Credit WHO
#15,226
Unlike influenza, which usually hits a patient like a freight train 2 to 4 days after infection, COVID-19 can have a much longer incubation period, followed by a slow ramping up of symptoms.
While most people will experience only a mild-to-moderate illness - and then recover - a significant number of patients report a week or more of mild illness before worsening symptoms force them to seek medical care.Some patients have reported improving symptoms, only to see their condition abruptly deteriorate in the second or third week of their illness. The CDC's Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19) describes this `delayed crash' phenomenon.
Clinical Progression
Among patients who developed severe disease, the medium time to dyspnea ranged from 5 to 8 days, the median time to acute respiratory distress syndrome (ARDS) ranged from 8 to 12 days, and the median time to ICU admission ranged from 10 to 12 days.5,6,10,11
Clinicians should be aware of the potential for some patients to rapidly deteriorate one week after illness onset. Among all hospitalized patients, a range of 26% to 32% of patients were admitted to the ICU.6,8,11 Among all patients, a range of 3% to 17% developed ARDS compared to a range of 20% to 42% for hospitalized patients and 67% to 85% for patients admitted to the ICU.1,4-6,8,11 Mortality among patients admitted to the ICU ranges from 39% to 72% depending on the study.5,8,10,11 The median length of hospitalization among survivors was 10 to 13 days.1,6,8While originally thought of as primarily a respiratory illness, over the past few weeks it has become increasingly clear that SARS-CoV-2 can cause a wide range of serious, systemic cardiovascular and hematological complications (primarily hypercoagulability).
Two days ago the NEJM published Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young, while last weekend the UK's NHS issued an alert for possible vascular and cardiac inflammation in children with COVID-19.
There is obviously a lot more going on with COVID-19 disease than was originally suspected.A week ago, the journal Radiology released a special report on the diagnosis and treatment of complications due to blood clots in patients with COVID-19. This from the Radiological Society of North America (RSNA):
“Imaging and pathological investigations confirmed the COVID-19 syndrome is a thrombo-inflammatory process that initially affects lung perfusion, but consecutively affects all organs of the body,” Professor van Beek said. “This highly thrombotic syndrome leads to macro-thrombosis and embolism. Therefore, strict thrombosis prophylaxis, close laboratory and appropriate imaging monitoring with early anti-coagulant therapy in case of suspected venous thromboembolism are indicated.”
Yesterday the CDC's EID Journal published three case histories of COVID-19 patients who developed pulmonary embolisms in the second week of their hospitalization (roughly 18 days into their illness). All three had elevated d-Dimer levels, which is a test for active coagulation and fibrinolysis.
I've only included excerpts (slightly reformatted for readability) from a much larger research report, so follow the link to read it in its entirety.
Volume 26, Number 8—August 2020
Research Letter
Pulmonary Embolism and Increased Levels of d-Dimer in Patients with Coronavirus Disease
Daniel O. Griffin, Alexandra Jensen, Mushmoom Khan, Jessica Chin, Kelly Chin, Jennifer Saad, Ryan Parnell, Christopher Awwad, and Darshan Patel
ABSTRACT
We report 3 patients with coronavirus disease who had a decline in respiratory status during their hospital course that responded well to intravenous steroids and interleukin-6 receptor antagonist therapy. These patients later showed development of persistent hypoxia with increased levels of d-dimer levels and were given a diagnosis of pulmonary embolisms.
Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, has been extensively reported since the outbreak in Wuhan, China, and can progress to involve major respiratory complications (1). Patients commonly have fever, cough, abdominal pain, and diarrhea.
During the second week of illness, decompensation occurs in some patients, possibly driven by the cytokine storm associated with increased levels of interleukin-6. We report 3 case-patients with COVID-19 who were improving after successful treatment during the critical period but showed development of pulmonary emboli (PEs) despite deep vein thrombosis (DVT) prophylaxis.
Three patients admitted to Northwell Plainview Hospital (Plainview, NY, USA) showed positive results for COVID-19 and had acute hypoxic respiratory failure secondary to COVID-19. All 3 patients received azithromycin and hydroxychloroquine, but their conditions continued to progress to more severe respiratory failure.
During what was assumed to be the cytokine storm phase, on the basis of laboratory parameters and an increasing requirement for oxygen, the patients received intravenous steroids (solumedrol, 1–2 mg/kg/d for 5–8 d) and the interleukin-6 receptor antagonist tocilizumab (400 mg intravenously). Patients showed improvement and did not require intubation but later showed development of persistent hypoxemia with increases in levels of d-dimer. Computed tomography angiograms (CTAs) confirmed bilateral PEs, and the patients required supplemental oxygen (Table).
(SNIP 3 Case histories)
PEs can occur after the cytokine storm in COVID-19 patients, despite DVT prophylaxis. After initial improvements, patients might continue to have high or increasing oxygen requirements because of development of thromboembolic disease.
Previous studies showed that low levels of platelets, increased levels of d-dimer, and increasing levels of prothrombin in COVID-19 were associated with poor outcome, which might be explained by thromboembolic complications in patients with severe disease (2). Platelet counts remained within reference ranges for 2 of our patients and only decreased for 1 patient. Two patients had increases in d-dimer levels, and the third patient was admitted with a highly increased d-dimer level.
Autopsy reports from COVID-19 patients have shown microthrombi in lungs and in other organs with associated foci of hemorrhage (3,4). These findings suggest that severe endothelial dysfunction, driven by the cytokine storm and associated hypoxemia, leads to disseminated intravascular coagulation, causing thromboembolic complications.
In these patients, other parameters, such as the neutrophil–lymphocyte ratio, and inflammatory markers, including ferritin, C-reactive protein, and lactate dehydrogenase, were returning to reference levels despite increased d-dimer levels and increasing oxygen requirements. Standard dose DVT prophylaxis did not prevent this complication. This hypercoagulability was a consumptive coagulopathy and was not caused by an inhibitor, such as an anticardiolipin antibody; treatment with direct factor Xa inhibitors would be appropriate.
Although certain underlying conditions might have influenced the coagulation process in these patients, the hypothesis that hypercoagulability is driven by endothelial dysfunction is plausible. These case studies support the earlier observation that anticoagulation is associated with a decrease in mortality rates for COVID-19 patients (5). Monitoring disseminated intravascular coagulation and measurement of platelet counts, d-dimer and fibrinogen levels, and trending International Society of Thrombosis and Haemostasis scores might be beneficial for early diagnosis of PE in patients with COVID-19.
Dr. Griffin is an instructor in clinical medicine and associate research scientist at Columbia University Medical Center, New York, NY. His primary research interests are HIV, stem cells, and malignancies.
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