Stem Cell or Bone Marrow Transplant Side Effects

Problems soon after transplant

Many of the problems that can happen shortly after the transplant come from having the bone marrow wiped out by medicines or radiation just before the transplant. Others may be side effects of the conditioning treatments themselves.

Your transplant team can help you cope with side effects. Some can be prevented, and most can be treated to help you feel better.This is not a complete list and you should tell your doctor or transplant team about any problems you have or changes you notice. Some of these problems can be life-threatening, so it’s important to be able to reach your doctor or transplant team at night, on weekends, and during holidays. Ask for their after hours contact numbers to make sure you will be able to do this.

Mouth and throat pain

Mucositis (inflammation or sores in the mouth) is a short-term side effect that can happen with chemo and radiation. It usually gets better within a few weeks after treatment, but it can make it very painful to eat and drink.

Good nutrition is important for people with cancer. If mouth pain or sores make it hard to eat or swallow, your transplant team can help you develop a plan to manage your symptoms.

Nausea and vomiting

Because chemotherapy drugs can cause severe nausea and vomiting, doctors often give anti-nausea medicines at the same time as chemo to try to prevent it. As much as possible, the goal is to prevent nausea and vomiting, because it’s easier to prevent it than it is to stop it once it starts. Preventive treatment should start before chemo is given and should continue for as long as the chemo is likely to cause vomiting, which can be up to 7 to 10 days after the last dose.

No one drug can prevent or control chemo-related nausea and vomiting 100% of the time. In many cases, two or more medicines are used. You’ll need to tell your transplant team how well the medicines are controlling your nausea and vomiting. If they aren’t working, they will need to be changed.

Infection

For at least the first 6 weeks after transplant, until the new stem cells start making white blood cells (engraftment), you can easily get serious infections. Bacterial infections are most common during this time, but viral infections that were controlled by your immune system can become active again. Fungal infections can also be an issue. And even infections that cause only mild symptoms in people with normal immune systems can be quite dangerous for you. This is because right after the transplant you don't have many white blood cells that are working well, and they are the primary immune cells that fight off infections.

You may be given antibiotics to try to prevent infections until your blood counts reach a certain level. For instance, pneumocystis pneumonia (often called PCP) is a common infection that’s easy to catch. Even though the germ doesn’t harm people with normal immune systems, for others it can cause fever, cough, and serious breathing problems. Antibiotics are often used to keep transplant patients from getting this.

Your doctor may check you before the transplant for signs of certain infections that may become active after transplant, and give you special medicines to keep those germs under control. For example, the virus called CMV (cytomegalovirus) is a common infection that many adults have or had in the past. Adults with healthy immune systems may not have any symptoms because their immune system can keep the virus under control. But, CMV can be a cause of serious pneumonia in people who have had transplants, because the transplant lowers the amount of white blood cells they have. Pneumonia from CMV mainly happens to people who were already infected with CMV, or whose donor had the virus. If neither you nor your donor had CMV, the transplant team might follow special precautions to prevent this infection while you are in the hospital.

After engraftment, the risk of infection is lower, but it still can happen. It can take 6 months to a year after transplant for the immune system to work as well as it should. It can take even longer for patients with graft-versus-host disease (GVHD, see below). It's important to talk to your cancer care team about your risk for infection during this time.

Because of the increased risk, you will be watched closely for signs of infection, such as fever, cough, shortness of breath, or diarrhea. Your doctor may check your blood often, and extra precautions will be needed to keep you from being exposed to germs. While in the hospital, everyone who enters your room must wash their hands well. They may also wear gowns, shoe coverings, gloves, and masks.

Since flowers and plants can carry bacteria and fungi, they’re not allowed in your room. For the same reason, you may be told not to eat certain fresh fruits and vegetables. All your food must be well cooked and handled very carefully by you and family members. You might need to avoid certain foods for a while.

You may also be told to avoid contact with soil, feces (stool, both human and animal), aquariums, reptiles, and exotic pets. Your team may tell you to avoid being near disturbed soil, bird droppings, or mold. You will need to wash your hands after touching pets. Your family may need to move the cat’s litter box away from places you eat or spend your time. Also, you should not clean pet cages or litter boxes during this time. Instead, give this task to a family member or friend.

Your transplant team will tell you and your family in detail about the precautions you need to follow. There are many viruses, bacteria, and fungi that can cause infection after your transplant. You may be at risk for some more than others.

Despite all these precautions, patients often develop fevers, one of the first signs of infection. In fact, sometimes fever is the only sign of infection, so it's very important to contact your cancer care team if you have one or if you have any other signs of infection. You'll probably be asked to take your temperature by mouth every day or twice a day for a while. And your cancer care team will let you know when you should call in your temperature to them. If you get a fever, tests will be done to look for possible causes of the infection (chest x-rays, urine tests, and blood cultures) and antibiotics will be started.

Bleeding and transfusions

After transplant, you’re at risk for bleeding because the conditioning treatment destroys your body’s ability to make platelets. Platelets are the blood cells that help blood to clot. While you wait for your transplanted stem cells to start working, your transplant team may have you follow special precautions to avoid injury and bleeding.

Platelet counts are low for at least several weeks after transplant. In the meantime, you might notice easy bruising and bleeding, such as nosebleeds and bleeding gums. If your platelet count drops below a certain level, a platelet transfusion may be needed. You’ll need to follow precautions until your platelet counts stay at safe levels.

It also takes time for your bone marrow to start making red blood cells, and you might need red blood cell transfusions from time to time as you recover.

For more information on the transfusion process, see Blood Transfusion and Donation.

Interstitial pneumonitis and other lung problems

Pneumonitis is a type of inflammation (swelling) in lung tissue that’s most common in the first 100 days after transplant. But some lung problems can happen much later – even 2 or more years after transplant.

Pneumonia caused by infection happens more often, but pneumonitis may be caused by radiation, graft-versus-host disease, or chemo rather than germs. It’s caused by damage to the areas between the cells of the lungs (called interstitial spaces).

Pneumonitis can be severe, especially if total body irradiation was given with chemo as part of the pre-transplant (conditioning) treatment. Chest x-rays will be taken in the hospital to watch for pneumonitis as well as pneumonia. Some doctors will do breathing tests every few months if you have graft-versus-host disease (see next section).

You should report any shortness of breath or changes in your breathing to your doctor or transplant team right away. There are many other types of lung and breathing problems that also need to be handled quickly.

Graft-versus-host disease

Graft-versus-host disease (GVHD) can happen in allogeneic transplants when the immune cells from the donor see your body as foreign. (Remember: The recipient’s immune system has mostly been destroyed by conditioning treatment and cannot fight back, so the new stem cells make up most of the immune system after transplant.) The donor immune cells may attack certain organs, most often the skin, gastrointestinal (GI) tract, and liver. This can change the way the organs work and increase the chances of infection.

GVHD reactions are very common and can range from barely noticeable to life-threatening. Doctors think of GVHD as acute or chronic. Acute GVHD starts soon after transplant and lasts a short time. Chronic GVHD starts later and lasts a long time. A person could have one, both, or neither type of GVHD.

Acute GVHD

Acute GVHD can happen 10 to 90 days after a transplant, though the average time is around 25 days.

About one-third to one-half of allogeneic transplant recipients will develop acute GVHD. It’s less common in younger patients and in those with closer HLA matches between donor and the patient.

The first signs are usually a rash, burning, and redness of the skin on the palms and soles. This can spread over the entire body. Other symptoms can include:

  • Nausea
  • Vomiting
  • Stomach cramps
  • Diarrhea (watery and sometimes bloody)
  • Loss of appetite
  • Yellowing of the skin and eyes (jaundice)
  • Abdominal (belly) pain
  • Weight loss

Doctors try to prevent acute GVHD by giving drugs that suppress the immune system, such as steroids (glucocorticoids), methotrexate, cyclosporine, tacrolimus, or certain monoclonal antibodies. These drugs are given before acute GVHD starts and can help prevent serious GVHD. Still, mild GVHD will almost always happen in allogeneic transplant patients. Other drugs are being tested in different combinations for GVHD prevention.

The risk of acute GVHD can also be lowered by removing immune cells called T-cells from the donor stem cells before the transplant. But this can also increase the risk of viral infection, leukemia relapse, and graft failure (which is discussed later). Researchers are looking at new ways to remove only certain cells, called alloactivated T-cells, from donor grafts. This would reduce the severity of GVHD and still let the donor T-cells destroy any cancer cells left.

If acute GVHD does occur, it is most often mild, mainly affecting the skin. But sometimes it can be more serious, or even life-threatening. 

Mild cases can often be treated with a steroid drug applied to the skin (topically) as an ointment, cream, or lotion, or with other skin treatments. More serious cases of GVHD might need to be treated with a steroid drug taken as a pill or injected into a vein. If steroids aren’t effective, other drugs that affect the immune system can be used.

Chronic GVHD

Chronic GVHD can start anywhere from about 90 to 600 days after the stem cell transplant. A rash on the palms of the hands or the soles of the feet is often the earliest sign. The rash can spread and is usually itchy and dry. In severe cases, the skin may blister and peel, like a bad sunburn. A fever may also develop. Other symptoms of chronic GVHD can include:

  • Decreased appetite
  • Diarrhea
  • Abdominal (belly) cramps
  • Weight loss
  • Yellowing of the skin and eyes (jaundice)
  • Enlarged liver
  • Bloated abdomen (belly)
  • Pain in the upper right part of the abdomen (belly)
  • Increased levels of liver enzymes in the blood (seen on blood tests)
  • Skin that feels tight
  • Dry, burning eyes
  • Dryness or painful sores in the mouth
  • Burning sensations when eating acidic foods
  • Bacterial infections
  • Blockages in the smaller airways of the lungs

Chronic GVHD is treated with medicines that suppress the immune system, much like those used for acute GVHD. These drugs can increase your risk of infection for as long as you are treated for GVHD. Most patients with chronic GVHD can stop the immunosuppressive drugs after their symptoms improve.

Hepatic veno-occlusive disease (VOD)

Hepatic veno-occlusive disease (VOD) is a serious problem in which tiny veins and other blood vessels inside the liver become blocked. It’s not common, and it only happens in people with allogeneic transplants, and mainly in those who got the drugs busulfan or melphalan as part of conditioning, or treatment that was given before the transplant.

VOD usually happens within about 3 weeks after transplant. It’s more common in older people who had liver problems before the transplant, and in those with acute GVHD. It starts with yellowing skin and eyes, dark urine, tenderness below the right ribs (this is where the liver is), and quick weight gain (mostly from fluid that bloats the belly). It is life-threatening, so early diagnosis of VOD is very important. Researchers continue to find ways to try to measure a person's chances of getting VOD so that treatment can start as soon as possible.

Graft failure

Grafts fail when the body does not accept the new stem cells (the graft). The stem cells that were given do not go into the bone marrow and multiply like they should. Graft failure is more common when the patient and donor are not well matched and when patients get stem cells that have had the T-cells removed. It can also happen in patients who get a low number of stem cells, such as a single umbilical cord unit. Still, it’s not very common.

Graft failure can lead to serious bleeding and/or infection. Graft failure is suspected in patients whose counts do not start going up within 3 to 4 weeks of a bone marrow or peripheral blood transplant, or within 7 weeks of a cord blood transplant.

Although it can be very upsetting to have this happen, these people can get treated with a second dose of stem cells, if they are available. Grafts rarely fail, but if they do it can result in death.

Transplant problems that may show up later

The type of problems that can happen after a transplant depend on many factors, such as the type of transplant done, the pre-transplant chemo or radiation treatment used, the patient’s overall health, the patient’s age when the transplant was done, the length and degree of immune system suppression, and whether chronic graft-versus-host-disease (GVHD) is present and how bad it is. The problems can be caused by the conditioning treatment (the pre-transplant chemotherapy and radiation therapy), especially total body irradiation, or by other drugs used during transplant (such as the drugs that may be needed to suppress the immune system after transplant). Possible long-term risks of transplant include:

  • Organ damage
  • Relapse (the cancer comes back)
  • Secondary (new) cancers
  • Abnormal growth of lymph tissues
  • Infertility (the inability to produce children)
  • Hormone changes, such as changes in the thyroid or pituitary gland
  • Cataracts (clouding of the lens of the eye, which causes vision loss)

The medicines used in transplants can harm the body’s organs, such as the heart, lungs, kidneys, liver, bones/joints, and nervous system. You may need careful follow-up with close monitoring and treatment of the long-term organ problems that the transplant can cause. Some of these, like infertility, should be discussed before the transplant, so you can prepare for them.

It’s important to find and quickly treat any long-term problems. Tell your doctor right away if you notice any changes or problems. Physical exams by your doctor, blood work, imaging tests, lung/breathing studies, and other tests will help look for and keep tabs on organ problems.

As transplant methods have improved, more people are living longer and doctors are learning more about the long-term results of stem cell transplant. Researchers continue to look for better ways to care for these survivors to give them the best possible quality of life.

Cancer that comes back

The goal of a stem cell transplant in cancer is to prolong life and, in many cases, even cure the cancer. But in some cases, the cancer comes back (sometimes called relapse or recurrence depending on when it might occur after a transplant). Relapse or recurrence can happen a few months to a few years after transplant. It happens much more rarely 5 or more years after transplant.

If cancer comes back, treatment options are often quite limited. A lot depends on your overall health at that point, and whether the type of cancer you have responds well to drug treatment. Treatment for those who are otherwise healthy and strong may include chemotherapy or targeted therapy. Some patients who have had allogeneic transplants may be helped by getting white blood cells from the same donor (this is called donor lymphocyte infusion) to boost the graft-versus-cancer effect. Sometimes a second transplant is possible. But most of these treatments pose serious risks even to healthier patients, so those who are frail, older, or have chronic health problems are often unable to have them.

Other options may include palliative (comfort) care, or a clinical trial of an investigational treatment. It’s important to know what the expected outcome of any further treatment might be, so talk with your doctor about the purpose of the treatment. Be sure you understand the benefits and risks before you decide.

Second cancers (new cancers caused by treatment)

Along with the possibility of the original cancer coming back (relapse) after it was treated with a stem cell transplant, there is also a chance of having a second cancer after transplant. Studies have shown that people who have had allogeneic transplants have a higher risk of second cancer than people who got a different type of stem cell transplant.

A cancer called post-transplant lymphoproliferative disease (PTLD), if it occurs, usually develops within the first year after the transplant. Other conditions and cancers that can happen are solid tumor cancers in different organs, leukemia, and myelodysplastic syndromes. These other conditions, if they occur, tend to develop a few years or longer after the transplant.

Risk factors for developing a second cancer are being studied and may include:

  • Radiation (such as total body irradiation) and high-dose chemo as part of the conditioning treatment
  • Previous chemo or radiation treatment that was not part of the transplant process; the younger a person is when radiation is given, the more that person is at risk for certain types of cancer.
  • Immune system problems (such as graft-versus-host disease, HLA-mismatched allogeneic transplant, and immunosuppressant therapy)
  • Infection with viruses such as Epstein-Barr (EBV), cytomegalovirus (CMV), hepatitis B (HBV), or hepatitis C (HCV)
  • The type of cancer you received the transplant for: for people who had their transplant when younger than 30 years old, those who had certain leukemias had a higher risk of having another cancer than people who did not have these leukemias.

Successfully treating a first cancer gives a second cancer time (and the chance) to develop. No matter what type of cancer is treated, and even without the high doses used for transplant, treatments like radiation and chemo can lead to a second cancer in the future.

Post-transplant lymphoproliferative disorder

Post-transplant lymphoproliferative disorder (PTLD) is an out-of-control growth of lymph cells, actually a type of lymphoma, that can develop after an allogeneic stem cell transplant. It’s linked to T-cells (a type of white blood cell that is part of the immune system) and the presence of Epstein-Barr virus (EBV). T-cells normally help rid the body of cells that contain viruses. When the T-cells aren’t working well, EBV-infected B-lymphocytes (a type of white blood cell) can grow and multiply. Most people are infected with EBV at some time during their lives, but the infection is controlled by a healthy immune system. The pre-transplant treatment given weakens the immune system, allowing the EBV infection to get out of control, which can lead to a PTLD.

Still, PTLD after allogeneic stem cell transplant is fairly rare. It most often develops within 1 to 6 months after allogeneic stem cell transplant, when the immune system is still very weak.

PTLD is life-threatening. It may show up as lymph node swelling, fever, and chills. There’s no one standard treatment, but it’s often treated by cutting back on immunosuppressant drugs to let the patient’s immune system fight back. Other treatments include white blood cell (lymphocyte) transfusions to boost the immune response, using drugs like rituximab to kill the B cells, and giving anti-viral drugs to treat the EBV.

Even though PTLD doesn’t often happen after transplant, it’s more likely to occur with less well-matched donors and when strong suppression of the immune system is needed. Studies are being done to identify risk factors for PTLD and look for ways to prevent it in transplant patients who are at risk.

Stem cell transplants and fertility

Most people who have stem cell transplants become infertile (unable to have children). This is not caused by the cells that are transplanted, but rather by the high doses of chemo and/or radiation therapy used. These treatments affect both normal and abnormal cells, and often damage reproductive organs.

If having children is important to you, or if you think it might be important in the future, talk to your doctor about ways to protect your fertility before treatment. Your doctor may be able to tell you if a particular treatment will be likely to cause infertility.

After chemo or radiation, some women may find their menstrual periods become irregular or stop completely. This doesn’t always mean they cannot get pregnant, so birth control should be used before and after a transplant. The drugs used in transplants can harm a growing fetus.

The drugs used during transplant can also damage sperm, so men should use birth control to avoid starting a pregnancy during and for some time after the transplant process. Transplants may cause temporary or permanent infertility for men as well. Fertility returns in some men, but the timing is unpredictable. Men might consider storing their sperm before having a transplant.

For more information on having children after being treated for cancer or sexual problems related to cancer treatment, see Fertility and Sexual Side Effects.

The American Cancer Society medical and editorial content team

Our team is made up of doctors and oncology certified nurses with deep knowledge of cancer care as well as journalists, editors, and translators with extensive experience in medical writing.

American Society of Clinical Oncology (ASCO).  Side effects of a bone marrow transplant (stem cell transplant). 2018. Accessed at https://www.cancer.net/navigating-cancer-care/how-cancer-treated/bone-marrowstem-cell-transplantation/side-effects-bone-marrow-transplant-stem-cell-transplant on March 17, 2020.

Atilla E, Atilla PA, Demirer T. A review of myeloablative vs reduced intensity/non-myeloablative regimens in allogeneic hematopoietic stem cell transplantations. Balkan Med J. 2017;34(1):1-9. Accessed at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322516/ on March 17, 2020.

Fontana L, Strasfeld, L. Respiratory virus infections of the stem cell transplant recipient and the hematologic malignancy patient. Infect Dis Clin North Am. 2019; 33(2):523-544.

Im A, Pavletic SZ. Hematopoietic stem cell transplantation. In Niederhuber JE, Armitage JO, Kastan MB, Doroshow JH, Tepper JE, eds. Abeloff’s Clinical Oncology. 6th ed. Philadelphia, PA: Elsevier;2020:461-469.

Kamboj M, Shah MK. Vaccination of the stem cell transplant recipient and the hematologic malignancy patient. Infect Dis Clin North Am. 2019; 33(2):593-609.

Misch AE, Andes DR. Bacterial infections in the stem cell transplant recipient and hematologic malignancy patient. Infect Dis Clin North Am. 2019; 33(2):399-445.

Nathan S, Ustun C. Complications of stem cell transplantation that affect infections in stem cell transplant recipients, with analogies to patients with hematologic malignancies. Infect Dis Clin North Am. 2019; 33(2):331-359.

National Institutes of Health (NIH).  Stem cell basics. 2016. Access at https://stemcells.nih.gov/info/basics.htm on March 17, 2020.

National Cancer Institute (NCI). Adult acute lymphoblastic leukemia treatment (PDQ®): Health professional version. 2019. Accessed at https://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq on March 17, 2020.

National Cancer Institute (NCI). Childhood hematopoietic cell transplantation (PDQ®): Health professional version. 2019. Accessed at https://www.cancer.gov/types/childhood-cancers/child-hct-hp-pdq on March 17, 2020.

National Comprehensive Cancer Network (NCCN). Multiple myeloma: NCCN Clinical Practice Guidelines in Oncology. Version 3.2020. Accessed at https://www.nccn.org/patients/guidelines/myeloma/ on March 17, 2020.

Saygin C, Matei D, Majeti R, et al. Targeting cancer stemness in the clinic: From hype to hope. Cell Stem Cell. 2019; 24(1):25-40.

Soiffer RJ, Chen YB. Pharmacologic agents to prevent and treat relapse after allogeneic hematopoietic cell transplantation. Hematology Am Soc Hematol Educ Program. 2017; 1:699-707. Access at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142540/ on March 17, 2020.

Zhang L, Yu J, Wei W. Advances in targeted immunotherapy for graft-versus-host disease. Front Immunol. 2018;9:1087. Accessed at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964137/ on March 17, 2020.

Zhao XS, Huang XJ. Seeking biomarkers for acute graft-versus host disease: Where we are and where we are heading? Biomark Res. 2019; 7:17. Accessed at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685226/ on March 17, 2020.

References

American Society of Clinical Oncology (ASCO).  Side effects of a bone marrow transplant (stem cell transplant). 2018. Accessed at https://www.cancer.net/navigating-cancer-care/how-cancer-treated/bone-marrowstem-cell-transplantation/side-effects-bone-marrow-transplant-stem-cell-transplant on March 17, 2020.

Atilla E, Atilla PA, Demirer T. A review of myeloablative vs reduced intensity/non-myeloablative regimens in allogeneic hematopoietic stem cell transplantations. Balkan Med J. 2017;34(1):1-9. Accessed at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322516/ on March 17, 2020.

Fontana L, Strasfeld, L. Respiratory virus infections of the stem cell transplant recipient and the hematologic malignancy patient. Infect Dis Clin North Am. 2019; 33(2):523-544.

Im A, Pavletic SZ. Hematopoietic stem cell transplantation. In Niederhuber JE, Armitage JO, Kastan MB, Doroshow JH, Tepper JE, eds. Abeloff’s Clinical Oncology. 6th ed. Philadelphia, PA: Elsevier;2020:461-469.

Kamboj M, Shah MK. Vaccination of the stem cell transplant recipient and the hematologic malignancy patient. Infect Dis Clin North Am. 2019; 33(2):593-609.

Misch AE, Andes DR. Bacterial infections in the stem cell transplant recipient and hematologic malignancy patient. Infect Dis Clin North Am. 2019; 33(2):399-445.

Nathan S, Ustun C. Complications of stem cell transplantation that affect infections in stem cell transplant recipients, with analogies to patients with hematologic malignancies. Infect Dis Clin North Am. 2019; 33(2):331-359.

National Institutes of Health (NIH).  Stem cell basics. 2016. Access at https://stemcells.nih.gov/info/basics.htm on March 17, 2020.

National Cancer Institute (NCI). Adult acute lymphoblastic leukemia treatment (PDQ®): Health professional version. 2019. Accessed at https://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq on March 17, 2020.

National Cancer Institute (NCI). Childhood hematopoietic cell transplantation (PDQ®): Health professional version. 2019. Accessed at https://www.cancer.gov/types/childhood-cancers/child-hct-hp-pdq on March 17, 2020.

National Comprehensive Cancer Network (NCCN). Multiple myeloma: NCCN Clinical Practice Guidelines in Oncology. Version 3.2020. Accessed at https://www.nccn.org/patients/guidelines/myeloma/ on March 17, 2020.

Saygin C, Matei D, Majeti R, et al. Targeting cancer stemness in the clinic: From hype to hope. Cell Stem Cell. 2019; 24(1):25-40.

Soiffer RJ, Chen YB. Pharmacologic agents to prevent and treat relapse after allogeneic hematopoietic cell transplantation. Hematology Am Soc Hematol Educ Program. 2017; 1:699-707. Access at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142540/ on March 17, 2020.

Zhang L, Yu J, Wei W. Advances in targeted immunotherapy for graft-versus-host disease. Front Immunol. 2018;9:1087. Accessed at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964137/ on March 17, 2020.

Zhao XS, Huang XJ. Seeking biomarkers for acute graft-versus host disease: Where we are and where we are heading? Biomark Res. 2019; 7:17. Accessed at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685226/ on March 17, 2020.

Last Revised: March 20, 2020

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