July Case 2021

A female patient in her 20s with no prior significant medical history presented with fevers, chills, dyspnea, dysphonia, and pharyngitis. On examination, she was tachycardic and tachypneic, with mild disorientation. Further examination showed cervical adenopathy and a large, exophytic oropharyngeal mass, which ultimately revealed infection with Fusobacterium. CT imaging identified jugular chain lymphadenopathy, consistent with Lemierre's syndrome. Her laboratory exam was significant for a white blood cell (WBC) count of 0.47 x10³ cells/µL, and an absolute neutrophil count (ANC) of 40 cells/µL. Following debridement and broad-spectrum antibiotics, the patient's clinical presentation dramatically improved. Her WBC and neutrophil numbers returned to normal range, and patient was discharged with further outpatient antimicrobial therapy that led to complete resolution of the neutropenia and disease manifestations.

Approximately 3 months after discharge from hospital, the patient presented again with fever, chills, and concern for bacterial sepsis. Her WBC was 0.46 x10³ cells/µL, with an ANC of 0.0. Blood cultures were positive for Streptococcus Mitis. The patient was again started on broad spectrum antibiotics. However, repeat differential counts and examination of the peripheral smear this time continued to show no circulating neutrophils. Trials of filgrastim (a recombinant G-CSF) and steroids failed to stimulate granulocyte production and release into the circulation. A bone marrow biopsy was considered to determine etiology of the neutropenia. But the patient was deemed too unstable to undergo the procedure.

Ultimately, the Transfusion Medicine service was consulted to consider granulocyte transfusion (GTX). Previous qualified blood donors who had met granulocyte donation criteria as determined by the FDA and institutional guidelines were quickly assembled. One donor received G-CSF and dexamethasone to optimize successful harvesting of adequate neutrophils for donation. Unfortunately, the patient expired several hours prior to granulocyte harvesting.

On limited autopsy, the lung showed evidence of aspiration pneumonia with diffuse alveolar damage, but neither the lung nor spleen showed marginated neutrophils. Interestingly, the bone marrow revealed myeloid precursors with extreme left shift. Genomic profiling was also performed, which failed to identify aberrations associated with bone marrow failure syndromes including cyclic neutropenia. Given the history of normal baseline neutrophil count, coupled with normal neutrophil recovery after the first episode, it was thought that the neutropenia was sepsis related.

Granulocyte transfusions (GTX) rose to prominence in the early 1970's, after initial studies showed that patients with neutropenic sepsis in the setting of hematopoietic transplant or chemotherapy showed improved recovery and overall survival when transfused with granulocytes in conjunction with standard therapy (1, 2). However, subsequent studies found little to no benefit to GTX (3). Numerous factors contributed to the apparent ineffectiveness of GTX, including lack of adequate number of neutrophils transfused, and poorly selected candidate recipients. Nonetheless, these disappointing results, along with enhanced antimicrobials and improved general supportive care, subsequently dampened enthusiasm for GTX. Unfortunately, the recent "Resolving Infection in people with Neutropenia with Granulocytes (RING)" trial to re-assess the efficacy of GTX in neutropenic sepsis was inconclusive, as low enrollment decreased power to detect statistical significance (4). Ergo, the efficacy and clinical benefit of GTX remains incompletely defined.

Indeed, logistical challenges remain with GTX. First, qualified donors with known transfusion screening history willing to tolerate potential side effects of G-CSF and dexamethasone stimulation must be quickly assembled. These donors must, at the very least, have satisfactory vascular access, be ABO and Rh compatible with the recipient, have current (<30 days) evidence of negative transfusion-related infection markers, and have no contraindication to receiving steroids and G-CSF. Second, the short half-life of neutrophils warrants that harvested cells must be transfused immediately, requiring exquisite coordination between donor schedule and patient needs. Related to this, each day of transfusion dependence may require new donors, which increases the likelihood of unsuccessful granulocyte harvesting. Then there is also the possibility of risks and complications associated with procedure, both to the donors and the recipient. Given these challenges, it is imperative that clinicians immediately involve Transfusion Medicine in patient care as soon as sepsis in the setting of neutropenia is identified, even if all other modalities for mobilizing neutrophils have not been exhausted. For these same reasons, certain minimal criteria must be met before GTX is considered. ANC should be less than 500 cells/µL, except in the case of chronic granulomatous disease. There must be radiographic and pathologic evidence of bacterial or fungal infection; preferably microbiology culture positivity to support the diagnosis. There must be demonstrable evidence of unresponsiveness to antimicrobial treatment for at least 48 hours, unless the infection is imminently life-threatening. Lastly, there must be the likelihood of return of granulopoiesis, either intrinsic or due to stem cell transplantation.

Patients with neutropenia secondary to chemotherapy and hematopoietic cell transplantation (HCT) are most considered for GTX. However, we believe that GTX is a potentially powerful therapeutic modality that remains underutilized for several categories of patients. For instance, serious consideration must be given to those with aplastic anemia at risk of infection, patients with chronic granulomatous diseases, neonatal sepsis, and acute myeloid suppression of uncertain etiology. Particularly for young patients with healthy baseline function, such as was the case with our patient, the benefit of GTX to bridge to normal recovery of bone marrow function far outweighs the risk associated with GTX. To that end, continued engagement and exposure to clinical teams with Transfusion Medicine is an essential first step to implementing increased use of GTX.

1. Alavi JB, et al. A randomized clinical trial of granulocyte transfusions for infection in acute leukemia. N Engl J Med. 1977;296(13):706. PMID: 320477
2. Herzig RH, et al. Successful granulocyte transfusion therapy for gram-negative septicemia. A prospectively randomized controlled study. N Engl J Med. 1977;296(13):701.
3. Winston DJ, et al. Therapeutic granulocyte transfusions for documented infections. A controlled trial in ninety-five infectious granulocytopenic episodes. Ann Intern Med. 1982;97(4):509. PMID: 6751183
4. Price T, et al. Efficacy of transfusion with granulocytes from G-CSF/dexamethasone-treated donors in neutropenic patients with infection. Blood. 2015;126(18):2153-61. PMID: 26333778