ABSTRACT
Background: Immune reconstitution inflammatory syndrome (IRIS) is a rapid inflammatory response with immune recovery, most commonly observed following antiretroviral therapy initiation in people with HIV and underlying opportunistic infections. To date there is one reported case of COVID-associated IRIS in a neutropenic patient treated with granulocyte colony-stimulating factor (G-CSF). Here we describe a second case of COVID-associated IRIS in a patient with history of follicular lymphoma who received G-CSF during acute COVID-19 infection. Case: A 64-year-old woman with history of follicular lymphoma and autologous stem cell transplant one year prior presented with dyspnea, diarrhea, and fever, and tested positive for SARS-CoV-2. She had received three doses of the Pfizer BioNTech vaccine. She was admitted to the hospital for acute hypoxic respiratory failure and treated with remdesivir 100mg, dexamethasone 6mg, and 2 L/min supplemental oxygen via nasal cannula for five days. Twelve days after discharge, the patient returned with persistent diarrhea, fatigue, fever, and an oxygen saturation of 87% on room air. She again tested positive for SARS-CoV-2 by PCR. She was admitted to the intensive care unit for high-flow nasal cannula (HFNC) with oxygen at 30 L/min and 50% FiO2 and treated with methylprednisolone 1 mg/kg daily. On admission, her D-dimer was 3943 ng/mL, C-reactive protein 136 mg/L, absolute neutrophil count (ANC) 767/mcL, platelets 84/mcL. Her chest CT scan was negative for pulmonary embolism but demonstrated bilateral ground glass opacities characteristic of COVID-19 pneumonia. Her ANC reached a nadir of 186 on day 3 at which point G-CSF (filgrastim 300 mcg/day) was administered for three days with subsequent neutrophil recovery. On day 6, in light of a negative test for COVID antibodies, she received high-dose monoclonal antibodies through a compassionate use program. At that time, her oxygen requirements were stable and inflammatory markers had decreased to CRP 25 and D-Dimer 940. However, her oxygen requirements and inflammatory markers rapidly increased thereafter, with HFNC settings up to 60L/80%, D-dimer 27754, and CRP 135. After a repeat chest CT on day 8 showed worsened ground glass opacities throughout all lung fields, her steroid dose was increased to methylprednisolone 2 mg/kg daily out of concern for COVID-associated IRIS following G-CSF administration. Her oxygen requirement and inflammatory markers declined over the following 2-3 days and she was transferred out of the ICU. Discussion: We present here an unusual case of COVID-associated IRIS after G-CSF administration in a transplant patient with COVID-19 pneumonia. Given the increased risk of infection and severe illness in immunosuppressed patients despite vaccination, it is important for providers to be aware of complications associated with adjunct therapies such as G-CSF in this vulnerable population.
ABSTRACT
Background. Most individuals diagnosed with mild to moderate COVID-19 are no longer infectious after day 10 of symptom onset and those with severe or critical illness from COVID are typically not infection after day 20 day of symptom onset. Recovered persons can continue to test positive for SARS-CoV-2 by PCR via detection of non-viable RNA in nasopharyngeal specimens for up to three months (or longer) after illness onset. It is also know known that severely immunocompromised patients may produce replication-competent virus greater than 20 days from symptom onset and may require, per CDC recommendations, "additional testing and consultation with infectious diseases specialists and infection control experts". We aim to discuss four case studies of severely immunocompromised patients who exhibited signs of persistent COVID-19 infection of COVID and how we managed transmission-based precautions in our hospital through sequencing and evaluation of cycle thresholds (CT) values and subgenomic RNA detection. Methods. Residual nasopharyngeal (NP) samples were collected on patients exhibiting persistent COVID like symptoms. These samples underwent N gene and N gene subgenomic RNA (sgRNA) real-time reverse transcription polymerase chain reaction (rRT-PCR) testing. Results. Analysis of longitudinal SARS-CoV-2 sequence data demonstrated within-patient virus evolution, including mutations in the receptor binding domain and deletions in the N-terminal domain of the spike protein, which have been implicated in antibody escape. See Figures 1 and 2. Figure 1. Timelines of Identified Patients 1 and 2 Patient 1: 46-year-old woman with recently diagnosed stage IV diffuse large B-cell lymphoma for which she was treated with 2 cycles of R-CHOP. Patient 2: 38-year-old woman with history of myelodysplastic syndrome, peripheral blood stem cell transplant with chronic graft versus host disease of the GI tract, skin, and eyes as well as CMV enteritis, and she was maintained on rituximab, mycophenolate mofetil, prednisone, and monthly IVIG without recent changes to her immunosuppression. Figure 2. Timeline of Identified Patients 3 and 4 Patient 3: 44 year-old man with prior history of thymoma s/p thymectomy Patient 4: 46 year-old man who was initially diagnosed with marginal zone lymphoma approximately 2.5 years ago. He was initially treated with bendamustine and rituximab and achieved remission. He was then continued on maintenance rituximab without significant complications for a planned two years. Conclusion. Differentiating between prolonged viral shedding of non-infectious RNA and persistent replicating viable virus can be difficult to determine without full evaluation of a patient's clinical picture and timeline. Consultation between laboratory, infectious diseases, and infection prevention experts to provide appropriate level of guidance for precautions and treatment may be warranted. Testing by PCR and analysis of CT values may provide key findings of viral replication in immunocompromised hosts, indicating the need for evaluation of additional treatment and maintaining isolation status in healthcare settings.