Doctors on the frontline of the COVID-19 outbreak in New York City have published the first comprehensive review of the disease’s widespread effects on organ systems beyond the lungs. They also provide guidelines for managing these diverse effects.

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A new review collates information about COVID-19’s impact on the body beyond the lungs.

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At the time of writing, globally, there have been more than 13 million confirmed cases of COVID-19, the illness that the coronavirus SARS-CoV-2 causes, and more than 570,000 deaths.

While experts initially thought that the illness was principally a respiratory infection, doctors treating critically ill patients quickly recognized that its effects are far more widespread.

“I was on the frontlines right from the beginning,” says Dr. Aakriti Gupta, who was one of the first cardiology specialists to be deployed to COVID-19 intensive care units at Columbia University Irving Medical Center. “I observed that patients were clotting a lot, they had high blood sugars even if they did not have diabetes, and many were experiencing injury to their hearts and kidneys.”

In early March 2020, there was little clinical guidance for doctors treating the effects of COVID-19 outside the lungs, so Gupta decided to combine the findings that were emerging from early studies with what she and other doctors were learning on the ground.

Gupta and her colleagues at Columbia collaborated with doctors across the United States to create the first comprehensive clinical guidelines on the disease’s nonrespiratory symptoms.

They summarize how the disease manifests in particular organ systems, the possible causes, and management options.

One section of the paper focuses on the clinical presentation and treatment of children and pregnant women with COVID-19.

The review appears in Nature Medicine.

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One of the first things that doctors treating people on ventilators noticed was that their blood clotted unusually easily.

However, this was not sufficient to explain the widespread effects on organs around the body.

“Physicians need to think of COVID-19 as a multisystem disease,” says Gupta. “There’s a lot of news about clotting, but it’s also important to understand that a substantial proportion of these patients [experience] kidney, heart, and brain damage, and physicians need to treat those conditions along with the respiratory disease.”

Among the manifestations of the disease that the authors describe are:

  • increased blood clotting or thrombosis
  • cardiovascular complications
  • kidney injury
  • gastrointestinal symptoms
  • liver injury
  • hyperglycemia (high blood sugar levels) and ketosis (a metabolic state in which the body produces energy from fat instead of glucose, producing ketones)
  • effects on the central nervous system
  • effects on the eyes
  • dermatological (skin) complications

They single out four mechanisms that could explain these widespread effects:

  • direct damage to cells that the virus itself inflicts
  • damage to the endothelial cells that line blood vessels, resulting in blood clots and inflammation
  • dysregulation of the immune response
  • disruption of the hormones that regulate blood pressure and fluid balance, known as the renin-angiotensin-aldosterone system (RAAS)

To gain entry to a host cell, part of the spike proteins that give the coronavirus its characteristic, crown-like appearance must bind to a receptor on the cell’s surface.

Before this can happen, however, a protease (protein-degrading enzyme) in the cell membrane must “prime” the spike.

The receptor is called angiotensin converting enzyme 2 (ACE2), and the usual enzyme that primes the spike is called TMPRSS2.

Tissues that carry a lot of ACE2 and TMPRSS2 on their cell surfaces may, therefore, be especially vulnerable to SARS-CoV-2 infection and injury.

In addition to cells lining the airways of the lungs, the authors write, these tissues include cells in the nose, gut, pancreas, and kidneys.

The doctors note that ACE2 receptors reside on endothelial cells that line the blood vessels supplying organs.

Damage to the endothelial cells triggers inflammation and promotes the formation of blood clots, known as thrombosis.

“In just the first few weeks of the pandemic, we were seeing a lot of thrombotic complications — more than what we would have anticipated from experience with other viral illnesses,” says Dr. Kartik Sehgal, a hematology and oncology specialist at Beth Israel Deaconess Medical Center in Boston, MA, and one of the authors. “They can have profound consequences [for] the patient.”

Clots impair the blood supply to tissues. When they break free, they can also lodge elsewhere in the circulatory system, causing further blockages, inflammation, and tissue damage.

Clinicians at Columbia, including several of the review’s co-authors, are conducting a clinical trial to find the optimal dose and timing of anticoagulant therapy for critically ill COVID-19 patients.

When a pathogen activates immune cells, they release signaling molecules called cytokines that recruit more immune cells to tackle the infection. This can cause an immune overreaction, or “cytokine release syndrome,” with potentially fatal results.

The authors write that elevated markers of inflammation, such as C-reactive protein, in the blood of people with COVID-19 are associated with more severe illness and mortality.

A recent clinical trial found that the steroid dexamethasone, which suppresses the overall immune response, reduced deaths in patients on ventilators or supplemental oxygen by one-third.

Clinical trials of drugs that target specific components of the immune response, such as the cytokine interleukin-6, are underway.

The fourth and final mechanism that the authors say may contribute to tissue damage in COVID-19 is the disruption of the RAAS.

The RAAS regulates key physiological processes in the body, including fluid and electrolyte balance, blood pressure, the permeability of blood vessels, and tissue growth.

The membrane-bound protein ACE2 strongly influences this system because its role is to break down the regulatory hormones angiotensin 1 and 2, removing them from the circulation.

As mentioned above, SARS-CoV-2 invades host cells by binding to ACE2, which may disrupt its normal regulatory function and contribute to tissue damage in particular organs.

Concluding their evidence review, the authors write:

“Beyond the life threatening pulmonary complications of SARS-CoV-2, the widespread organ-specific manifestations of COVID-19 are increasingly being appreciated. As clinicians around the world brace themselves to care for patients with COVID-19 for the foreseeable future, the development of a comprehensive understanding of the common and organ-specific pathophysiologies and clinical manifestations of this multisystem disease is imperative.”