In patients with COVID-19 pneumonia, high risk of thrombosis became a current issue, and d-dimer levels indicating fibrin degradation products (FDPs) in the plasma were found as a predictor for mortality [1, 2]. Although unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) decrease the production of FDPs by inhibiting factors Xa and II, they cannot contribute metabolization of existing FDPs. Furthermore, FDPs cannot be filtered by known cytokine filters because of their molecular weight (minimum 240 kDa) [3, 4]. Yet, FDPs can be removed by therapeutic plasma exchange (TPE) [5]. Therefore, recently, three consecutive TPE sessions were performed in selected patients with COVID-19 pneumonia in intensive care units (ICUs) after the assessment of their clinical and coagulation status. In the study, the effect of TPE on outcomes was retrospectively investigated in patients with COVID-19 pneumonia.
All COVID-19 patients admitted to 5 different tertiary ICUs between 10 March and 10 May 2020 were evaluated, and 73 of 91 patients were included in the study. The patients who died within the first 4 days and who were still in the ICUs on 10 May were excluded. According to the Turkish Health Minister Algorithm for COVID-19, all included patients received the same antiviral (favipiravir, hydroxychloroquine, azithromycin) therapy and anticoagulant prophylaxis (UFH infusion 100 mcg/kg or LMWH 0.01 mL/kg). Since two different protocols were used in 5 ICUs, patients with d-dimer ≥ 2 in 3 ICUs had only received therapeutic anticoagulation whereas patients with d-dimer ≥ 2 in the other 2 ICUs had received TPE plus therapeutic anticoagulation. In all ICUs, for all patients in GII, echocardiography, lower extremity venous Doppler, and, if pulmonary thrombosis suspected, thorax computerized tomography angiography were performed. After collecting data, 73 patients were divided into 2 groups as group I (GI) (d-dimer < 2 mg/L) and group II (GII) (d-dimer ≥ 2 mg/L), and then GII was also divided into 2 groups as GIIa (TPE+) and GIIb (TPE−). Patients’ characteristics, respiratory and laboratory parameters, and outcomes were recorded. Propensity score matching (PSM) analysis was conducted on R v4.0.1 (0.2 caliper without replacement and nearest neighbor model, 1:1 ratio) by using 14 covariates (age, gender, CCI, APACHE II, SOFA score, lactate, leucocyte, lymphocyte, d-dimer and creatinine at the ICU admission, maximum respiratory support, the usage of steroid, IL-6 blocker, and cytokine filter).
The total mortality rate was 27.4%. Mortality rates of GI and GII were 5% and 35.9%, respectively. In GII, major thromboembolic events were not detected in any patients. The median (min-max) day for the starting TPE was 3 (2–4). In GIIa, APACHE II, SOFA scores, d-dimer and interleukin-6 (IL-6) levels at the ICU admission, and length of ICU stay were significantly higher than those of GI whereas mortality rates were similar in those groups (Table 1). The median values of the LOS-ICU in survivors and non-survivors in GII were 14 (6.5–21.5) and 15.5 (8–23), respectively (p = 0.630). In GIIa, lactate dehydrogenase (LDH), d-dimer, ferritin, IL-6, C-reactive protein (CRP), and procalcitonin levels were significantly decreased after three consecutive TPEs (Table 2). Furthermore, although ferritin level at the ICU admission was higher in GIIa, the mortality rate in both before and after PSM was higher in GIIb (45.7% and 58.3%) than in GIIa (16.7% and 8.3%) (p = 0.037, p = 0.009, respectively) (Table 1).
Table 1.
Comparisons of patients groups
| GI (d-dimer < 2) (n = 20) | GII (d-dimer ≥ 2) | |||||||
|---|---|---|---|---|---|---|---|---|
| Before PSM | After PSM | |||||||
| GIIa (TPE+) (n = 18) | GIIb (TPE−) (n = 35) | p1 (GI and GIIa) | p2 (GIIa and GIIb) | GIIa (TPE+) (n = 12) | GIIb (TPE−) (n = 12) | p2 (GIIa and GIIb) | ||
| Age (years) | 60 ± 14 | 62 ± 12 | 62 ± 15 | 0.615 | 0.951 | 61 ± 14 | 64 ± 17 | 0.605 |
| Male, n (%) | 13 (65.0) | 14 (77.8) | 26 (74.3) | 0.386 | 0.780 | 8 (66.7) | 8 (66.7) | 1.000 |
| BMI (kg/m2) | 27.3 (5.8) | 27.9 (5.5) | 27.3 (6.6) | 0.290 | 0.237 | 28.5 (6.1) | 25.0 (6.6) | 0.078 |
| CCI | 2.5 (4) | 3 (3) | 4 (3) | 0.919 | 0.422 | 3.0 ± 2.2 | 3.8 ± 1.7 | 0.270 |
| At the ICU admission | ||||||||
| APACHE II | 12 ± 4 | 17 ± 4 | 17 ± 5 | 0.002 | 0.886 | 17 ± 3.3 | 17.5 ± 5.6 | 0.794 |
| SOFA Score | 5 (3) | 6 (1) | 7 (3) | 0.002 | 0.223 | 6 (2) | 6 (2) | 0.713 |
| PaO2/FiO2 ratio | 128 (68) | 97 (51) | 113 (79) | 0.251 | 0.229 | 108 (106) | 125 (103) | 0.551 |
| SpO2 (%) | 89 (5) | 91 (7) | 89 (5) | 0.377 | 0.597 | 92 (10) | 91 (5) | 0.590 |
| Lactate (mmol/L) | 1.4 (0.6) | 1.4 (0.7) | 1.4 (0.9) | 0.988 | 0.631 | 1.5 (0.8) | 1.3 (0.5) | 0.291 |
| WBC (×103/μL) | 9.6 (3.9) | 6.9 (6.4) | 8.2 (6.5) | 0.573 | 0.353 | 8.7 ± 4.9 | 7.4 ± 2.7 | 0.430 |
| Lymc (×103/μL) | 0.82 ± 0.40 | 0.80 ± 0.34 | 0.89 ± 0.42 | 0.553 | 0.271 | 0.83 ± 0.3 | 0.82 ± 0.5 | 0.963 |
| d-dimer (mg/L)& | 1.2 (0.3–1.9) | 5.0 (2.1–35.2) | 7.2 (2.1–35.5) | < 0.001 | 0.151 | 4.5 (2.1–35.2) | 6.0 (2.2–32.2) | 0.514 |
| Ferritin (ng/mL) | 1015 (1735) | 1735 (1853) | 900 (1454) | 0.158 | 0.018 | 1742 (2117) | 605 (1346) | 0.012 |
| IL-6 (pg/mL)& | 28.3 (5.3–1418)(8) | 134 (36.2–2958)(13) | 254 (33–5233)(13) | 0.036 | 0.101 | 155 (39.6–2958)(8) | 237 (33–4885)(4) | 0.933 |
| CRP (mg/dL) | 18.6 ± 10.9 | 22.2 ± 12.1 | 27.8 ± 10.4 | 0.340 | 0.086 | 19.2 ± 10.3 | 24.0 ± 11.0 | 0.275 |
| Creatinine (mg/dL) | 0.88 (0.29) | 0.87 (0.37) | 0.99 (0.82) | 0.874 | 0.051 | 0.91 ± 0.3 | 0.90 ± 0.3 | 0.944 |
| Urea (mg/dL) | 28 (29) | 32 (19) | 36 (26) | 0.942 | 0.288 | 28 (32) | 35 (14) | 0.291 |
| Number of damaged lobes, n (%)& | 3 (2–4) | 3 (2–5) | 3 (2–5) | 0.149 | 0.118 | 3 (2–5) | 3 (3–5) | 0.671 |
| In the first 48 h | ||||||||
| Breath rate/min (max) | 34 (6) | 33 (9) | 33 (5) | 0.988 | 0.713 | 33 (11) | 33 (5) | 0.590 |
| PaO2/FiO2 ratio (min) | 117 ± 42 | 98 ± 30 | 105 ± 34 | 0.087 | 0.376 | 104 ± 32.4 | 120 ± 32.5 | 0.235 |
| FiO2 (%) (max) | 75 (48) | 80 (30) | 80 (35) | 0.082 | 0.969 | 80 (25) | 80 (30) | 0.799 |
| PEEP (cmH2O) (max) | 12 (6) | 12 (4) | 14 (4) | 0.502 | 0.056 | 12.0 ± 2.3 | 13.0 ± 1.9 | 0.215 |
| Cdyn (ml/cmH2O) (min) | 44 (6) | 37 (12) | 41 (8) | 0.003 | 0.058 | 36.3 ± 6.6 | 39.5 ± 7.0 | 0.265 |
| In the first week | ||||||||
| WBC (×103/μL) (max) | 13.2 (5.8) | 11.0 (8.9) | 12.6 (6.6) | 0.077 | 0.086 | 10.4 (10.3) | 11.0 (6.7) | 0.590 |
| WBC (×103/μL) (min) | 5.9 (2) | 6.3 (4) | 4.9 (4) | 0.718 | 0.612 | 6.7 (4.4) | 4.6 (1.5) | 0.219 |
| Lymc (×103/μL) (min) | 0.48 (0.40) | 0.5 (0.28) | 0.49 (0.46) | 0.919 | 0.573 | 0.52 (0.29) | 0.45 (0.28) | 0.551 |
| NLCR (max) | 16.4 (16.2) | 15 (8) | 11 (11) | 0.460 | 0.517 | 13.6 (10.1) | 11.6 (11.5) | 0.843 |
| Lactate (mmol/L) (max) | 2.1 (0.7) | 2.4 (1.1) | 2.4 (0.8) | 0.087 | 0.955 | 2.3 (1.0) | 2.4 (1.6) | 0.347 |
| Fluid balance (mL) | 3670 (3198) | 4552 (2973) | 3849 (2196) | 0.874 | 0.441 | 4174 ± 2907 | 5331 ± 3170 | 0.361 |
| Total fluid (mL/kg/day) | 40.7 (9.3) | 44.3 (15.5) | 44.8 (11) | 0.696 | 0.910 | 44.8 ± 13.5 | 48.7 ± 12.0 | 0.460 |
| Respiratory support (max), n (%) | ||||||||
| IMV | 13 (65.0) | 16 (88.8) | 30 (85.7) | 0.084 | 0.746 | 11 (91.7) | 12 (100) | 0.307 |
| NIMV | 3 (15.0) | 1 (5.6) | 3 (8.6) | 0.344 | 0.694 | 1 (8.3) | 0 | 0.307 |
| HFOT | 4 (20.0) | 1 (5.6) | 2 (5.7) | 0.188 | 0.981 | 0 | 0 | NA |
| Additional therapies, n (%) | ||||||||
| Cytokine filters | 1 (5.0) | 3 (16.7) | 3 (8.1) | 0.427 | 0.434 | 2 (16.7) | 1 (8.3) | 0.592 |
| IL-6 blocker | 12 (60.0) | 9 (50.0) | 20 (57.1) | 0.536 | 0.621 | 7 (58.3) | 6 (50) | 0.682 |
| Steroids | 11 (55.0) | 10 (55.6) | 20 (57.1) | 0.357 | 0.912 | 7 (58.3) | 7 (58.3) | 1.000 |
| Duration of IMV (h)& | 168 (0–816) | 286 (0–1008) | 192 (0–720) | 0.1 12 | 0.067 | 316 ± 271 | 278 ± 139 | 0.671 |
| AKI, n (%) | 7 (35.0) | 6 (33.3) | 19 (54.3) | 0.914 | 0.148 | 3 (25) | 6 (50) | 0.206 |
| Tracheotomized patients, n (%) | 2 (10.0) | 2 (11.1) | 1 (2.9) | 0.911 | 0.218 | 1 (8.3) | 0 (0) | 0.307 |
| LOS-ICU, (days)& | 12 (6–34) | 20 (5–42) | 11 (7–35) | 0.017 | 0.003 | 20 ± 10 | 14 ± 5 | 0.067 |
| Mortality, n (%) | 1 (5.0) | 3 (16.7) | 16 (45.7) | 0.242 | 0.037 | 1 (8.3) | 7 (58.3) | 0.009 |
AKI acute kidney injury, APACHE II Acute Physiology and Chronic Health Evaluation, BMI body mass index, CCI Charlson comorbidity index, Cdyn dynamic compliance, CRP C-reactive protein, HFOT high-flow oxygen therapy, ICU intensive care unit, IL-6 interleukin-6, IMV invasive mechanical ventilation, LOS length of stay, Lymc lymphocyte count, NIMV non-invasive mechanical ventilation, NLCR neutrophil-lymphocyte count ratio, PSM propensity score matching, SOFA, sequential organ failure assessment, TPE therapeutic plasma exchange, WBC white blood cell. Results were given as percentage, mean ± sd, and median (IQR or min-max). &Minimum and maximum values. Student t and Mann-Whitney U tests were used for statistical analysis
Table 2.
Comparisons of laboratory parameters in pre and post-TPE procedure
| Pre-TPE | Post-TPE | p | |
|---|---|---|---|
| WBC (× 103/μL) | 9.08 ± 4.1 | 9.14 ± 3.5 | 0.951 |
| Neuc (×103/μL) | 7.38 ± 3.1 | 7.33 ± 3.3 | 0.953 |
| Lymc (× 103/μL) | 0.9 (0.5–1.3) | 1.02 (0.77–1.27) | 0.053 |
| NLCR | 6.8 (1.8–11.7) | 6.7 (4.2–9.2) | 0.184 |
| LDH (IU/L) | 436 (322–550) | 239 (181–297) | 0.001 |
| d-dimer (mg/L)& | 7.8 (2.1–35.2) | 1.3 (0.6–3.9) | < 0.001 |
| Ferritin (ng/mL)& | 1268 (399–6110) | 405 (157–1650) | 0.001 |
| IL-6 (pq/mL)(13)& | 161 (36.2–2958) | 24.5 (1.5–130) | 0.001 |
| CRP (mg/dL)& | 11.8 (0.4–29.7) | 0.9 (0.3–7.2) | < 0.001 |
| Procalcitonin (ng/mL)& | 0.27 (0.02–87) | 0.1 (0.01–39) | 0.002 |
CRP C-reactive protein, IL-6 interleukin-6, LDH lactate dehydrogenase, Lymc lymphocyte count, Neuc neutrophil count, NLCR neutrophil-lymphocyte count ratio, TPE therapeutic plasma exchange, WBC white blood cell. Results were given as percentage, mean ± sd, and median (quartiles or min-max). &Minimum and maximum values. Paired sample and Wilcoxon tests were used for the statistical analysis
Some patients with COVID-19 pneumonia have a high risk of thrombosis leading to worse outcomes. Therefore, monitoring d-dimer levels is crucial. In these groups of patients, TPE seems to be a treatment which may improve outcomes by effectively removing FDPs and restoring coagulation status. We are aware that TPE may not be routinely required in these patients [6]. However, we think that it should be featured as a part of the treatment especially in COVID-19 pneumonia patients with a high risk of thrombosis.
Acknowledgements
We would like to express our gratitude to our nurses who have taken care of the patients and performed TPE procedure in the ICU and COVID-19 Study Group. COVID-19 Group collaborating authors: Aylin Ogan2, Aylin Cimet Ayyildiz2, Berrin Yalcin2, Behiye Oren6, Fadıl Havas6, Sevda Dizi6, Birsen Kose6, Umran Yakici6, Cenk Sahan6, Elif Ozkilitci6, Ugur Tunali6, Deniz Gunes7, Ozlem Dincer7, Reyhan Sahin7, Duran Ozdemir7, Mehtap Selcuk8, Ceyhun Solakoglu8, Unsal Arif Turan8, Erkan Kaya8, Mustafa Emre Kavlak3, Pelin Katar3, Hande Aygun9, Kerim Cikim10, Ozkan Uysal10, Nur Ozturk Kaskir11, Aysun Soylu12.
2General Intensive Care Unit, Acibadem International Hospital, Istanbul, Turkey
3General Intensive Care Unit, Memorial Atasehir Hospital, Istanbul, Turkey
6General Intensive Care Unit, Acibadem Atakent Hospital, Istanbul, Turkey
7General Intensive Care Unit, Acibadem Bakirkoy Hospital, Istanbul, Turkey
8General Intensive Care Unit, Acibadem Kadikoy Hospital, Istanbul, Turkey
9Department of Infection Disease and Clinical Microbiology, Acibadem International Hospital, Istanbul, Turkey
10Department of Internal Medicine, Acibadem International Hospital, Istanbul, Turkey
11Department of Chest Disease, Acibadem International Hospital, Istanbul, Turkey
12Department of Biochemistry, Acibadem International Hospital, Istanbul, Turkey
Authors’ contributions
BG: design of the work, analysis and interpretation of data, and writing. EO: acquisition of the data. HKA: acquisition and interpretation of the data and substantial contribution to the conception. UC and LT drafted the work. COVID-19 Study Group: acquisition of the data. The authors read and approved the final manuscript.
Funding
There was no funding for the research reported.
Availability of data and materials
All data was added as an Excel file in a supplementary information file.
Ethics approval and consent to participate
The study was approved by The Scientific Committee of the Turkish Health Ministry (2020-05-11T22_01_29).
Consent for publication
No applicable
Competing interests
The authors declare that they have no competing interests.
Footnotes
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Contributor Information
Bulent Gucyetmez, Email: bulentgucyetmez@gmail.com.
COVID-19 Study Group:
Aylin Ogan, Aylin Cimet Ayyildiz, Berrin Yalcin, Behiye Oren, Fadıl Havas, Sevda Dizi, Birsen Kose, Umran Yakici, Cenk Sahan, Elif Ozkilitci, Ugur Tunali, Deniz Gunes, Ozlem Dincer, Reyhan Sahin, Duran Ozdemir, Mehtap Selcuk, Ceyhun Solakoglu, Unsal Arif Turan, Erkan Kaya, Mustafa Emre Kavlak, Pelin Katar, Hande Aygun, Kerim Cikim, Ozkan Uysal, Nur Ozturk Kaskir, and Aysun Soylu
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Data Availability Statement
All data was added as an Excel file in a supplementary information file.