Severe Pulmonary Adverse Events in Healthy Unrelated Donors of Peripheral Blood Stem Cells Following G-CSF Administration,
Authors: Wetzko Katrin , Blechschmidt Matthias , Hölig Kristina , Poppe-Thiede Kirsten , Ganepola Susanne , Fischbach Roman , Ordemann Rainer , Laniado Michael , Schulte-Hubbert Bernhard , Schuler Markus , Cotta Livia , Braumann Dietrich , Ehninger Gerhard , Kroschinsky Frank 
Published: October 2019

Abstract
Abstract 4057
Short-term treatment with recombinant human granulocyte colony-stimulating factor (rhG-CSF) followed by leukapheresis (LPH) is the common procedure to obtain CD34+ peripheral blood progenitor cells (PBPC) from allogeneic donors. While bone pain, headache and flu-like symptoms are well-known G-CSF associated side effects, gastrointestinal, cardiovascular and pulmonary symptoms are rare.
We are reporting about two cases of healthy unrelated PBPC donor with severe lung injury/ interstitial pneumonia.

Case 1:
A 31years old female PBPC donor was mobilized with G-CSF (Lenograstim 8.5 μg/kg, 5 days) and donated PBPC without unexpected adverse events. Three days after leukapheresis she experienced symptoms of common cold. Two days later she was admitted to hospital due to fever, thoracic pain and dyspnoea. At this time WBC count was 41.0 × 10^9/L. Chest-CT scan demonstrated bipulmonary disseminated cloudy infiltrates. In addition, papular skin lesions, muscle pain and impairment of renal function occurred. Due to worsened respiratory distress and pleural-effusion, she had to be monitored on the ICU temporarily.
Because the symptoms seemed to be associated with disseminated overwhelming inflammatory reaction after G-CSF administration, high-dose steroid treatment was initiated. Bronchoscopy demonstrated normal respiratory mucosa. Biopsies from lung tissue and skin lesions showed infiltration by neutrophiles. Microbiologic and virologic analyses, as well as auto-antibody testing remained negative. While exanthema and pain disappeared with prednisone, lung injury continued (Horowitz index 245). In follow-up chest CT scan the pattern of infiltrates was changed and now compatible with lobular pneumonia. Antibiotic treatment was re-initiated with Piperacillin/Tazobactam and Clarithromycin, and steroids were tapered. During the following days the donor recovered and could be discharged from hospital in a good condition.

Case 2:
A 20 year old male presented to pre-donation health check-up with symptoms of acute respiratory tract infection. At this time, influenza A (H1N1) was detected in nasal swab. He received oseltamivir 75 mg bid for 5 days and recovered completely.
Three weeks later mobilization with Lenograstim (8.5 μg/kg/day) was started. On day 3 of G-CSF treatment the donor developed dyspnoea and haemoptysis without any symptoms of infection. Because of stable respiratory and circulatory parameters G-CSF-application was continued and leukapheresis performed without complication on day 5 (WBC count 42.0 × 10^9/L). Subsequent diagnostic revealed disseminated, bipulmonary, interstitial infiltrates in CT corresponding to severe bronchitis. While relevant microbes could not be found in bronchoalveolar lavage, the PCR from nasal swabs was positive for influenza B. Therefore oseltamivir was restarted again. Because of possible bacterial superinfection levofloxacin was added. Some days later he could be discharged from hospital free from symptoms.

Discussion:
It is well known that G-CSF not only regulates the numbers of circulating neutrophiles but also modulates their function, i.e. adherence, movement, migration, and cytokine release. Increased cytokine release might induce pulmonary edema and lung damage.
We describe two cases of severe respiratory disturbances following G-CSF application for PBPC. In both cases the severe pulmonary injury based on a coexisting infection. Therefore we hypothesize that an inflammatory pulmonary reaction induced by a bacterial/viral infection is aggravated by persisting neutrophilia after G-CSF treatment.

Conclusion:
A different pathophysiology of infectious lung diseases in PBPC donors, caused by increased numbers of circulating neutrophiles, could lead to severe pulmonary failure. Therefore antiinfective treatment in PBPC donors with respiratory infections should be initiated early and consistently. Under careful monitoring and appropriate treatment stem cell collection should be possible to be finished successfully in most cases.

Disclosures:
No relevant conflicts of interest to declare.