Pathways Case Record: A Case of Neutropenia in a Young Adult
In This Case Study
- An 18-year-old woman was admitted to Massachusetts General Hospital for neutropenia (low neutrophil counts) and oral ulcers
- She was discharged though re-presented just a few weeks later for febrile neutropenia (occurrence of a fever during a period of low neutrophil counts), liver micro-abscesses, typhlitis, mouth ulcers, and recurrent skin and soft tissue infection
- On arrival at Mass General, she was noted to have recurrent mouth ulcers and her absolute neutrophil count was zero
- The Pathways Consult Service investigated this profound neutropenia, which led to two questions: what is the etiology of the patient's neutropenia, and what therapeutic options are available to target the suspected underlying etiology of her neutropenia?
An 18-year-old woman was admitted to Massachusetts General Hospital for neutropenia (low neutrophil counts) and oral ulcers. Approximately nine months before presentation to Mass General, the patient developed mouth sores without other symptoms or notable exposures. She was seen twice by her outpatient pediatrician for these sores, which were thought to be secondary to candidiasis (fungal infection by Candida) and improved with oral nystatin rinse. A few months later, she had an extended hospitalization for multiple infections, including tonsillitis, skin and soft tissue infections, and molluscum contagiosum virus infection. During this hospitalization, she was noted to be profoundly neutropenic. Evaluation then showed no evidence of lymphoma or leukemia but did show minimal granulocyte precursors. She was discharged though re-presented just a few weeks later for febrile neutropenia (occurrence of a fever during a period of low neutrophil counts), liver micro-abscesses, typhlitis, mouth ulcers, and recurrent skin and soft tissue infection. On admission during that hospital stay, she had an absolute neutrophil count of zero. She was treated with granulocyte colony-stimulating factor (G-CSF), which did not improve her neutrophil count. She ultimately responded to two rounds of intravenous immune globulin (IVIG), with a rapid but transient resolution of her neutropenia. She then presented to Mass General for further workup.
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Before the present illness, she recalled occasional ear and upper respiratory infections as a child but had not been hospitalized and did not receive antibiotics in the several years leading up to this presentation. She took no medications and did not use drugs or alcohol. Her family history was notable for hyperthyroidism in her mother, Bechet's disease in a paternal aunt, and rheumatoid arthritis in a maternal cousin.
On arrival at Mass General, she was again noted to have recurrent mouth ulcers, and her absolute neutrophil count was zero. A bone marrow biopsy showed decreased production of erythroid cells with a shift towards more immature cell precursors. Her T cell subset workups were normal. An extensive serologic workup was performed, which was only remarkable for a mildly elevated antinuclear antibodies (ANA) titer without symptom or exam findings concerning connective tissue disease. She received both IVIG and G-CSF; her neutrophil count improved to normal, and her oral ulcers resolved.
The Pathways Consult Service in the Department of Medicine at Mass General was consulted and focused on the patient's profound neutropenia, which led to two major questions:
- What is the etiology of the patient's neutropenia?
- What therapeutic options are available to target the suspected underlying etiology of her neutropenia?
Background and Diagnosis
Symptomatic neutropenia can broadly be categorized as arising from either congenital or acquired causes (Hematology Am Soc Hematol Educ Program). Congenital causes of neutropenia include cyclic neutropenia and severe congenital neutropenia, which both can arise from mutations in ELA2, which is the gene for neutrophil elastase (Blood). Cyclic neutropenia causes 21-day cycles of transient profound neutropenia, which was inconsistent with our patient's persistent neutropenia without cycling. Severe congenital neutropenia often is diagnosed shortly after birth, given severe infections and febrile neutropenia. Given our patient's age at presentation (18 years old) and improvement of neutrophil counts after IVIG on three separate episodes, a diagnosis of severe congenital neutropenia was unlikely. Other congenital neutropenia syndromes, including Chediak-Higashi and Hemarnsky-Pudlak syndrome, have several extra-immune features not present in our patient, and were ruled out. Thus, this patient likely has acquired neutropenia.
The differential diagnosis of acquired neutropenia includes nutritional, drug-induced, malignant, and autoimmune causes. Her nutritional status was normal, and there were no signs of nutritional deficiency in other laboratory studies. Notably, hemoglobin level, platelet count, and red density width were all normal. She was not taking any medications prior to onset of her neutropenia, thus drug-induced neutropenia was also ruled out.
Next, we considered malignant causes of neutropenia. There was no evidence of myelodysplastic syndrome, and bone marrow biopsy was notable only for lack of neutrophil precursors. T cell large granular lymphocytic leukemia (LGL) is a clonal disorder of cytotoxic T lymphocytes that results in cytopenias (including isolated neutropenia), and tissue infiltration to bone marrow, spleen, liver (Cancers (Basel)) Interestingly, LGL is thought to be the pathologic correlate of Felty's syndrome which was initially described in patients with severe longstanding rheumatoid arthritis who presented with neutropenia, low platelet count, and enlarged spleen. In our patient, there was no evidence of end-organ infiltration, and the normal proportion of CD3+, CD16+ T cells on flow cytometry from bone marrow biopsy was reassuring against LGL.
Given the family history of autoimmune disease and response to IVIG in our patient, we considered autoimmune causes of neutropenia at the top of our differential. Immune neutropenia is well described in the literature and idiopathic cases of acquired neutropenia are often thought to be immune-related (Hematology Am Soc Hematol Educ Program). Possible mechanisms of autoimmune neutropenia include a B cell clone producing anti-neutrophil antibody or antibody against G-CSF receptor, or cytotoxic CD8+ T cells autoreactive to neutrophil precursors. A retrospective analysis of an Italian neutropenia registry described demographic and clinical features of participants with neutropenia lasting more than three months with positive indirect anti-neutrophil antibody testing (Blood Adv). Thirty-one participants were categorized as "late-onset neutropenia" with a diagnosis age 5 to 18 years old, and 55% of these participants had evidence of another autoimmune disease, suggesting that our patients with late-onset immune neutropenia may be at risk for future systemic autoimmune disease. While autoreactive T cells attacking neutrophil precursors is possible, this mechanism is not well reported in the literature, possibly owing to significant challenges in performing assays of cytotoxic activity against neutrophils.
Summary and Future Steps
We hypothesize that this young woman with a family history of autoimmune disease presenting with recurrent infections and severe neutropenia responsive to IVIG has antibody-mediated autoimmune neutropenia which would likely respond to B cell depleting therapy. Though assays for antibody-mediated neutropenia are technically challenging, we recommend assessing for antibodies to human neutrophil antigens (NA-1, NA-2), the most common antigens targeted in autoimmune neutropenia. Granulocyte immunofluorescence tests are conducted by incubating patient plasma with donor neutrophils typed for NA-1 and NA-2, then fluorescent anti-IgG antibodies are added, and flow cytometry is performed (Transfusion). If antibody-specific assays are unrevealing, tests for a cytotoxic T cell-mediated process, such as co-culture of CD8+ T cells and neutrophils with cytokine release assay to assess cytotoxic killing of neutrophils may be performed. Regarding management, rituximab is typically used for suppressing humoral immunity. While medications inhibiting the FcRN receptor (neonatal Fc receptor) have not been studied for use in autoimmune neutropenia, this approach could be considered as these medications increase the cycling of circulating immunoglobulin, therefore, decreasing the half-life of pathologic antibodies (J Allergy Clin Immunol).
Our exploration into the cause of this patient's neutropenia culminates in the following two clinical recommendations: [1] Assessment for antibodies to human neutrophil antigens via granulocyte immunofluorescence testing; and [2] a course of B-cell depleting therapy (e.g., with rituximab infusion) would be reasonable to treat the cause of her autoimmune neutropenia. Mechanistic assays to determine the precise cause of this patient's acquired neutropenia should point towards targeted therapies in the future for her and other patients with debilitating autoimmune disorders.
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