This is dedicated to all human survival modes. Robust health is essential if we want to meet our goals in this life. It is never too late to be wise. It is never too early to revise.
When your body temperature rises because of an infection, it's called a fever. Fevers are caused by chemicals called pyrogens flowing in the bloodstream. Pyrogens make their way to the hypothalamus in the brain, which is in charge of regulating body temperature. When pyrogens bind to certain receptors in the hypothalamus, body temperature rises.
One common pyrogen is called Interleukin-1 (IL-1). IL-1 is produced by white blood cells called macrophages when they come into contact with certain bacteria and viruses. IL-1 has multiple purposes, one of which is to signal other white blood cells, called helper T cells, into action.
One purpose of a fever is thought to be to raise the body's temperature high enough to kill off certain bacteria and viruses sensitive to temperature changes. One interesting debate right now, therefore, is, "Should you lower a fever?" Aspirin, for example, will reduce fever; but if the fever is actually helping rid the body of infection, then lowering it might not be a good idea. On the other hand, people sometimes die from fever. Right now the general medical consensus falls on the "reduce the fever" side of the fence.
Recommended to drink enough water and take salt to prevent cellular dehydration to set in during the period of fever.
Strong nutritional tools like grape seed extract have become more popular in recent years, but before you can derive the benefits of these concentrated substances, it is best to understand where they come from, what potential benefits they hold, and whether there are any side effects for people who use them.
Grape seed extract is a substance derived from the seeds of grapes. Scientifically belonging to the Vitis genus, most grape seed extract is made from Vitis vinifera, as are many types of wine, but there are a handful of other species from which this extract can be made. Grape seed extract is produced by grinding up the seeds found at the center of grapes and then using a steam distillation or cold-pressing method to extract the pure compounds of the seeds. Some of the most important compounds found in grape seed extract are tannins, oligomeric procyanidins, catechins and epicatechins, as well as vitamin E, and linoleic acid.
Grape seed extract is most commonly taken in supplement form, and the recommended amount is between 100-300 milligrams per day. Given that the only food source for this extract is grape seeds, supplements are the most logical form.
Some people who have a cold press or grinder at home can also make this extract themselves, particularly if they work at a vineyard and have an excess of grapes to work with. In most cases, you will find grape seed extract in tablet, capsule or pill form, all of which will be able to deliver some of the following health benefits.
Health Benefits of Grape Seed Extract
The many health benefits of grape seed extract include improving the appearance of the skin, lowering cholesterol levels, aiding in weight loss, and increasing cognitive function. It also helps in regulating blood pressure, optimizing fluid balance, speeding the healing of wounds, reducing swelling after injury, and preventing muscle damage.
Weight Loss
Research has shown that the active ingredients within grape seed extract inhibit fat deposition within the body, and even lower the level of fat absorption from our diet. Combined with a negligible amount of calories, this extract can give you an energetic boost and speed up the metabolism, which can further aid your weight loss efforts.
Skin Care
The presence of numerous antioxidants and flavonoid compounds in grape seed extract have been linked to improved skin appearance. These compounds are able to seek out and neutralize the free radicals in the skin that threaten the elasticity and durability of the skin. By eliminating oxidative stress and improving elasticity, this extract can help reduce the presence of wrinkles, age spots, and blemishes, while also promoting the growth of new, healthy cells that keep you looking young.
Lowers Cholesterol Levels
The flavonoids that can be found in such high quantities within grape seed extract are responsible for lowering overall cholesterol levels and improving the balance between HDL and LDL cholesterol. This can reduce the dangers of plaque deposition in the arteries and blood vessels, which will lower your risk of heart attack, stroke, coronary heart diseases, and other cardiovascular issues.
Grape seeds are bitter in taste but are treasured for their benefits like regulating cholesterol levels.
Controls Blood Pressure
Research has found that the oligomeric procyanidins in this extract are able to protect blood vessels and arteries from damage, which can lead to high blood pressure and other cardiovascular problems. Furthermore, the compounds in grape seed extract are able to stimulate the activity of vitamin C in the body, which will boost collagen production and speed up the repair process on damaged blood vessels.
Lowers Oxidative Stress
Widely known as an anti-aging secret, the regular consumption of grape seed extract can help flood the body with antioxidants, which will counter the effects of oxidative stress in your organs as well as your skin and hair. These compounds will also reduce your risk of chronic disease, which becomes much more of a threat as we age.
Boosts Immune System
The flavonoids in grape seed extract stimulate the vitamin C already present in the body, but there is also a moderate amount of vitamin E in this extract, which can help boost the function of the immune system to defend against bacterial and viral pathogens. Furthermore, the antioxidants in this extract are considered 30-50 times more potent than vitamin C in terms of protecting the body from pathogens.
Prevents Edema
Anecdotal evidence has argued that the regular use of grape seed extract is able to prevent edema from occurring in the body. This excess storing of fluid in the body can be painful and unsightly, but it can easily be remedied with a supplement that regulates fluid transfer and balance between the cells and tissues.
Stimulates Brain Function
Oligomeric procyanidins have been researched extensively and it has been found that the compounds can stimulate cognitive function, which can help with things like concentration, retention, memory formation and mood. This is also important for people who are suffering from or are at high risk for Alzheimer’s and other neurodegenerative diseases.
Improves Vision
With a notable amount of carotenoids and antioxidants, this extract has long been known as a means to improve vision. Antioxidants are able to counter oxidative stress in the retina and lower your chances of developing macular degeneration.
Delays Cancer Growth
The Journal of Nutrition has published an article in 2009, which encourages the use of grapes and grape seed extracts helps in destroying cancer cells. The research suggests that this is possible because of the presence of excellent anticancer agents in grapes and grape-based products.
Moreover, a study led by Dr. Debasis Bagchi from the University of Houston College of Pharmacy, USA, shows that grapeseed extract is a novel chemoprotectant against liver cancer.
The School of Dental Medicine, University of Nevada, USA, in a 2011 study, has shown that grape seed extracts are very powerful in inhibiting oral cancer proliferation.
Research has found that grape seed extract is able to minimize the severity of pancreatic cancer, and even slow the growth of skin tumor formation, allowing the body’s immune system to control the disease much more effectively.
Speeds Healing Process
The procyanidins in this extract have a direct stimulating effect on a certain endothelial growth factor, which is crucial to the wound-healing process. Consumption of this extract will speed blood clotting and increase your chances of the wound to heal without a scar.
Relieves Allergies
Thanks to the presence of resveratrol, one of the highly praised compounds in wine, grape seed extract can also minimize the impact of allergic reactions, due to its anti-inflammatory nature. This is also good for aches and pains, either from acute injuries or from more chronic issues such as arthritis or gout.
Fights Fungal Infections
Grape seed extract has proven itself to be very effective against a variety of fungal infections, particularly those of the Candida genus. This can help people who regularly suffer from yeast infections, oral thrush, Athlete’s foot, and other common fungal infections.
Uses of Grape Seed Extract
There are a limited number of forms for grape seed extract, as such small quantities are needed for the effects to be felt. The most common form of this extract is as a supplement, with the average amount being between 100 and 300 milligrams per day. These supplements are widely available at health food stores and will come in either liquid, tablet or capsule form.
Other people choose to get their grape seed extract by purchasing the grape seeds in the whole form and eating them directly. The taste of this can be quite bitter, but some people choose this over a processed supplement. Eating grapes and not spitting out the seeds is not recommended, as you would need to eat a very large amount of grapes, which have high levels of fructose.
Side Effects of Grape Seed Extract
While the benefits of using this extract are clear, there are some possible side effects of which you should be aware, including bleeding disorders, drug interactions, complications with pregnancy, allergic reactions, stomach upset and dizziness.
Drug Interactions: Depending on what medications you are taking, grape seed extract could cause some unwanted side effects, including medications for blood clotting or cholesterol. For example, this extract can slow down blood clotting, and lower cholesterol, so it may complicate the use of anticoagulant drugs and cholesterol-suppressing medication.
Pregnancy: As an herbal remedy, rather than a formal pharmaceutical one, there can be some unexpected hormonal fluctuations when using this powerful substance. For pregnant women, this can stimulate menstruation, or be dangerous for your unborn child. Speak with your doctor before using this or any other herbal remedy if you are pregnant.
Bleeding Disorders: As mentioned, the anticoagulant nature of grape seed extract can cause internal and external bleeding, so do not consume this extract within 1-2 weeks of any major surgery.
Allergic Reactions: The concentration of organic compounds in this extract can cause allergic reactions in certain people, even if they aren’t allergic to grapes. The symptoms include upset stomach and diarrhea, as well as skin inflammation, rashes or hives. Consuming an excessive amount of grape seed extract may also cause abdominal pain and discomfort.
Dizziness: Some people have reported dizziness, cognitive confusion, and lightheadedness when using this extract, particularly when more than 1 supplement is taken. As with any herbal medicine, only use this extract in moderation, and speak with your doctor or a trained herbalist about any specific risk factors for you.
1. Kidneys are the chief organs of homeostasis in the human body because they are the ultimate regulator of blood composition.
2. Kidneys detoxify the blood, produce hormones, and influence red blood cell production.
3. Kidneys also absorb minerals, remove excess water, and neutralize the pH level of blood.
Here's a list of Ten Habits that can damage and endanger your kidneys.
HABIT #1: NOT DRINKING ENOUGH WATER.
NOTE:FOR EVERY ONE KG OF YOUR BODY WEIGHT YOU NEED 32.53 MILLILITERS OF PLAIN WATER, DAILY.
Since the kidneys filter blood and eliminate metabolic wastes, you must drink an ample amount of water regularly to prevent cellular dehydration and toxins from building up in your body. It's also the best way to avoid painful kidney stones.
HABIT #2: OVERDOSE OF PAINKILLERS.
NOTE: YOU ARE NOT SICK, YOUR BODY IS CRYING FOR WATER. PAIN IS A REGISTERED MARKER FOR DEHYDRATION
Painkillers drugs may ease your pain temporarily but they damage if consumed above the prescribed dosage. Pain medications have been found to decrease blood flow to the kidneys, as a result, increasing the risk of chronic kidney disease.
HABIT #3: CONSUMING TOO MUCH WHITE TABLE SALT.
White table salt is notoriously known as slow poison or pinch-by-pinch killer, because overeating white salt and water deficit causes hypertension and heart diseases. Insufficiency of fresh water and excessive consumption of white table salt end up stressing kidneys so much it may result in kidney failure. Good rule of thumb, is 1/4 teaspoon of Himalayan Pink Salt or natural sea salt for every 1250 ml of water intake, daily. Never go on a salt free diet. Not even on the Pan Salt. Drooling and leg cramps are signs that the body is lack of nstural salt.
HABIT#4: HOLDING YOUR PEE FOR TOO LONG PERIOD.
Never ignore or postpone nature's call to empty your bladder, no matter how busy you are. Research found that blocking urine for too long time, increases the risk of UTI ( Urinary Tract Infections), exposes the body to extremely harmful bacteria, in some cases, it may result in kidney failure.
HABIT #5: SATISFYING YOUR SWEET TOOTH TOO MUCH.
White sugar and artificial sweeteners promote obesity which puts you at risk of developing diabetes type-2 and high blood pressure, two of the leading causes of chronic kidney disease. Kidneys filter and estimated 180 mg glucose every day. When you eat too much white sugar, your kidney has to work much harder to get rid of it.
HABIT #6: NOT GETTING ENOUGH SLEEP.
Sleep is important for your kidneys and your health, six to eight hours of good sleep every night is important for your health. Kidneys regenerate its tissues during the night, and poor sleep may cause damage to this organ. Kidney function is regulated by the sleep-wake cycle which helps coordinate the kidneys' workload over 24 hours. Researchers found that sleepless nights may cause high blood pressure and atherosclerosis ( blockage of the arteries). Which in turn increases the risk of developing chronic kidney disease.
HABIT #7: EATING TOO MUCH PROTEIN.
Protein ( amino acids) is the building block of the body but the excessive intake of animal protein, especially red meat, increases the metabolic load on the kidneys, which may lead to kidney problems such as acidosis, a condition when your kidneys cannot keep your body's PHOTO in balance.
Quality sleep is the highest impact thing you can do to elevate your brain function, live longer, and perform better at work and life. When you sleep well, you’re more alert, you’re resilient to stress, and you feel alive and ready for the day.
Conventional advice tells you to find more time for sleeping, but more time in bed does not equal more quality sleep. You can create the conditions for quality, restorative sleep with the right foods, targeted supplements, and small, easy habits throughout the day.
BENEFITS OF SLEEP:-
MEMORY & FOCUS
WEIGHT MANAGEMENT
IMPROVED MOOD
ENERGY / PERFORMANCE
IMMUNITY
THE SCIENCE BEHIND A GOOD NIGHT’S SLEEP:-
1. ACTIVITY
Moving during the day helps prime your body and mind for deeper, more restful sleep.
2. ENVIRONMENT
Your sleep space and routine greatly impact your sleep-wake cycle.
3. MOOD
Reducing stress and nervousness can clear your mind and ease you into restful sleep.
4. NUTRITION
The right nutrients at the right time can maximize the restorative benefits of sleep.
5. REHYDRATION
Drink the right amount of water for your body weight at the right time can prevent and reverse insomnia and charge up your body's optimal performance when awaken.
Being active during the day helps prime your body and mind for deeper, more restful sleep. But the type of activity and timing are critical in maximizing physical and emotional well-being.
FOR DEEPER SLEEP, UPGRADE YOUR EXERCISE ROUTINE
Regular exercise slows aging, helps you focus, relieves stress — and helps you sleep better at night. Read on to find out how exercise improves sleep, the best workouts for maximum Z’s, and when in your day to schedule them.
If you don't fuel your body properly with the right pre- and post-workout meal, you won't take full advantage of your workouts. Find out what to eat and when to eat it for the best results. Water and mineral salts are two primary sources of clean fuel for the body.
Your sleep environment plays a huge role in your body’s sleep-wake cycle. Encourage your body to wind down when it’s time and stay asleep until morning with these tips, tricks, and hacks.
While sleeping pills may be necessary for some, they can come with a range of unhelpful side effects. Here are some research-backed techniques you can discuss with your healthcare provider to help support longer, deeper and better sleep. Cellular prolonged dehydration can cause the body not to be rested and restored to it's optimal health. Just before going your bed, drink one glass of plain water follows by putting a pinch of Himalayan Pink salt on the tongue. Zzzzzzzz
WHY BLUE LIGHT IS MESSING WITH YOUR SLEEP — AND WHAT TO DO ABOUT IT
If you have a habit of scrolling on your phone before bed, your sleep troubles might be easy to solve. Screens emit blue wavelengths of light that confuse your body’s internal clock, causing you to lose restful sleep. Here’s how to minimize sleep disruption (and resulting stress to your body and immune system) from blue light without swearing off tech.
Nothing keeps you awake like the stresses of a hard day and worries about the days ahead. When it takes more than a few minutes to shake that frazzled feeling, these articles can point you to stress-busting techniques that work.
SUPPLEMENTS TO REDUCE STRESS
Certain vitamins and supplements for stress can help you keep your cool and feel more resilient.
Eating the right things at the right times helps you perform at max power through the day and slip easily into a restorative state at night. On the flipside, the wrong foods, missing nutrients, or even a late meal can throw off your entire night. Here’s how to nourish your body properly to ensure the best sleep. What you eat has a direct connection to how your brain works, and how efficient your brain is while you’re sleeping directly affects how refreshed you feel when you wake up.
The new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused more than 210 000 deaths worldwide. However, little is known about the causes of death and the virus's pathologic features.
Objective:
To validate and compare clinical findings with data from medical autopsy, virtual autopsy, and virologic tests.
Design:
Prospective cohort study.
Setting:
Autopsies performed at a single academic medical center, as mandated by the German federal state of Hamburg for patients dying with a polymerase chain reaction–confirmed diagnosis of COVID-19.
Patients:
The first 12 consecutive COVID-19–positive deaths.
Measurements:
Complete autopsy, including postmortem computed tomography and histopathologic and virologic analysis, was performed. Clinical data and medical course were evaluated.
Results:
Median patient age was 73 years (range, 52 to 87 years), 75% of patients were male, and death occurred in the hospital (n = 10) or outpatient sector (n = 2). Coronary heart disease and asthma or chronic obstructive pulmonary disease were the most common comorbid conditions (50% and 25%, respectively). Autopsy revealed deep venous thrombosis in 7 of 12 patients (58%) in whom venous thromboembolism was not suspected before death; pulmonary embolism was the direct cause of death in 4 patients. Postmortem computed tomography revealed reticular infiltration of the lungs with severe bilateral, dense consolidation, whereas histomorphologically diffuse alveolar damage was seen in 8 patients. In all patients, SARS-CoV-2 RNA was detected in the lung at high concentrations; viremia in 6 of 10 and 5 of 12 patients demonstrated high viral RNA titers in the liver, kidney, or heart.
Limitation:
Limited sample size.
Conclusion:
The high incidence of thromboembolic events suggests an important role of COVID-19–induced coagulopathy. Further studies are needed to investigate the molecular mechanism and overall clinical incidence of COVID-19–related death, as well as possible therapeutic interventions to reduce it.
Primary Funding Source:
University Medical Center Hamburg-Eppendorf.
Since it was first detected in December 2019, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread from the central Chinese province of Hubei to almost every country in the world (1, 2). Most persons with COVID-19 have a mild disease course, but about 20% develop a more severe course with a high mortality rate (3). As of 26 April 2020, more than 2.9 million persons have been diagnosed with COVID-19 and 210 000 of them have died (4). Why the new coronavirus seems to have a much higher mortality rate than the seasonal flu is not completely understood. Some authors have reported potential risk factors for a more severe disease course, including elevated D-dimer levels, a high Sequential Organ Failure Assessment score, and older age (5, 6). Because of the novelty of the pathogen, little is known about the causes of death in affected patients and its specific pathologic features. Despite modern diagnostic tests, autopsy is still of great importance and may be a key to understanding the biological characteristics of SARS-CoV-2 and the pathogenesis of the disease. Ideally, knowledge gained in this way can influence therapeutic strategies and ultimately reduce mortality. To our knowledge, only 3 case reports have been published about COVID-19 patients who have undergone complete autopsy (7, 8). Therefore, in this study we investigated the value of autopsy for determining the cause of death and describe the pathologic characteristics in patients who died of COVID-19.
Methods
Study Design
In response to the pandemic spread of SARS-CoV-2, the authorities of the German federal state of Hamburg ordered mandatory autopsies in all patients dying with a diagnosis of COVID-19 confirmed by polymerase chain reaction (PCR). The legal basis for this was section 25(4) of the German Infection Protection Act. Because of legal regulations, no COVID-19 death was exempted from this order, even if its clinical cause seemed obvious. The case series demonstrated herein consists of 12 consecutive autopsies, starting with the first known SARS-CoV-2–positive death occurring in Hamburg (the second largest city in Germany, with 1.8 million inhabitants). All autopsies were performed at the Department of Legal Medicine of University Medical Center Hamburg-Eppendorf. The Ethics Committee of the Hamburg Chamber of Physicians was informed about the study (no. WF-051/20). The study was approved by the local clinical institutional review board and complied with the Declaration of Helsinki. In all deceased patients, postmortem computed tomography (PMCT) and a complete autopsy, including histopathologic and virologic evaluation, were performed. Clinical records were checked for preexisting medical conditions and medications, current medical course, and antemortem diagnostic findings.
PMCT, Autopsy, and Histologic Examination
Computed tomographic examination was done at the Department of Legal Medicine with a Philips Brilliance 16-slice multidetector scanner in accordance with an established protocol (9). In brief, full-body computed tomography was performed from top to thigh (slice thickness, 1 mm; pitch, 1.5; 120 kV; 230 to 250 mAs), complemented by dedicated scans of the thorax with higher resolution (slice thickness, 0.8 mm; pitch, 1.0; 120 kV; 230 to 250 mAs). We performed external examinations and full-body autopsies on all deceased persons with SARS-CoV-2 positivity (PCR confirmed) as soon as possible after taking proper safety precautions (using personal protective equipment with proper donning and doffing), following guidelines from the German Association of Pathologists, which are closely aligned with relevant international guidelines. The recently published recommendations for the performance of autopsies in cases of suspected COVID-19 were taken into account (10). The interval from death to postmortem imaging and autopsy (postmortem interval) ranged from 1 to 5 days. During autopsy, tissue samples for histology were taken from the following organs: heart, lungs, liver, kidneys, spleen, pancreas, brain, prostate and testes (in males), ovaries (in females), small bowel, saphenous vein, common carotid artery, pharynx, and muscle.
For virologic testing, we took small samples of heart, lungs, liver, kidney, saphenous vein, and pharynx and sampled the venous blood.
Tissue samples for histopathologic examination were fixed in buffered 4% formaldehyde and processed via standard procedure to slides stained with hematoxylin–eosin. For the lung samples, we also used the keratin marker AE1/AE3 (Dako) for immunohistochemistry.
Quantitative SARS-CoV-2 RNA Reverse Transcription PCR From Tissue
Tissue samples were ground by using ceramic beads (Precellys lysing kit) and extracted by using automated nucleic acid extraction (MagNA Pure 96 [Roche]) according to manufacturer recommendations. For virus quantification in tissues, a previously published assay was adopted with modifications (11). One-step real-time PCR was run on the LightCycler 480 system (Roche) by using a 1-step RNA control kit (Roche) as master mix. The Ct (cycle threshold) value for the target SARS-CoV-2 RNA (fluorescein) and whole-process RNA control (Cy5) was determined by using the second derivative maximum method. For quantification, standard in vitro–transcribed RNA of the E gene of SARS-CoV-2 was used (12). These samples were also analyzed in a study focusing on renal tropism of SARS-CoV-2 (Puelles V, et al. Multi-organ and renal tropism of SARS-CoV-2. In preparation).
Statistical Analysis
Data that were normally distributed are presented as means (SDs); data outside the normal distribution are presented as medians (ranges). Categorical variables were summarized as counts and percentages. All data were analyzed with Statistica, version 13 (StatSoft).
Role of the Funding Source
The sponsor was not involved in the design or conduct of the study, nor in the analysis of the data or the decision to submit the manuscript.
Results
Clinical Data
The median age of the 12 patients included in this study was 73 years (interquartile range, 18.5 years); 25% were women. For all patients, preexisting chronic medical conditions, such as obesity, coronary heart disease, asthma or chronic obstructive pulmonary disease, peripheral artery disease, diabetes mellitus type 2, and neurodegenerative diseases, could be identified (Table 1). Two patients died out of the hospital after unsuccessful cardiopulmonary resuscitation, 5 died after treatment in the intensive care unit, and the remaining 5 had an advanced directive for best supportive care and died in the non–intensive care ward. Laboratory results for clinical chemistry, hematology, and coagulation were not available for the patients who died out of the hospital. In the remaining patients, the most striking features of the initial laboratory test were elevated levels of lactate dehydrogenase (median, 7.83 µkat/L [range, 2.71 to 11.42 µkat/L]), D-dimer (available for 5 patients; median, 495.24 nmol/L [range, 20.38 to >1904.76 nmol/L]), and C-reactive protein (median, 189 mg/L [range, 18 to 348 mg/L]), as well as mild thrombocytopenia in 4 of 10 patients. A procalcitonin test had been performed in 6 patients, and the results were negative in all but 1 patient with pneumonia (case 10). Table 2 provides an overview of the initial laboratory results.
Table 1. Patient Characteristics and Autopsy Findings
Table 2. Overview of Laboratory Results Taken at the Time of Hospitalization*
Postmortem Computed Tomography
In 2 cases (2 and 4), PMCT was not possible for logistic reasons. In the remaining cases, PMCT demonstrated mixed patterns of reticular infiltrations and severe, dense, consolidating infiltrates in both lungs in the absence of known preexisting pathology (such as emphysema or tumor). A juxtaposition of antemortem and postmortem findings is demonstrated in Figure 1. A complete summary of PMCT findings is presented in Table 1.
Top. Contrast medium–enhanced CT scan demonstrates the antemortem findings: bilateral ground glass opacities in the lower lobes of both lungs (yellow asterisks) and a chest tube (yellow arrow), which has been introduced to treat a pneumothorax (yellow arrowheads). Bottom. CT scan without contrast medium enhancement demonstrates the corresponding postmortem findings. For technical reasons, the postmortem image has a lower resolution. To protect the staff from potential infection, bodies were scanned in a double-layer body bag with the arms positioned alongside the body. Although the findings correspond to the antemortem images, ground glass opacities in both lower lobes (yellow asterisks) and a chest tube (yellow arrow) are seen. In addition, a central venous line (red arrowhead) and gastric tube (red arrow) are visible.
In 4 cases (1, 3, 4, and 12), massive pulmonary embolism was the cause of death, with the thrombi deriving from the deep veins of the lower extremities. In another 3 cases (5, 8, and 11), fresh deep venous thrombosis was present in the absence of pulmonary embolism. In all cases with deep venous thrombosis, both legs were involved (Figure 2). In 6 of the 9 men (two thirds) included in the study, fresh thrombosis was also present in the prostatic venous plexus (Appendix Figure 1).
Figure 2. Macroscopic autopsy findings.
A. Patchy aspect of the lung surface (case 1). B. Cutting surface of the lung in case 4. C. Pulmonary embolism (case 3). D. Deep venous thrombosis (case 5).
In all 12 cases, the cause of death was found within the lungs or the pulmonary vascular system. However, macroscopically differentiating viral pneumonia with subsequent diffuse alveolar damage (a histologic diagnosis) from bacterial pneumonia was not always possible. Typically, the lungs were congested and heavy, with a maximum combined lung weight of 3420 g in case 11. The mean combined lung weight was 1988 g (median, 2088 g). Standard lung weights for men and women are 840 g and 639 g, respectively (13, 14). Only cases 6 and 9 presented with a relatively low lung weight: 550 g and 890 g, respectively (Appendix Table 1). The lung surface often displayed mild pleurisy and a distinct patchy pattern, with pale areas alternating with slightly protruding and firm, deep reddish blue hypercapillarized areas. On the cutting surfaces, this pattern was also visible (Figure 2). The consistency of the lung tissue was firm yet friable. In 8 cases, all parts of the lungs were affected by these changes. Cases 6, 7, and 9—occurring in the 3 women of the case series—presented with changes compatible with focal purulent bronchopneumonia. Macroscopically, no changes were observed outside the lungs and respiratory tract, except for splenomegaly in 3 cases, which suggested a viral infection.
Appendix Table 1. Weights of Individual Organs, in Grams, for All Cases*
During autopsy, all cases except for case 6 presented with preexisting heart disease, including high-grade coronary artery sclerosis (7 of 12); myocardial scarring, indicating ischemic heart disease (6 of 12); and congestive cardiomyopathy. Mean heart weight was 503 g (median, 513 g). In addition to this finding, the most common accompanying diseases were pulmonary emphysema (6 of 12) and ischemic enteritis (3 of 12). Often these conditions were known to the treating physician before death (compare columns 4 and 10 of Table 1). The macroscopic autopsy findings are presented organ by organ in Appendix Table 2 and the lung findings in Table 1.
Appendix Table 2. Macroscopic Autopsy Findings in Organs Other Than the Lung in Patients Dying of COVID-19*
A clear trend toward obesity was observed among the cases (mean body mass index, 28.7 kg/m2; median, 28.7 kg/m2). However, case 9, involving a patient with known neuroendocrine tumor of the lung, presented with severe cachexia (body mass index, 15.4 kg/m2). The comorbid conditions found are summarized in Table 1.
Histology
Histopathology of the lungs showed diffuse alveolar damage, consistent with early acute respiratory distress syndrome in 8 cases. Predominant findings were hyaline membranes (Figure 3, A and B), activated pneumocytes, microvascular thromboemboli, capillary congestion, and protein-enriched interstitial edema. As described by Wang and colleagues (15), a moderate degree of inflammatory infiltrates concurred with clinically described leukopenia in patients with COVID-19 and predominant infiltration of lymphocytes fit the picture of a viral pathogenesis. In later stages, squamous metaplasia was present (Figure 3, C). Long-term changes, such as destruction of alveolar septae and lymphocytic infiltration of the bronchi, were often visible as preexisting conditions. Four cases (6, 8, 9, and 10) showed no diffuse alveolar damage but extensive granulocytic infiltration of the alveoli and bronchi, resembling bacterial focal bronchopneumonia. Histologically, thromboemboli were detectable in cases 1, 3, 4, and 5 (Figure 3, D). Microthrombi were regularly found within small lung arteries, occasionally within the prostate, but not in other organs.
Figure 3. Histopathologic findings.
A. Diffuse alveolar damage with hyaline membranes (case 4) (hematoxylin–eosin [H&E] stain; original magnification, × 50). B. Hyaline membranes (case 4) (cytokeratin AE1/AE3 stain; original magnification, × 50). C. Squamous metaplasia in the lung (case 5) (H&E stain; original magnification, × 100). D. Pulmonary embolism (case 1) (H&E stain; original magnification, × 100).
In addition to the lung changes described in Table 1, there were isolated histologic findings that might indicate a viral infection. The pharyngeal mucosa was examined in 7 cases. In 6 of them, hyperemia and alternating dense, predominantly lymphocytic infiltrates were found as signs of chronic pharyngitis. In 1 case (case 3), lymphocytic myocarditis was seen in the right ventricle (Appendix Figure 2). The remaining histologic changes were compatible with shock changes in part of the deceased patient (liver, kidneys, intestine) or corresponded to the macroscopically determined virus-independent preexisting pathology (such as ischemic cardiomyopathy).
Appendix Figure 2. Mononuclear infiltrations consisting of lymphocytes (arrows) in the myocardium of the right ventricle (case 3) (hematoxylin–eosin stain; original magnification, × 100).
Apart from findings related to SARS-CoV-2 infection, patients showed other histopathologic findings related to their chronic preexisting conditions, including hypertrophy of myocardial fibers or scarring of the myocardium. The peripheral veins, including those occluded by thrombi, showed no abnormalities on hematoxylin–eosin staining.
PCR Results
Quantitative reverse transcription PCR detected SARS-CoV-2 RNA in the lungs of all 12 patients (range, 1.2 × 104 to 9 × 109 copies/mL) and in the pharynx of 9 patients. Six patients showed moderate viremia (<4 × 104 copies/mL). In 5 of these patients, viral RNA was also detected in other tissues (heart, liver, or kidney) in concentrations exceeding viremia. Patients without viremia showed no or a low virus load in the other tissues. Only 4 patients had detectable viral RNA in the brain and saphenous vein.
Discussion
In this autopsy study of 12 consecutive patients who died of COVID-19, we found a high incidence of deep venous thrombosis (58%). One third of the patients had a pulmonary embolism as the direct cause of death. Furthermore, diffuse alveolar damage was demonstrated by histology in 8 patients (67%).
To our knowledge, this is the first case series summarizing and comparing clinical data of consecutive COVID-19 cases with findings obtained by a full autopsy, supplemented by PMCT, histology, and virology.
The high rate of death-causing pulmonary embolism at autopsy correlates well with the unsuccessful resuscitation of 3 of 4 patients, 2 of whom died out of the hospital. Apart from that, no preclinical evidence had been reported of pulmonary embolism or deep venous thrombosis.
In studies that examined deceased patients with COVID-19 without relying on autopsy, no increased rates of pulmonary embolism were observed clinically. However, it is known that many cases of pulmonary embolism remain clinically overlooked and are often associated with sudden, unexpected death. This may have been aggravated by the method for diagnosing COVID-19 in Germany, which is based on PCR tests rather than computed tomographic imaging because of concerns about infection of medical staff and other patients. A recent report described clinical features of 85 fatal cases of COVID-19 from Wuhan (16). Besides respiratory failure, the cause of death was multiorgan failure in 16% and cardiac arrest in 9%. No autopsies were performed. The gold standard for identifying cause of death is still the autopsy (17). However, in-hospital autopsy rates have declined worldwide over the past decades. Also, because of pathologists' potential risk for SARS-CoV-2 infection, very few autopsies have been performed worldwide (18). To our knowledge, only 3 case reports have been published on patients with COVID-19 who have undergone complete autopsy and a few more in which only lung tissue was examined (7, 8).
Other researchers have described coagulopathy as a common complication in patients with severe COVID-19 (5, 6, 19). In a recent study of 191 patients with COVID-19, 50% of those who died had coagulopathy, compared with 7% of survivors. D-dimer levels greater than 1000 µg/L were associated with a fatal outcome (6).
COVID-19 may predispose to venous thromboembolism in several ways. The coagulation system may be activated by many different viruses, including HIV, dengue virus, and Ebola virus (20, 21). In particular, coronavirus infections may be a trigger for venous thromboembolism, and several pathogenetic mechanisms are involved, including endothelial dysfunction, characterized by increased levels of von Willebrand factor; systemic inflammation, by Toll-like receptor activation; and a procoagulatory state, by tissue factor pathway activation (22). In a subgroup of patients with severe COVID-19, high plasma levels of proinflammatory cytokines were observed (23). The direct activation of the coagulation cascade by a cytokine storm is conceivable. With COVID-19, severe hypoxemia develops in some patients (24). Thrombus formation under hypoxic conditions is facilitated both in animal models of thrombosis and in humans. The vascular response to hypoxia is controlled primarily by the hypoxia-inducible transcription factors, whose target genes include several factors that regulate thrombus formation (25). Lastly, indirect causes, such as immune-mediated damage by antiphospholipid antibodies, may partially contribute, as speculated by Zhang and colleagues (26).
The macroscopic findings in our autopsy series—with rather heavy, consolidated, friable, basically air-free lungs in most of the cases—were impressive and explain the difficulties in sufficiently ventilating some of these patients. The histopathologic changes in most of our cases with diffuse alveolar damage as the main finding resemble those described by Xu and colleagues (7) and Barton and colleagues (8), who reported single cases; Zhang and colleagues (26), who reported on lung biopsy in a patient with SARS-CoV-2 positivity; and Tian and colleagues (27), who described macroscopic and histologic pulmonary findings in 2 patients with lung cancer who received positive results on SARS-CoV-2 testing. However, the full-blown picture of diffuse alveolar damage seems to be more prevalent in younger patients with fewer preexisting diseases and longer survival, whereas older patients with more comorbid conditions tend to die in the early stages of the disease.
In line with clinical, macroscopic, and histopathologic findings, PCR detected the highest concentration of SARS-CoV-2 RNA in lung and pharyngeal tissue. Of interest, in most patients with disease, high titers of RNA were also detected in postmortem samples. The clinical relevance of this is not yet clear. Clearance of viral RNA from blood 7 days after transfusion of COVID-19 convalescent plasma was associated with substantial clinical improvement, but studies have not shown a correlation between viremia and acute respiratory distress syndrome in patients with severe COVID-19 (28, 29). As in patients with SARS-CoV-1, in whom viral replication could be detected in other organs, including the liver, kidney, spleen, and cerebrum (30), we detected viral RNA at high titers in other organs (liver, kidney, and heart) in 5 patients. These data suggest that SARS-CoV-2 may spread via the bloodstream and infect other organs. To prove this, replication intermediates must be detected.
The current study had some limitations. First, the sample size was small, possibly leading to overestimation of the rate of pulmonary embolism. However, both the clinical and postmortem observations agree well with the current knowledge about SARS-CoV-2 pathology. This includes the sex and age distribution as well as the preexisting conditions among the patients, but also the histologic findings. Second, although viral titers in swabs (pharynx) taken longitudinally up to 7 days after death remained similar, we lack data on how postmortem processes affect viral titers and dynamics in different tissues and body fluids. Moreover, the quantitative PCR assay used cannot discriminate between genomic and subgenomic RNA. As stated earlier, to prove viral replication, detection of replication intermediates or antigenomic RNA would be necessary.
In conclusion, we found a high incidence of thromboembolic events in patients with COVID-19. When hemodynamic deterioration occurs in a patient with COVID-19, pulmonary embolism should always be suspected. That patients with COVID-19 who have increased D-dimer levels, a sign of coagulopathy, may benefit from anticoagulant treatment seems plausible (31). As demonstrated in our cohort, this might be important for hospitalized patients and outpatients. In this context, some professional societies have already made recommendations for antithrombotic therapy for patients with COVID-19 (32). Robust evidence, however, remains scant, and further prospective studies are urgently needed to confirm and validate these results.
This article was published at Annals.org on 6 May 2020.
* Drs. Wichmann and Sperhake share first authorship.
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