If at first you don't succeed: Try, try again
Authors: Mahwash Saeed, Morel Rubinger, Arshad Ahsanuddin, Carmen Morales, Brian Penner, David Robinson, Hani El‐Gabalawy, Ryan Zarychanski
Journal: American Journal of Hematology (2011)

A 51-year-old gentleman presented to a rheumatologist with a 3 week history of fevers, diarrhea, arthralgias, and generalized pruritis. Blood work revealed mild anemia (hemoglobin 13.5 g/dL). The erythrocyte sedimentation rate (ESR) was within normal limits. Given the acuity of onset, rash, and arthralgias, parvovirus B19 was suspected. Cytomegalovirus, Epstein Barr virus, adenovirus, and coxsackievirus were also possible given these presenting signs and symptoms. Systemic lupus erythematosus, rheumatoid arthritis, adult onset Still's disease, or another connective tissue disease could not be excluded. A reactive gastrointestinal disorder was less likely, but possible considering the history of diarrhea. Over the following 2 weeks, the patient's clinical condition deteriorated and he presented to an emergency department. His temperature was 99.5 degrees Fahrenheit and his pulse was 115 bpm. All other vital signs were within normal limits. The physical examination revealed a lacy macular rash over the arms and anterior chest wall. There was no palpable lymphadenopathy or organomegaly. The patient reported a 3 week history of weight loss, but denied chills or night sweats. He had no risk factors for human immunodeficiency virus infection (HIV) or hepatitis. Travel history included trips to Cuba in the year preceding presentation. Laboratory testing revealed elevated liver transaminases (aspartate aminotransferase (AST) 69 U/L, alanine aminotransferase (ALT) 182 U/L, gamma glutamyl transferase (GGT) 95 U/L), and evidence of systemic inflammation (C-reactive protein (CRP) 64 mg/L, ESR 25 mm/hr, ferritin 328 μg/L). Serum lactate dehydrogenase (LDH) (357 U/L) and bilirubin were elevated (total bilirubin peaked at 92 μmol/L, direct at 92 μmol/L). A complete blood count at admission to hospital revealed hemoglobin of 11 g/dL (Mean corpuscular volume (MCV) 86 fL), platelets of 69 × 109/L, and a white blood cell count of 2.3 × 109/L, with a normal white cell differential. The patient looked distinctly unwell, with new pancytopenia, hyperbilirubinemia, elevated liver enzymes, and signs of systemic inflammation. Infection was suspected, but in the absence of intravenous drug use, high risk sexual behavior, or blood transfusions, HIV, or hepatitis was unlikely. With no history of immunosuppression or evidence of pulmonary pathology cytomegalovirus infection was improbable. Bacterial infections, including Streptococcus pyogenes, syphilis, bartonella, or mycobacteria were considered. The presenting symptoms were not characteristic of a specific connective tissue disease. Microbiologic cultures from blood, urine, and cerebral sinus fluid were negative for bacteria, fungi, and acid-fast bacilli. Immune serology including antinuclear antibody, double stranded DNA, perinuclear antineutrophil cytoplasmic antibody, cytoplasmic antineutrophil cytoplasmic antibody, anti-smooth muscle, and assays for extractable nuclear antigens (anti-Ro, anti-La, anti-Scl-70, and anti-Jo-1 antibodies) were normal. Complement levels were decreased (C3 = 0.13 g/L, C4 = 0.04 g/L). Protein electrophoresis revealed an increase in polyclonal immunoglobulins. Viral serology was negative for Hepatitis A, B, or C, parvovirus B19, and HIV. Serology and PCR for Epstein Barr and cytomegalovirus were negative. Computed tomographic scans of the thorax, abdomen, and pelvis revealed mild hepatosplenomegaly and normal sized lymph nodes throughout the abdomen and thorax. The patient's liver transaminases continued to rise in hospital and the pancytopenia progressed. An infectious etiology could not be identified and immune serology was negative. The patient's rapid clinical decline, in association with rising transaminases and progressive pancytopenia, was concerning for a hematological malignancy, and/or hemophagocytic syndrome. In an attempt to secure a diagnosis, liver and bone marrow biopsies were performed. A transjugular liver biopsy revealed no evidence of neoplastic infiltration, and no evidence of autoimmune hepatitis or viral inclusion bodies. The bone marrow biopsy and aspiration was of normal cellularity, and unremarkable morphology (Fig. 1). A slight increase in plasma cells was noted. Bone marrow cultures were negative for bacteria, acid-fast bacilli, fungi, and viruses. Normal bone marrow aspirate with trilineage representation and no evidence of neoplasia. Arrowheads indicate erythroid precursosrs (Wright-Giemsa, 63× Oil Immersion, Olympus AxioCam ICc3). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] The patient's hemoglobin declined steadily in hospital, in the absence of blood loss, while the LDH and unconjugated bilirubin increased. The absolute reticulocyte count was 254 × 109/L, serum haptoglobin was <0.01 μmol/L, and the direct antiglobulin test (DAT) was positive for IgG. Thrombocytopenia worsened; the platelet nadir was 13 × 109/L on day 6 of hospital admission. Based on the positive DAT (IgG), low haptoglobin and increased reticulocytes, a diagnosis of warm autoimmune hemolytic anemia (AIHA) was established. Ample megakaryocytes in the bone marrow, along with peripheral thrombocytopenia, were consistent with immune thrombocytopenia (ITP). AIHA occurring in combination with ITP (Evans Syndrome) may be secondary to infection, autoimmune disorders, connective tissue disease, drugs, and malignancy (particularly lymphoproliferative disorders and chronic lymphocytic leukemia). Laboratory testing and tissue pathology, however, remained unrevealing while an offending drug could not be identified. Due to continued clinical deterioration, including increasing liver transaminases, declining renal function, worsening pancytopenia, and a profound systemic inflammatory response syndrome (SIRS), high dose methylprednisolone (1 g, intravenously, for 3 days) was prescribed. Within 7 days, all of the patient's signs and symptoms, including the macular skin rash, systemic inflammation, thrombocytopenia, and measures of organ dysfunction had resolved, except for a mild, well compensated hemolytic anemia (hemoglobin 12–13 g/dL). The patient was discharged from hospital on a tapering dose of oral prednisone. Over the following 4 months the patient slowly returned to his baseline state of health. However, when the dose of prednisone was tapered to 10 mg/day, he had recrudescence of his original symptoms, including fatigue, fever, diarrhea, and the pruritic skin rash on his arms and chest. The patient was also found to have palpable cervical adenopathy, and developed a decompensated hemolytic anemia that rendered him transfusion dependent. The absolute reticulocyte count fell from 254 × 109/L on his original admission to 7 × 109/L. A repeat bone marrow biopsy demonstrated the selective loss of red cell precursors, but was otherwise unremarkable (Fig. 2). In addition to Evans syndrome, the patient was diagnosed with pure red cell aplasia (PRCA). Bone marrow with selective loss of erythroid precursors, consistent with PRCA (Wright Giemsa, 63× Oil Immersion, Olympus AxioCam ICc3). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary. com.] The persistence and severity of his illness, in the absence of positive rheumatologic serology, made a primary autoimmune condition unlikely. New cervical adenopathy was especially concerning for a lymphoproliferative disorder; however, Castleman's or Kikuchi's disease was diagnostic considerations. Multi-centric Castleman's Disease, which is often associated with systemic symptoms, is classically associated with HIV infection, but our patient was confirmed to be HIV negative. The patient was admitted to hospital with fever, neck pain, diarrhea, and dehydration. Repeat CT scans of the neck, chest, abdomen, and pelvis were performed. He was once again treated with high dose steroids, but with marginal improvement in his symptoms. Due to progressive cervical, supraclavicular, and axillary lymphadenopathy, in conjunction with enlarging splenomegaly, an axillary lymph node biopsy was performed. Tissue pathology was consistent with mixed cellularity classical Hodgkin lymphoma (Fig. 3). The patient was treated with six cycles of ABVD (adriamycin, bleomycin, vincristine, dacarbazine). His early treatment course was complicated by pulmonary emboli and Pneumocystis jiroveci pneumonia, both requiring hospitalization. All laboratory indicators of Evans syndrome and PRCA resolved with the first cycle of therapy. A post-treatment positron emission tomographic (PET) scan showed no evidence of residual disease. Mononuclear variant Hodgkin cells, consistent with mixed cellularity classical Hodgkin Lymphoma (a,b: Hematoxylin and Eosin, 40×, arrowheads below Hodgkin cells; (c): CD30 immunohistochemical stain highlighting Hodgkin cells, 40×; (d): CD15 immunohistochemical stain highlighting Hodgkin cells, 40×; Olympus AxioCam ICc3). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Hodgkin's lymphoma (HL), was originally described in 1832, and was the first of the malignant lymphomas to be recognized as a distinct entity [1]. In the United States, the incidence of HL is 2.8 per 100,000 men and women per year [2]. Contrary to the rising incidence of non-Hodgkin lymphoma (NHL), the incidence of HL has remained stable over the past 70 years [3, 4]. The most common manifestation of Hodgkin's lymphoma is persistent and painless lymphadenopathy, commonly in the neck, supraclavicular fossa, or mediastinum, less often in the axilla [5]. Rare manifestations of HL, present in less than 1% patients at diagnosis, include paraneoplastic neurologic deficits, renal disease (e.g., glomerulonephropathies and nephritic syndrome), or various immunologic abnormalities including autoimmune disorders [5]. Autoimmune conditions, preceding or existing concomitant with a new diagnosis of HL or NHL, are uncommon, but have been described. Hematologic manifestations include AIHA [6, 7], ITP [8, 9], PRCA [10-12], and autoimmune neutropenia (AIN) [8, 13]. Non-hematologic autoimmune conditions include thyroiditis, hepatitis, myasthenia gravis, and polymyalgic syndromes [14]. These protean manifestations of a single disorder can pose a significant challenge to clinicians and represent a source of frustration to patients. AIHA in patients with HL occurs with a reported frequency ranging from 0.2% to 3% [15, 16]. Although an unusual feature of HL, especially at presentation, AIHA is often associated with advanced stage disease [9, 10, 16,]. In 1980, Levine et al. retrospectively analyzed 71 HL cases for DAT positivity and found positive DAT tests in 7 (10%) patients, all with advanced (Stage III or IV) disease, and “B” symptoms [15]. While this small study failed to make a strong association between the presence of Coombs positivity and poor prognosis in HL, it did emphasize the potential for HL in cases of unexplained AIHA. Although autoimmune phenomena have been described in association with HL for several decades, the mechanisms responsible for their occurrence are poorly understood. Reed–Sternberg cells are known to induce aberrant production of cytokines and chemokines, resulting in a prominent inflammatory response in involved tissues [10, 17, 18]. Autoimmune paraneoplastic cytopenias associated with chronic lymphocytic leukemia have been mechanistically described as an immune dysregulation resulting in the loss of tolerance to self-antigens, which in turn leads to immune-based cytopenias [17]. Perhaps in HL, also a germinal B-cell center disorder, a similar mechanism exists [19]. Acute therapy of autoimmune paraneoplastic disorders is non-specific and aimed at initial disease control with high dose steroids and supportive care. Definitive treatment involves treatment of the underlying lymphoma [19, 20]. Although there are cases of successful control of ITP associated with HL using cyclophosphamide and azathioprine, no cases describe successful control of AIHA with these same immunosuppressive regimens [20]. Improvement in ITP with the use cyclophosphamide may have been related to partial treatment of the underlying HL. Several reports have also described AIHA and ITP associated with HL being controlled, at least transiently, by splenectomy alone [19, 21]. Generally, autoimmune symptoms abate with specific lymphoma treatment, but can recur, especially in the setting of relapsed disease [10, 16, 20]. Several cases of AIHA, Evans Syndrome, and PRCA have been described in association with NHL [22]. It appears that, in this setting as well, it is the treatment of the underlying NHL that definitively treats the concurrent cytopenias. The use of prolonged steroids to control autoimmune symptoms is not without risk, including steroid-induced hyperglycemia, osteoporosis, and increased risk of life threatening opportunistic infections, such as Pneumocystis jiroveci as in the case presented. HL is a treatable and often curable malignancy, even in advanced stage disease. Autoimmune disorders preceding or occurring concurrently with HL can complicate the diagnosis and management of both disease processes. Physicians should maintain a high index of suspicion for lymphoproliferative disorders when confronted with a patient with persistent or combined autoimmune disorders, especially in the setting of new lymphadenopathy. Close observation and persistence with a tissue diagnosis may be necessary to secure an eventual diagnosis of a lymphoproliferative disorder. The most effective treatment of autoimmune disorders in this setting remains treatment of the underlying malignancy. Additional Supporting Information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.