Background: Acute Respiratory Distress Syndrome (ARDS) is associated with significant mortality causing death in 46 percent of the patients with severe COVID-19 disease. In these cases, respiratory distress appears to include a crucial vascular insult that mandates a different treatment approach. Attenuating circulating cytokines, and other mediators, by blood purification techniques with the removal of bioactive molecules via therapeutic plasma exchange (TPE) can be a useful adjunct to mechanical ventilation in COVID-19 induced ARDS in conjunction with convalescent plasma.
Methods: Therapeutic plasma exchange treatment was administered to a critically ill patient with confirmed COVID-19 infection complicated by Adult Respiratory Distress Syndrome, after obtaining consent from the Health Proxy.
Results: This report describes rapid improvement of a critically ill patient with confirmed COVID-19 infection following therapeutic plasmapheresis procedure administered in an ICU after re-intubation and supplementedby infusion of convalescent plasma at the end of the plasma exchange procedure.
Conclusions: This abstract demonstrates therapeutic potential of plasma exchange in patients with COVID-19 multi-focal pneumonia and Adult Respiratory Distress Syndrome, directs attention to currently available treatment modalities, and calls for further research of therapeutic plasma exchange in patients with SARS-CoV2 pneumonia.
ARDS: Adult Respiratory Distress Syndrome
ASFA: American Society for Apheresis
AST: Aspartate transaminase
BMI: Body Mass Index
CT: Computer Tomography
COVID-19: Corona Virus Disease-19
ICU: Intensive Care Unit
INR: International Normalized Ratio
IVIG: Intravenous Immunoglobulins
MAS: Macrophage Activation Syndrome
MOD: Multiorgan Dysfunction
MRI: Magnetic Resonance Imaging
PEX: Plasma Exchange
PT: Prothrombin Time
RNA: Ribonucleic Acid
SARS: Severe Acute Respiratory Syndrome
SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 2
CSF: Cerebrospinal Fluid
CSR: Cytokine Resolution Score
TPE: Therapeutic Plasma Exchange
USFDA: United States Food and Drug Administration
WBC: White Blood Count
WHO: World Health Organization
Acute Respiratory Distress Syndrome (ARDS) is associated with significant mortality causing death in 46 percent of the patients with severe COVID-19 disease. In these cases, respiratory distress appears to include a crucial vascular insult that mandates a different treatment approach. Attenuating circulating cytokines, and other mediators, by blood purification techniques with the removal of bioactive molecules via therapeutic plasma exchange (TPE) can be a useful adjunct to mechanical ventilation in COVID-19-induced ARDS in conjunction with convalescent plasma.
Therapeutic plasma exchange treatment was administered to a critically ill patient with confirmed COVID-19 infection complicated by Adult Respiratory Distress Syndrome. Consent was obtained from Health Proxy.
A 58-year-old female with confirmed COVID-19 infection, weight 80.7 kg, height 162 cm, BMI 30.7, with history of hypertension, was admitted to the ICU in severe respiratory distress. She was unable to tolerate prone positioning and non-invasive bi-level positive pressure ventilation and was intubated within seven days after ICU admission. Following eight days on mechanical ventilation, she was extubated, but within 72 hours patient developed respiratory distress. Arterial blood gases values were pH 7.52, PaCO2 32mmHg, PaO2 93mmHg, HCO3- 25mEq/L. Worsening O2 saturation to 80-82% range shortly after the patient was re-intubated, and sedated. Ventilation required proning according to our protocol. Patient also required vasopressors. Chest x-ray revealed bilateral low lung volumes and airspace disease of the left upper lobe apex consistent with pneumonia, and no change in the coarsening of interstitial markings, consistent with viral infection or edema. There were no pleural effusions or pneumothoraces and the mediastinum was normal (Figure 1). Post extubation, after plasmapheresis, radiographic improvement followed clinical recovery (Figure 2).
Figure 1: Chest X-ray prior to PEX treatment-note bilateral low lung volumes and airspace disease of the left upper lobe apex consistent with pneumonia, and no change in the coarsening of interstitial markings, consistent with viral infection or edema.
Figure 2: Chest X-ray after PEX procedure and extubation demonstrating significant improvement of the radiologic pulmonary presentation.
Laboratory evaluation demonstrated WBC of 9,900 cells/mcL, Hb 11.2 grams/dL, Ht 35.1%, platelets 195,000/mL, normal creatinine; PT/INR was 13 sec/1.1; AST was mildly elevated (46U/L). A consult for Hematology/Oncology and Nephrology services was requested, and within 12 hours, the patient underwent plasmapheresis (TPE) of approximately 1.25 plasma volume with 4.75L of albumin (since there were no signs of active bleeding), based on the rounded up calculation of [1.25 x 0.07 x weight in kg x (1-hematocrit)]/[1.25 x 0.07 x 80.7 x (1-.351)]=4.575) and followed by infusion of 1 unit of convalescent plasma. Plasmapheresis was given over 5 hours at low output and input power levels. Within 24 hours, the patient showed rapid clinical and laboratory improvement, including arterial blood gas measurements and inflammatory indicators; Rapid Shallow Breathing Index (RSBI) was estimated at 53 (RR of 24 per minute, tidal volume of 450ml), and the patient was extubated. She was initially maintained on oxygen via a non-rebreather mask, followed by O2 via nasal cannula. Vasopressors and sedatives were weaned over a 24-hour period. She was able to follow commands and converse in her native language. She was downgraded to step down and subsequently to telemetry observation. The patient started ambulating and was discharged home within 14 days after leaving the ICU with a referral for pulmonary rehabilitation.
While there are large clinical trials being conducted by the World Health Organization (WHO) to determine which therapies will be efficacious against SARS-CoV-2, doctors need urgent solutions that will save their gravely ill patients in the ICU . In our study, we decided to treat one patient with both convalescent plasma and plasmapheresis or therapeutic plasma exchange (TPE) based on the following data.
Plasmapheresis or therapeutic plasma exchange
Plasmapheresis or therapeutic plasma exchange is an extracorporeal treatment that selectively removes abnormal larger molecules from the blood. The American Society for Apheresis (ASFA) 2019 guidelines designated sepsis with multiorgan failure (MOD) as category 3 and thus qualified it for TPE therapy in order to improve organ function by eliminating excess cytokines, inflammatory mediators, and viral RNA particles similar to its use with hepatitis C that also has larger particle sizes [2-7].
Therapeutic plasma exchange (TPE) may be useful in a wide variety of illnesses characterized by cytokine storms, microvascular thrombosis, auto-antibodies, and in some infections complicated by ARDS . A comprehensive review of the evidence conducted by Tabibi et al. concluded that the following conditions qualify for TPE .
1.Early acute lung injury/early ARDS; or
2.Severe disease, defined as:
b.Respiratory frequency ≥ 30/minute
c.Blood O2 sat ≤ 93%
d.Partial pressure of arterial O2 to fraction of inspired O2<300
e.Lung infiltrates >50% within 24 to 48 hours
3. Life-threatening disease, defined as:
b.Septic shock, and/or
c.Multiple organ dysfunction or failure
Similar to the overactive, autoimmune, cytokine storm of COVID-19, there have been instances where Secondary Hemophagocytic Lymphohistiocytosis (HLH) occurs from an infectious trigger which results in pathologic hyperactive inflammation due to unchecked immune activation .
In these cases, TPE has been shown to be beneficial in reducing the cytokine storm and providing hematologic support in patients with primary and secondary HLH [11-20]. Another small study found a significantly improved survival in seventeen patients with secondary HLH who received plasma exchange, steroids, and IVIG compared to six patients who received plasma exchange, steroids, and/or cyclosporine, and/or etoposide .
In a three-case study of pediatric patients with H1N1 Influenza A and acute respiratory distress syndrome combined with hemodynamic compromise, therapeutic plasma exchange via the filtration method appeared to mitigate the associated cytokine storm, and all survived despite statistics suggesting an abysmal outcome .
In another case report, nano-membrane-based apheresis was used to cleanse the plasma from the harmful inflammatory bioactive mediators in a 41-year-old man with myasthenia gravis and pneumonia with worsening hypoxemia. After 3 sessions of plasmapheresis, his condition improved, and he was weaned from mechanical ventilation .
In a non-peer-reviewed, retrospective propensity-matched controlled study of 90 patients with a median duration of symptoms of 7 days with 93.4% having either severe or critical disease, TPE significantly improved survival (91.1% versus 61.5%), reduced days in the hospital (10 vs.15) and showed reduced cytokine resolution scores (CSR) from 12 to 6 days . Dogan et al. recently demonstrated that plasmapheresis helped extremely ill COVID-19 patients with autoimmune meningoencephalitis. In their series of cases, they showed that a cytokine storm was occurring in the severely ill ICU patients based on the following points:
1) Increased level of inflammatory markers, such as ferritin that can be a useful marker for disease severity;
2) High protein levels and albumin in CSF without pleocytosis;
3) Reversible MRI findings; and
4) Dramatic improvement following plasmapheresis in both clinical and laboratory findings [25,26].
Convalescent plasma or Immunoglobulins (IVIG)
Likewise, convalescent plasma therapy or intravenous immunoglobulins (IVIG) has been used in other cases of acute respiratory distress (ARDS) from viral infections. The United States Food and Drug Administration (US FDA) has issued guidelines for investigating this therapy for use in COVID-19 patients due to the global pandemic emergency .
IVIG is plasma rich in bacterial and viral IgG antibodies, and the use of IVIG influences the process of differentiation and maturation of lymphocytes, impairs the normal immune response, and inhibits the production of inflammatory factors [28-30]. In certain patients, IVIG can be used as adjuvant treatment for COVID-19 pneumonia, by reducing the use of mechanical ventilation, hospitalizations, and results in earlier recovery of patients .
A meta-analysis of 1703 patients in 8 different studies during the Spanish flu epidemic in the first quarter of the twentieth century showed better results with fewer deaths by using convalescent blood products . Furthermore, a comprehensive review from 2015 of convalescent plasma and immunoglobulin for ARDS showed a 75% reduction in the risk of mortality . However, seven studies using convalescent plasma or IVIG for SARS did show such a benefit .
A study by Mohtadi et al. demonstrated that shortly after IVIG administration, there was an improvement in clinical and respiratory status in all patients, translated into higher oxygen levels, faster extubations, and improved pulmonary lesions by lung CT  Similar results with IVIG were obtained in China during this pandemic [36,37].
IVIG and TPE
Demirkol et al. concluded their study that children with elevated plasma ferritin and secondary HLH/sepsis/MODS/MAS can be successfully treated with plasma exchange, intravenous immunoglobulin, and methylprednisone .
This report describes rapid improvement of a critically ill patient with confirmed COVID-19 infection following therapeutic plasmapheresis procedure administered in an ICU after re-intubation and supplanted by infusion of convalescent plasma at the end of the plasma exchange procedure.
This case illustrates that plasmapheresis treatment combined with transfusion of convalescent plasma may be a viable treatment modality for COVID-19 patients with ARDS with endothelial injury. Although this is a single example of a successful treatment, further research is indicated to obtain statistically significant outcomes. Plasma exchange treatment presents minimal risks with potentially a substantial reduction of morbidity and mortality in COVID-19 patients.
Ethics approval: This manuscript constitutes a Case Report, and meets or exceeds 2017 CARE Guidelines. This submission does not report studies involving human participants, human data or human tissue, and as such does not require ethics committee approval.
Consent for publication: Health Care Proxy has provided consent for both treatment and publications of the treatment result at the point of service.
Availability of data and materials: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Competing interests: The authors declare that they have no competing interests.
Funding: No funding was either requestedor received by the authors.
Authors' contributions: Each co-author has made substantial contributions to the conception and design of this case report and have drafted the work or substantively revised it. Each co-author has approved the submitted version for publication.
Acknowledgements: Dr. Talalaev, DO, Dr. Dungo, DO, Dr. Islas, MD are US NAVY Reserve Medical Corps officers, who were deployed to New York City, NY in support of US NAVY COVID-19 relief mission, Operation Gotham 2020.