Case Report: Heparin-induced thrombocytopenia during COVID-19 outbreak: the importance of scoring system in differentiating with sepsis-induced coagulopathy

Background: COVID-19 disease is accompanied by derangement of coagulation with a risk of fatal thromboembolic formation. COVID-19 patients are among those indicative for heparin treatment. Increased heparin administration among COVID-19 patients increased heparin induced-thrombocytopenia's risk with/without thrombocytopenia. Case presentation: We present a 71-year-old male patient who came to the emergency room (ER) with a COVID-19 clinical manifestation followed by positive PCR nasopharyngeal swab result. He was assessed to have acute respiratory distress syndrome (ARDS), as shown by rapid progression of hypoxemic respiratory failure and bilateral pulmonary infiltrate. He was then treated with moxifloxacin, remdesivir, dexamethasone, unfractionated heparin (UFH) pump, and multivitamins. During admission, his respiratory symptoms got worse, so he transferred to the ICU for NIV support. On the ninth day of admission, he had gross hematuria followed by a rapid fall of platelet count. We used two different scoring systems (4Ts and HEP scoring system) to confirm the diagnosis of heparin-induced thrombocytopenia (HIT). Following the discontinuation of UFH injection, the thrombocyte continued to rise, and hematuria disappeared. Conclusion: Heparin-induced thrombocytopenia is associated with an increased risk of severe disease and mortality among COVID-19 patients. The differential diagnosis of HIT could be difficult as thrombocytopenia can also be caused by the progression of infection. We use two scoring systems (4Ts and HEP scoring) in order to help us managing the patient. These could improve the outcomes, thus avoiding morbidity and mortality.

Case Report: Heparin-induced thrombocytopenia during COVID-19 outbreak: the importance of scoring system in differentiating with sepsis-induced coagulopathy

Background: COVID-19 disease is accompanied by derangement of coagulation with a risk of fatal thromboembolic formation. COVID-19 patients are among those indicative for heparin treatment. Increased heparin administration among COVID-19 patients increased heparin induced-thrombocytopenia's risk with/without thrombocytopenia. Case presentation: We present a 71-year-old male patient who came to the emergency department (ED) with a COVID-19 clinical manifestation that PCR nasopharyngeal swab confirmed. He was assessed to have acute respiratory distress syndrome (ARDS), as shown by rapid progression of hypoxemic respiratory failure and bilateral pulmonary infiltrate. He was then treated with moxifloxacin, remdesivir, dexamethasone, heparin pump, and multivitamins. During admission, his respiratory symptoms got worse, so he transferred to the ICU for NIV support. On the ninth day of admission, he had gross hematuria followed by a rapid fall of platelet count. We used two different scoring systems (4Ts and HEP scoring system) to confirm the diagnosis of heparin-induced thrombocytopenia (HIT). Following the discontinuation of heparin injection, the thrombocyte continued to rise, and hematuria disappeared. Conclusion: Heparin-induced thrombocytopenia is associated with an increased risk of severe disease and mortality among COVID-19 patients. The differential diagnosis of HIT could be difficult among COVID-19 patients as thrombocytopenia can also be caused by infection progression. We use two scoring systems, 4Ts and HEP scoring, that can help us to manage the patient. With good management, we can avoid patient morbidity and mortality.

Community-acquired pneumonia in children – problems and solutions

Pneumonia in children remains one of the most serious diseases. Despite intensive study, the diagnosis and treatment still present a variety of problems. The article is aimed to identify these problems and show the ways of their solution.One of the criteria for the diagnosis of pneumonia is pulmonary infiltrate on the X-ray image. Community-acquired pneumonia is often caused by Pneumococci and mycoplasma; respiratory viruses, influenza usually serve as contributing factors for bacterial infection. The high level of hyperand underdiagnosis of community-acquired pneumonia is associated with its similarity with ARVI; the registration of general violations (signs of the severity of the disease) improves the quality of diagnosis. The clinical and radiological picture helps to distinguish pneumococcal pneumonia from pneumonia caused by mycoplasma. To improve the diagnosis of community-acquired pneumonia, it is necessary to study inflammation markers during the first examination of the patient, which is impossible in the conditions of home care. Due to the growth of resistance of pneumococci to macrolides a community-acquired pneumonia of pneumococcal (and unclear) etiology requires the use of amoxicillin in high doses and macrolides (in case of atypical pneumonia). Gentle therapy of destructive pneumonia, steroids for metapneumonic pleurisy allow avoiding invasive interventions and help to repair lung tissue.

Gambaran Pasien Stroke Iskemik Akut dengan COVID-19 yang Masuk Ruang Perawatan Intensif

Acute ischemic stroke (AIS) has been reported in patients with coronavirus disease 2019 (COVID-19). The cause of AIS in COVID-19 patients has not been fully understood, but COVID-19 is known to cause hypercoagulation characterized by increased d-dimer levels, and cytokine storms. Some AIS patients with COVID-19 require intensive care. This study was aimed to determine the description of AIS patients with COVID-19 admitted to the intensive care unit. This was a literature review study using three databases, as follows: Pubmed, ClinicalKey, and Science Direct. The keywords used were acute ischemic stroke AND COVID-19 AND intensive care unit. The results showed that after being selected based on inclusion and exclusion criteria, 10 literatures were obtained. There were 20 subjects and most were female (55%) and age group of 60-69 years old (35%). The most common cardiovascular risk factor was hypertension (80%, n=10). There were some increases in the levels of LDH, CRP, d-dimer, ferritinin, and fibrinogen. On radiological examination performed, there were cases with bilateral pulmonary infiltrate (33%) and ground-glass opacities (67%) (n = 6). In conclusion, the characteristics of AIS patients with COVID-19 admitted to the intensive care room were mostly female, age group 60-69 years, had cardiovascular risk factors for hypertension, had elevated levels of LDH, CRP, d-dimer, ferritinin, and fibrinogen, and had ground-glass opacity on radiological imaging.Keywords: acute ischemic stroke, COVID-19, intensive care unit Abstrak: Stroke iskemik akut telah dilaporkan pada pasien dengan coronavirus disease 2019 (COVID-19). Penyebab stroke iskemik akut pada COVID-19 belum diketahui secara menyeluruh, tetapi COVID-19 dapat menyebabkan kejadian hiperkoagulasi ditandai dengan peningkatan kadar d-dimer serta menyebabkan badai sitokin. Beberapa pasien stroke iskemik akut dengan COVID-19 membutuhkan perawatan di ruang perawatan intensif. Penelitian ini bertujuan untuk mengetahui gambaran pasien stroke iskemik akut dengan COVID-19 yang masuk di ruang perawatan intensif. Jenis penelitian ialah literature review dengan pencarian data menggunakan tiga database yaitu Pubmed, ClinicalKey dan Science Direct dengan kata kunci acute ischemic stroke AND COVID-19 AND intensive care unit. Hasil penelitian mendapatkan 10 literatur dengan jumlah subyek penelitian sebanyak 20 orang, jenis kelamin terbanyak ialah perempuan (55%) dengan kelompok usia terbanyak ialah 60-69 tahun (35%). Faktor risiko kardiovaskular yang paling banyak dimiliki subyek penelitian ialah hipertensi (80%, n=10). Terdapat peningkatan kadar LDH, CRP, d-dimer, ferritinin, dan fibrinogen. Pada pemeriksaan radiologi ditemukan bilateral pulmonary infiltrate (33%) dan ground-glass opacitiy (67%) (n=6). Simpulan penelitian ini ialah karakteristik pasien stroke iskemik akut dengan COVID-19 yang masuk ruang perawatan intensif paling banyak ialah perempuan, usia 60-69 tahun, memiliki faktor risiko kardiovaskular hipertensi, mengalami peningkatan kadar LDH, CRP, d-dimer, ferritinin, fibrinogen, dan ditemukan ground-glass opacitiy pada gambaran radiologi.Kata kunci: Stroke iskemik akut, COVID-19, ruang perawatan intensif

Preliminary Results of a Phase II Study to Determine the Safety of Defibrotide in Children and Adolescents with Sickle Cell Disease-Associated Acute Chest Syndrome (IND 127812)

Background: Sickle cell disease (SCD) is a vasculopathy resulting in recurrent vaso-occlusive crises leading to endothelial dysfunction, chronic end-organ damage, poor quality of life, early mortality and the major curative therapy to date is allogeneic stem cell transplantation (AlloSCT) (Talano/Cairo, EJH, 2015). Acute chest syndrome (ACS) can result in pulmonary hypertension and is the leading cause of morbidity and mortality in patients with SCD (Gladwin et al, NEJM, 2008). ACS accounts for 25% of deaths (Vichinsky et al, Blood, 1997). Clinical definition of ACS is chest pain, fever, cough, dyspnea, and new pulmonary infiltrate on chest radiography. Defibrotide was approved in the US for the treatment of severe sinusoidal obstructive syndrome (SOS) with renal or pulmonary dysfunction following HSCT (Cairo et al, BJH, 2020). Defibrotide primarily targets endothelium in microvascular beds and has anti-inflammatory and anti-coagulant activity, which can treat the underlying pathophysiology of ACS (Falanga et al, Leukemia, 2003 and Scallia et al, Clin Pharm, 1996 and Pescador et al, Vasc Pharm, 2013). Objective: To determine the safety and toxicity of defibrotide in children, adolescents, and young adults with SCD-associated ACS. Design/Methods: Patients with SCD aged 2 to 40 years meeting ACS criteria (at least two of the following: fever, chest pain, cough, dyspnea, tachypnea, pulmonary infiltrate on chest imaging, decreased oxygen saturation with or without supplemental oxygen requirements) and eligibility were enrolled within 72 hours of diagnosis after consent was obtained (NCT03805581). Baseline studies comprised of chest radiograph, CT chest angiogram, echocardiography with TRJ velocity and brachial artery reactivity, pulmonary function tests, and biomarkers (IFN-a and -g, TNF-a, IL-6, 8, and 10, sCD163, TSP-1, secretory phospholipase A(2), sVCAM-1, sTNFR1, Ang2, sTei-2, PAI-1, sICAM-1, sP-and sE-selectin, sPECAM-1, VEGF-A, C, D and sVEGFR1 and 2). Defibrotide was administered at 6.25mg/kg IV q6 hours and continued for 7 days or until time of discharge, whichever occurred earlier and patients were followed until day +30 following defibrotide. Dose limiting toxicities include Grade III/IV infusion/allergic reaction or hemorrhage probably or directly related to defibrotide. Results: We have enrolled thirteen patients aged 3 to 18 years with a gender ratio (M/F) of 4/9. Patients' genotypes are as follows: hemoglobin SS disease in nine patients, hemoglobin SC disease in two patients, and hemoglobin Sb0/+ thalassemia in two patients. Presenting symptoms included fever, chest pain, cough, dyspnea, tachypnea, pulmonary infiltrate on imaging, and hypoxia.Eight patients completed seven days of treatment, one patient received 6 days of treatment, three patients were discharged after three days of treatment, and one patient withdrew due to recurrent fevers unrelated to defibrotide. All but one patient had resolution of fevers prior to end of treatment. Patients required an average of 1.15 days of oxygen support, with one patient requiring high flow nasal cannula, and no patients required mechanical ventilation. There were no adverse events possibly, probably, or directly related to defibrotide. There was no evidence of hemorrhage in any patient despite four patients receiving concomitant ketorolac or ibuprofen. Of the eleven patients who had pulmonary infiltrates on imaging, eight were evaluated on day +30, two had complete resolution of infiltrate, five had improvements, and one had no change. Seven patients did not follow-up for echocardiography or pulmonary function testing and two of those patients were unable to be evaluated at day +30 due to COVID-19. Discussion: The preliminary data suggest defibrotide is safe and well tolerated in patients with SCD-related ACS. All patients at diagnosis have had baseline studies, which included biomarkers; however, only eight of the thirteen patients have completed all required observations due to poor compliance. After four patients were enrolled and three failed to follow-up, changes to appointment schedules were made with detailed information on all follow-ups. Efforts at improving compliance post therapy are ongoing. Further accrual is needed to determine clinical significance of improvements in cardiac and/or pulmonary function. This study was funded in part by a grant from Jazz Pharmaceuticals. Disclosures Cooke: Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cairo:Nektar Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Technology Inc/Miltenyi Biotec: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Miltenyi: Research Funding. OffLabel Disclosure: Defibrotide is utilized in patients with acute chest syndrome to decrease the amount of time they are hospitalized and to assist in alleviating symptoms. Defibrotide is approved in the US for sinusoidal obstructive syndrome with renal or pulmonary dysfunction.

Trying to Find the Answer for Two Questions in Patients with COVID-19: 1. Is pulmonary infiltrate of COVID-19 infective or inflammatory in nature (Pneumonia or Pneumonitis)? 2. Is Hydroxychloroquine plus Azithromycin or Favipiravir plus Dexamethasone more effective in the COVID-19 treatment?

Background: During the current pandemic, a great effort is made to understand the COVID-19 and find an effective treatment. As of 17 August 2020, there is no specific drug or biologic agent which have been approved by the FDA for the prevention or treatment of COVID-19. Methods: We retrospectively analyzed the clinical and radiological findings of 211 COVID-19 in-patients that were treated between March - August 2020. Confirmation of a COVID-19 diagnosis was made according to a positive RT-PCR result with a consistent high-resolution-CT (HRCT) finding. Radiological images and the rate of clinical response of patients were investigated. Result: While 128 patients (58.7) did not develop pneumonia, the mild, moderate and severe pneumonia ratios were 28(13.2%), 31(18.7%) and 27(22.9%). 72 patients (34.1%) whose PCR tests were positive did not show any symptom and they were followed in isolation without treatment. 52 patients (24.6%) received hydroxychloroquine plus azithromycin, 57 patients (27%) received favipiravir and 30 patients (14.2%) received favipiravir plus dexamethasone as the first line of treatment. 63.1% of pneumonia patients who received hydroxychloroquine plus azithyromycine, 28.3% of patients who received favipiravir and 10% of patients who received favipiravir plus dexamethasone showed a failure of treatment. Conclusion: The pulmonary infiltrates of COVID-19 are not infective; therefore, the characteristic of the disease should be described as COVID-19 pneumonitis instead of pneumonia. The favipiravir plus dexamethasone seems to be the only drug combination to achieve the improvement of radiological presentation and clinical symptoms in COVID-19 pneumonia patients.

COVIDOSE: Low-dose tocilizumab in the treatment of Covid-19

Background Interleukin-6 (IL-6)-mediated hyperinflammation may contribute to the high mortality of coronavirus disease 2019 (Covid-19). Tocilizumab, an IL-6 receptor blocking monoclonal antibody, has been repurposed for Covid-19, but prospective trials and dose-finding studies in Covid-19 are lacking. Methods We conducted a phase 2 trial of low-dose tocilizumab in hospitalized adult patients with Covid-19, radiographic pulmonary infiltrate, fever, and C-reactive protein (CRP) >= 40 mg/L who did not require mechanical ventilation. Dose cohorts were determined by a trial Operations Committee, stratified by CRP and epidemiologic risk factors. A range of doses from 40 to 200 mg (low-dose tocilizumab) was evaluated, with allowance for one repeat dose at 24-48 hours. The primary objective was to assess the relationship of dose to fever resolution and CRP response. Outcomes were compared with retrospective controls with Covid-19. Correlative studies evaluating host antibody response were performed in parallel. Findings A total of 32 patients received low-dose tocilizumab. This cohort had improved fever resolution (75.0% vs. 34.2%, p = 0.001) and CRP decline (86.2% vs. 14.3%, p < 0.001) in the 24-48 hours following drug administration, as compared to the retrospective controls (N=41). The probabilities of fever resolution or CRP decline did not appear to be dose-related in this small study (p=0.80 and p=0.10, respectively). Within the 28-day follow-up, 5 (15.6%) patients died. For patients who recovered, median time to clinical recovery was 3 days (IQR, 2-5). Clinically presumed and/or cultured bacterial superinfections were reported in 5 (15.6%) patients. Correlative biological studies demonstrated that tocilizumab-treated patients produced anti-SARS-CoV-2 antibodies comparable to controls. Interpretation Low-dose tocilizumab was associated with rapid improvement in clinical and laboratory measures of hyperinflammation in hospitalized patients with Covid-19. Results of this trial and its correlative biological studies provide rationale for a randomized, controlled trial of low-dose tocilizumab in Covid-19.