What Is Engraftment Syndrome?

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Engraftment syndrome is a complication that can occur after bone marrow transplant, a procedure also known as hematopoietic stem cell transplant (HSCT). The engraftment syndrome is considered an inflammatory condition, and it is characterized by the following:

  • Fever and a rash not due to infection
  • Excess fluid in the lungs not due to a heart problem
  • Various other symptoms and findings

The syndrome develops around 7 to 11 days following transplant, during the time of neutrophil recovery.

Symptoms are usually mild, but they can range to more sever and life threatening forms. The syndrome may result in trouble breathing, fever ≥100.9˚F, a reddish rash that has both flat and raised skin areas, weight gain, low blood oxygen levels, and excess fluid in the lungs that is not due to a heart problem.

In its most extreme form, the term “aseptic shock” syndrome has been used, meaning that there is collapse of the circulatory system and multi-organ failure.

The engraftment syndrome has been reported to occur after both main types of HSCT: autologous (transplant from self) and allogeneic (from other, often related donor).

Relationship to Other Conditions

Engraftment refers to the newly transplanted cells “taking root and producing,” that is, when the transplanted cells find their niche in the bone marrow and start the process of making new red blood cells, white blood cells, and platelets.

The relationship of engraftment syndrome to other post-transplant events that have similar features is controversial. These other post-transplant events include conditions such as acute graft versus host disease (GVHD), pre-engraftment syndrome (PES), radiation- and drug-induced toxicities and infections, alone or in combination.

Pre-engraftment syndrome and peri-engraftment syndrome are other terms that scientists have used to describe this set of symptoms that may arise around the time of engraftment. Engraftment syndrome has also been called “capillary leak syndrome,” which refers to one of the possible underlying mechanisms of the syndrome—that is, due to cell signals that are out of balance, the body’s smallest blood vessels, the capillaries, become more permeable than normal, resulting in abnormal, excess fluid building up in various parts of the body. When this occurs in the lungs, it is pulmonary edema. More specifically, it is fluid in the lungs not due to a heart problem, so the term is “noncardiogenic pulmonary edema.”

What Causes Engraftment Syndrome?

The exact cause of engraftment syndrome is not known, but it is thought that overproduction of pro-inflammatory cell signals and cellular interactions may have a major role.

The fluid in the lungs is thought to be caused by cell signals that cause the body’s tiny capillaries to become leaky. This excess fluid is called pulmonary edema, or if seen on imaging studies, there may be mention of pleural effusions. In cases where the fluid in the lungs has been studied, sometimes they find high numbers of neutrophils, a type of white blood cell.

 In two patients who had their lungs biopsied, they also found damage to the alveoli—the lung’s air sacs—which was spread out diffusely.

Researchers reason that, because engraftment syndrome is seen after different types of transplant donors and different types of grafts, and since the syndrome may be distinct from GVHD and coincides with recovery of the white cells known as granulocytes, that it is likely mediated by activated white blood cells and proinflammatory cell signals. This mix of cell signals and interactions can cause a leaky circulatory system, organ dysfunction and symptoms such as fever.

How Is It Diagnosed?

Dr. Spitzer, a clinical researcher at the Bone Marrow Transplant Program at Massachusetts General Hospital in Boston, MA, published the seminal paper on engraftment syndrome back in 2001.

The Spitzer Criteria for engraftment syndrome are as follows:

Major criteria:

  • Temperature greater than or equal to 38.3 °C with no identifiable infectious cause
  • Red rash involving >25 percent of body surface area and not attributable to a medication 
  • Rash or excess fluid in the lungs not caused by a heart problem, as seen on imaging scans, and low oxygen in the blood

Minor criteria:

  • Liver dysfunction with certain parameters (bilirubin ≥2 mg/dL or transaminase ≥2 times normal)
  • Kidney insufficiency (serum creatinine ≥ 2x baseline)
  • Weight gain (≥2.5 percent of baseline body weight)
  • Temporary confusion/brain abnormalities unexplainable by other causes

Diagnosis requires all three major criteria or two major criteria and one or more minor criterion within 96 hours of engraftment.

There are other criteria in use to diagnose engraftment syndrome, as well. For instance, the Maiolino criteria were introduced in 2004. Different experts seem to have different thresholds for identifying engraftment syndrome, and overlapping signs may contribute to this problem. In 2015, Dr Spitzer published some characteristics that were “consistent with” and “not consistent with” engraftment syndrome:

Consistent with engraftment syndrome: Noninfectious fever; rash; signs of leaky capillaries (low blood pressure, weight gain, swelling, fluid in the belly, fluid in the lungs not caused by a heart condition); kidney, liver, or brain dysfunction; and diarrhea without another cause.

Not consistent with engraftment syndrome: An infectious cause of fever; rash with biopsy findings that suggest GVHD in the case of a transplant from a non-self donor; congestive heart failure; organ dysfunction due to another cause, (for instance, calcineurin inhibitor nephrotoxicity or liver GVHD); diarrhea due to another cause (for instance, infection, chemo toxicity, or GVHD).

How Is Engraftment Syndrome Managed?

According to a report by Dr. Spitzer, in about one-third of patients, engraftment syndrome may resolve on its own, and require no treatment. When treatment is necessary, engraftment syndrome appears to be very responsive to corticosteroid treatment given for as long as the symptoms persist, usually less than a week. The need for treatment is indicated by temperature of >39 °C without an identifiable infectious cause and clinically significant signs of leaky capillaries, especially excess fluid in the lungs.

What Else Is Known About Engraftment Syndrome?

There are different criteria in use for diagnosing engraftment syndrome, and this may account for a wide range of statistics on the topic of how common the syndrome develops in various categories of patients who receive stem cell transplants. Dr. Spitzer has been studying the syndrome since 2001, and publications and reviews of the biomedical literature were summarized recently in 2015:

  • Engraftment syndrome after hematopoietic cell transplantation (HCT) is increasingly diagnosed.
  • Different diagnostic criteria are in use, and likely account for the wide (7–90 percent) range of reported incidences.
  • Although the clinical manifestations of engraftment syndrome may be identical to those of acute GVHD, engraftment syndrome has also been well described in patients without acute GVHD.
  • It’s not known whether the syndrome leads to higher mortality and worse survival after HCT; studies have been done, but the data are conflicting.
  • Engraftment syndrome typically resolves on its own, but, like acute GVHD, it responds to corticosteroids.
  • Because engraftment syndrome and acute GVHD may have overlapping features and response to therapy, these disease processes may often not be distinct events.
  • Features of engraftment syndrome may overlap with those of drug- and radiation-induced toxicities and infection.

A Word From Verywell:

How common is this syndrome, and what are the chances a particular patient will develop its symptoms? Well, since there is no consensus on the precise definition, clinically, wide ranges of incidences have been reported in the literature, from as low as 7 percent to as high as 90 percent in autotransplants (transplant from self as donor). The higher rates have been reported after autotransplants for breast cancer and lymphomas other than Hodgkin lymphoma. The syndrome may affect children and adults at similar rates, but the impact may be greater in children in terms of mortality that is not related to relapse of the cancer.

The rates of engraftment syndrome appear to be lower in people who receive transplants from non-self donors. This is a difficult area to research, however, since the syndrome can look like acute GVHD. In one study, complete resolution of engraftment syndrome occurred in only 10 percent of subjects who did not later develop acute GVHD.

Sources:

Franquet T, Müller NL, Lee KS, et al. High-resolution CT and pathologic findings of noninfectious pulmonary complications after hematopoietic stem cell transplantation. AJR Am J Roentgenol. 2005;184(2):629-37.

Lee Y-H, Rah W-J. Pre-engraftment syndrome: clinical significance and pathophysiology. Blood Res. 2016;51(3):152-154.

Omer AK, Kim HT, Yalamarti B, McAfee S, Dey BR, Ballen KK et al. Engraftment syndrome after allogeneic hematopoietic cell transplantation in adults. Am J Hematol 2014; 89: 698–705.

Spitzer, TR. Engraftment syndrome: double-edged sword of hematopoietic cell transplants. Bone Marrow Transplant. 2015;50(4):469-75.

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