stain highlights the intracytoplasmic encapsulated cryptococcal yeasts (arrowheads). (a immunostaining, 100×; b H & E, 400×; c PAS, 400×)

No data available

Spindle Cell Hypogammaglobulinemia Absent myelopoiesis

Jevatha 2011 [6]

Ohuchi 2007 [5]

Crawford 1999 [2]

51♂ Febrile neutropenia, Spindle Cell Hypogammaglobulinemia Promyelocyte arrest respiratory Mild infection dyserythropoiesis Normal megakaryopoiesis Nearly absent 59♂ Fever, weight Spindle Cell IgA, IgG (↓), IgM (−); myelopoiesis loss, diarrhoea, CD4:CD8:0.46 Mildly decreased chest discomfort erythropoiesis, Normal megakaryopoiesis 61♂ Cough, mediastinal Type B1 IgA, IgG, IgM (↓), Hypercellularity mass, recurrent CD4:CD8:0.49 with promyelocyte infections arrest 43♂ Febrileneutropenia- Type AB CD4:CD8:(−) Nearly absent Respiratory IgG(↓), IgM, IgG(−) myelopoiesis infection

Granulocyte aplasia Severe erythroid hypoplasia

Yip 1996 [10]

Spindle Cell

68♀ No data available

64♂ Recurrent neutropenia

70♀ No data available

No data available

Factor XI deficiency

Anti-acetylcholine receptor antibody

None reported

Anti-striated muscle Abs—no apparent manifestations

CFU-GM Inhibitor

No data Hypogammaglobulinemia No data available Hypothyroidism, PRCA available Spindle Cell IgG, IgA(↓), Promyelocyte arrest CFU-GM Inhibitor Normal Erythropoiesis and Megakaryopoiesis Spindle Cell Hypogammaglobulinemia Absent myelopoiesis MG, CFU-GM Inhibitor Spindle Cell Hypogammaglobulinemia Promyelocyte arrest CLL CFU-GM Inhibitor

Postiglione 1995 [12]

Ackland 1988 [17] Weir 1989 [18]

Jacobson 1971 70♀ Sepsis [14] Young 1977 68♀ No data available [15] No data available Sugiura 1982a [16] Degos 1982 52♀ Recurrent [3] infections

Prednisone Testosterone propionate Thymectomy None reported

Spindle Cell Hypogammaglobulinemia Hypocellular None reported marrow Few plasma cells and lymphocytes seen Spindle Cell Hypogammaglobulinemia Promyelocyte arrest No data available

Discharge

Thymectomy Prednisone G-CSF iv IgG CHOP Prednisone Thymectomy

Plasma Exchange Chlorambucil

No data available

Thymectomy Filgrastim iv Ig G-CSF iv Ig Cyclosporine A

None reported

None reported

Methylprednisolone, None reported Prednisone, Azathioprine

G-CSF

Prednisone (later refractory) Thymectomy Vincristine Plasmapheresis Cyclophosphamide

iv Ig

Discharge on short duration CSF and cyclosporine

Discharge

Discharge on iv Ig

Discharge on iv Ig

Death

Discharge

No data available

Prednisone Discharge Thymectomy Cyclophosphamide

Plasmapheresis

No data available

No data available

Splenectomy Death Cyclophosphamide No data available Death

None reported

Death

Outcome

No data available

No data available

60♀ Bleeding manifestations, sore throat

No data available

No data available

Successful immune- Failed immunerelated therapy related therapy

Spindle Cell Hypogammaglobulinemia Promyelocyte arrest

Related features

53♂ Tonsillitis

Bone marrow

Thiele 1967a [13] Rogers 1968 [9]

γGlobulins and lymphocytes

Age Presentation sex

Reference

Thymoma histology

Table I List of thymoma cases exhibiting both Good’s Syndrome and White cell aplasia

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tumour being classified as a type A thymoma composed of bland spindle and oval cells with a few lymphocytes.

Only abstracts were available due to language restrains (Danish, Japanese); ♂ indicates male; ♀ female; ↓ decreased; (−) normal

Discussion

a

CLL chronic lymphocytic leukemia; CHOP cyclophosphamide, hydroxydaunorubicin, oncovin (vincristine), prednisone; G-CSF granulocyte colony-stimulating factor; PRCA pure red cell aplasia; CFUGM granulocyte monocyte colony forming unit; MG myasthenia gravis

Table I lists all reported cases of concomitant Good’s Syndrome and White Cell Aplasia. Table is divided in 15 horizontal rows illustrating reported cases including ours and ten vertical columns illustrating literature, patient age and sex, presentation, type of thymoma according to available WHO or traditional classification, information on serum globulins and lymphocyte subtypes, related manifestations, available information on successful and failed administration received and outcome respectively

None reported Current case

70♀ Febrile neutropenia- Spindle Cell IgA, IgM (↓), IgG (−), Cryptococcus CD4:CD8:0.016 infection

Promyelocyte arrest Normal erythropoiesis and megakaryopoiesis

None reported

Filgrastim, Prednisone and azathioprine Dexamethasone G-CSF iv Ig El Galaly 2011a [19]

No data available

No data available

Normal erythropoiesis and megakaryopoiesis Hypogammaglobulinemia No data available

Autoimmune neutropenia

Thymectomy

No data available

Outcome Successful immune- Failed immunerelated therapy related therapy Related features Bone marrow γGlobulins and lymphocytes Thymoma histology Age Presentation sex Reference

Table I (continued)

Discharge on corticosteroids and iv Ig

J Clin Immunol (2014) 34:283–288 Discharge on iv Ig

286

G o o d ’s s y n d r o m e ( G S ) , c h a r a c t e r i z e d b y hypogammaglobulinemia and thymoma, accounts for about 5 % of all patients with thymoma, with a mean age at presentation of about 62 years [1]. Usually all serum immunoglobulin isotypes are reduced [2–5], although patients with normal IgA [1] or IgG [6], and normal [2, 6] or even raised IgM concentrations [7] have been reported. Despite the hypogammaglobulinaemia , serum auto-antibodies occur in up to 30 % of cases (e.g. ANA in up to 3 %) [5, 8–10]. Similar to our case, marked lymphocytopenia occurs in 35 % of cases, with either absent or reduced numbers of B lymphocytes. CD4+ T lymphocytopenia is common (73 % of cases) and there is often a raised CD8+ T cell count (55 % of cases) [8], often but not always accounting for an inverted CD4/CD8 ratio [2, 5, 8]. The pathogenesis of the lymphopenia remains unclear although T cell suppression of pre-B cell differentiation in the bone marrow has been suggested [11]. Pure white blood cell aplasia (PWCA) or agranulocytosis with thymoma is extremely rare (1.1 % of all thymomas) [3, 6], and is often combined with other blood cell aplasias [12] (Table I). Very few cases of pure white cell aplasia in Good’s syndrome have been described with many of these being associated with a benign spindle cell tumour [2, 3, 8, 10, 20] and rarely type AB [6], although changes in the histological classification of thymomas over time prevents a full analysis of histological data from all published cases [21] (Table I). Immunological mechanisms for the granulocytopenia have been demonstrated in patients with PWCA, including lymphocyte or serum-mediated inhibition of granulocyte colony formation in the bone marrow [3, 8, 10–12, 17–20] . A lack of laboratory facilities has prevented us from investigating this in our patient, although the subsequent recovery of myelopoeisis after GCSF and anti-fungal therapy suggests that the disseminated cryptococcal infection itself was responsible. Severe infections in GS are usually due to the associated immunodeficiency, particularly when there is both hypogammaglobulinaemia and a CD4+ T-cell deficiency [1, 8]. Although cryptococcal infection has been described in a few patients with thymoma [22–25], our case is the first description in GS. The most common pathogens in GS are candida [2, 3], aspergillus [6] , multi-resistant Staphylococcus aureus, [10], Pseudomonas aeruginosa [10], Pneumonocystis jiroveci [10], cytomegalovirus [2] and Varicella zoster [2]. It is likely that the combination of lymphopenia and granulocytopenia was the main predisposing factor in our case, although other inherited subtle defects in innate host defence, normally of little consequence in isolation, may have

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increased susceptibility. Cryptococcal disease is a major problem in patients with AIDS in sub-Saharan Africa [26], particularly in dry dusty environments where the fungal spores can be inhaled from contaminated soil and bird droppings [27]. Interestingly, our patient lived in an urban environment and had no close contact with birds. In our case the initial diagnosis of cryptococcosis was made on bone marrow, confirmed subsequently by finding antigen in blood and CSF Fig. 1. The initial infection was presumably by lung inhalation and was responsible for the lung nodules seen on the CT scan. Typical epithelioid-cell granulomas are an infrequent finding in bone marrow trephines, with the number of cryptococcal organisms in the bone marrow apparently being inversely proportional to the extent of the granulomatous response [28–30]. Consequently negative blood smears and cultures do not rule out cryptococcosis, while antigen testing is falsenegative in 40 % of all extraneural infections [31]. As has been suggested in AIDS [32], it could be argued that routine cryptococcal antigen testing of blood in patients with known Good’s syndrome living in potentially contaminated environments might lead to earlier diagnosis and prevention of fatal disease. However, as in our case, GS is often diagnosed during the first severe opportunistic infection [8]. The prognosis of patients with Good’s syndrome complicated by white cell aplasia is dependent on the frequency and severity of infections, changes in the haematological parameters and co-morbidities such as autoimmune disease. The thymic tumour itself appears to have little influence on survival although surgical resection is usually recommended to exclude the possibility of metastases and a possible role in any autoimmune process [33]. Corticosteroids [2, 3, 9, 10, 12, 18, 19] and cyclophosphamide [3, 12, 14] have been used with a variable degree of success in reversing the granulocytopenia [8], and transient removal of a GM-CFU inhibitor has also been achieved in several patients with plasmapheresis [3, 12, 18]. From the reported patients with known outcome, 70 % (9/13) were successfully discharged from hospital [2, 3, 5, 6, 9, 10, 18, 19] on immunoglobulin replacement therapy [2, 5, 6, 10, 19] (Table I). Both of the two patients with a total block in myelopoiesis died while most of those (8 of10) with partial block survived.

Conclusion GS and PWCA are rare parathymic disorders with a poor prognosis. The rarity of this combination will require a multi-national approach to the investigation of individual patients to advance our knowledge of the mechanism of the inhibition of granulopoiesis and identify the best therapy. Meanwhile, clinicians need to consider fungal infection in

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affected patients with fever and attempt to reverse the granulocytopenia with growth factors.

Acknowledgments The authors would like to thank Dr David Webster for critical appraisal of our manuscript and fruitful feedback.

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Good's syndrome and pure white cell aplasia complicated by cryptococcus infection: A case report and review of the literature.

Thymomas can present with a variety of paraneoplastic manifestations, mostly of autoimmune origin, including Good's syndrome when there is associated ...
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