Systemic antiviral drugs, e.g. cidofovir and ribavirin, can be commenced, if the HC is confrmed or likely attributable to adeno- or BK virus. Decreased immunosuppression could be considered in particular in cases of relapsing viral cystitis. Note that anticoagulants such as tranexamic acid and aminocaproic acid are contraindicated in HC due to risk of clot formation and retention.

Some studies have demonstrated effectiveness of hyperbaric oxygen (HBO) (Savva-Bordalo et al. 2012; Hosokawa et al. 2021) in HC after HSCT, whereby the patient receives 100% oxygen in a hyperbaric chamber. However, this has not been established outside single-centre studies with small numbers of patients. Furthermore, limited access to hyperbaric chambers and the likely need and inability for the patient to move to another treatment unit often make this intervention less of an option.

# **10.3.9 Nursing Aspects**

During treatment with hyperhydration, the same need for close monitoring and assessments as in the prophylactic setting applies (see above). Assess the need for platelet transfusion prior to catheterisation as well as after. Blood transfusions may also be necessary with signifcant blood loss. Standard monitoring for signs of infection, injury, pain, clot formation and other potential complications from the urinary catheter is important. In cases of bladder irrigation, keeping the fuids for irrigation at ambient temperature may alleviate discomfort. Complications of the irrigation can be prevented or minimised by close monitoring and recording of fuid balance. It is also important to maintain patient comfort by adequate pain management and general nursing interventions such as comfortable positioning and assistance with personal hygiene. The need for information and psychological support should be observed for both patient and family.

Since in particular viral HC may occur after discharge from the hospital, careful assessment of any signs and symptoms related to the urinary tract that may indicate urinary bacterial or viral infection is just as important in the outpatient setting.

# **10.4 Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease**

# **10.4.1 Introduction**

Sinusoidal obstruction syndrome (SOS) is also known as veno-occlusive disease (VOD) and is referred to as SOS/VOD hereafter. Of the early complications that are considered to be of vascular endothelial origin, this is the most described. There are diagnosis and severity criteria (McDonald et al. 1984, 1993; Jones et al. 1987; deLeve et al. 2009; Mohty et al. 2016), with the EBMT criteria the most recently proposed and criteria for the development of late-onset disease (Mohty et al. 2016). Careful monitoring of HSCT patients allows early detection of SOS/ VOD. Treatment can then be started without delay, ultimately improving patient outcomes. From pre-transplant assessment to medical management and overall care of the patient, nurses thus have an essential role to play as part of a multidisciplinary team (Wallhult et al. 2017).

There are specifc differences between the clinical presentation of SOS/VOD in adults versus in children, which has not been refected in the older diagnosis and severity criteria. For this reason, EBMT has also developed a classifcation for diagnosis and severity criteria for SOS/VOD in paediatric patients (Corbacioglu et al. 2018). The information presented below is related to adults. For the paediatric population, please see original article (Corbacioglu et al. 2018), and for further information on VOD, visit the e-learning programme (2021) (https://www.ebmt.org/ hepatic-veno-occlusive-disease-vod).

# **10.4.2 Defnition and Pathogenesis**

When drugs used in haematopoietic stem cell transplant (HSCT) conditioning regimens are metabolised in the liver, it results in toxic metabolites being produced by the hepatocytes. The metabolites trigger the activation, damage and infammation of the endothelial cells lining the sinusoids (sinusoids being small capillary-like blood vessels in the liver). This trigger mechanism can start as soon as the conditioning treatment is administered. The activated sinusoidal endothelial cells release infammatory cytokines, chemokines and the enzyme heparanase, which breaks down the extracellular matrix that supports the structure of the sinusoids. The endothelial cells are then forced to round up, and gaps form between the cells. The gaps allow for red blood cells, white blood cells and other cellular debris to exit through these gaps in the sinusoid walls into the space of Disse. (The space of Disse is the perisinusoidal space that is located between the endothelium and the hepatocytes.) When cells and debris accumulate in this space, the sinusoids become narrower. Due to the sinusoidal damage, endothelial cells can dissect off and embolise further downstream thus contributing to the narrowing. The damage also leads to an increase in the expression of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1). This coagulopathy causes an increase in clot formation and a decrease in the breakdown of clots. The deposition of fbrin and the clot formation will contribute to the narrowing of the sinusoids and may ultimately lead to hepatic sinusoidal obstruction. The result is SOS/VOD, which is characterised by obstruction of the sinusoids, portal vein hypotension and reduced hepatic venous outfow. Severe cases can progress to multi-organ dysfunction (MOD)/multi-organ failure (MOF) and death.

SOS/VOD usually develops before day +21 after HSCT with a peak incidence around day 12, but about 15–20% of the SOS/VOD cases have a late onset, after day +21.

# **10.4.3 Incidence and Prognosis**

Although relatively rare, SOS/VOD is one of the main causes of non-relapse, transplant-related mortality. The incidence of VOD/SOS after transplantation varies substantially from 2 to 60% of both different settings of patients and transplant procedures and of application of different diagnostic criteria (Bonifazi et al. 2020).

It will also depend on risk factors including intensity of conditioning regimen and type of transplant. After allo-HSCT with myeloablative conditioning (MAC), the incidence is approximately 10–15%, but if reduced intensity conditioning (RIC) is used, the incidence is <5%. This is the same incidence as for auto-HSCT.

Mild SOS/VOD may not be particularly well recognised since the symptoms are subtle, may not require treatment and may spontaneously resolve within a few weeks. Unrecognised SOS/ VOD may however progress, sometimes very rapidly, into moderate or severe. Severe SOS/ VOD is associated with multi-organ dysfunction/ multi-organ failure (MOD/MOF) and a mortality rate of 84%.

# **10.4.4 Risk Factors**

The risk factors for SOS/VOD can be divided into patient- and disease-related and transplantrelated risk factors (Mohty et al. 2015). As mentioned above, the risk factors, as well as the clinical presentation of SOS/VOD, differ between the adult and the paediatric population, and the risk factors presented here are related to adults.

Risk factors are divided into three categories.

# **10.4.5 Diagnosis**

Despite the fact that diagnostic criteria were developed in the 1980s and have been used in clinical practice and research studies, it is often hard to identify early or mild cases of SOS/VOD before it progresses to a more severe form. Some reasons are lack of sensitivity and specifcity of the criteria, the dynamic manifestations that makes defnition of the condition hard and that early signs and symptoms often are subtle and makes differentiation from other transplant complications diffcult. Given the poor prognosis of severe SOS/VOD, it is however vital to identify mild cases before they progress to moderate, with signs of hepatic injury and requiring more aggressive intervention, or further progress to severe SOS/VOD with MOD/MOF. The most recent diagnostic criteria proposed by EBMT (Mohty et al. 2016) are the same as the Baltimore criteria (Jones et al. 1987) for classical SOS/VOD with onset within the frst 3 weeks after HSCT, but if SOS/VOD develops after day +21, elevated serum bilirubin level is not always seen, why a modifed version of the criteria can be used for diagnosis of late SOS/VOD (Mohty et al. 2016) (Table 10.5). The EBMT criteria also better capture the dynamic manifestations of the disease and thus facilitate an early diagnosis as well as a more accurate assessment of severity. Treatment can then be started at a stage with greater chance for treatment response.

Differential diagnoses will need to be excluded by assessing risk factors, symptoms and lab tests since liver dysfunction can also be seen in sepsis, viral infection, graft-versus-host disease (GvHD) and iron overload and as a side effect from many of the drugs used in the HSCT setting. In addition to the signs and symptoms required for diagnosis haemorrhagic complications, thrombocytopenia

**Table 10.5** SOS/VOD diagnosis criteria

a McDonald et al. (1984)

b McDonald et al. (1993)

c Jones et al. (1987)

d Mohty et al. (2016)

with platelet refractoriness, pulmonary dysfunction, renal dysfunction and encephalopathy are "late" signs that can be seen in more severe cases of SOS/VOD. Further, it is worth noting that all symptoms are also observed in other conditions and that many other complications may coexist with SOS/VOD (Eisenberg 2008). Examples of differential diagnosis for classical symptoms of SOS/VOD are listed in Table 10.6.

When SOS/VOD is diagnosed, it is important to classify the severity grade in order to intensify the monitoring and identify patients that will need therapeutic intervention. The EBMT severity grading criteria (Mohty et al. 2016) stress the importance of noting the time since the appearance of the symptoms. A rapid progression of symptoms, and in particular bilirubin kinetics (the rate of increase) with a doubling time of 48 h, should be classifed as a more severe grade than if symptoms develop more slowly over several days (Table 10.7).

#### **Table 10.6** SOS/VOD symptoms

Eisenberg (2008)

**Table 10.7** EBMT criteria for severity grading of a suspected SOS/VOD in adults

Patients belong to the category that fulfls two or more criteria. If patients fulfl two or more criteria in two different categories, they must be classifed in the most severe category. Patients' weight increase ≥5% and <10% is considered by default as a criterion for severe SOS/VOD; however, if patients do not fulfl other criteria for severe SOS/VOD, weight increase ≥5% and <10% is therefore considered as a criterion for moderate SOS/VOD

*EBMT* European Society for Blood and Marrow Transplantation, *MOD* multi-organ dysfunction, *MOF* multi-organ failure, *SOS* sinusoidal obstruction syndrome, *VOD* veno-occlusive disease

a In the case of presence of two or more risk factors for SOS/VOD, patients should be in the upper grade

b Patients with multi-organ dysfunction must be classifed as very severe

c Time from the date when the frst signs/symptoms of SOS/VOD began to appear (retrospectively determined) and the date when the symptoms fulflled SOS/VOD diagnostic criteria

# **10.4.6 Prevention**

The frst strategy for prevention is to be aware of pre-existing risk factors and try and eliminate them as far as possible and potentially establish supportive or treatment measures prior to transplant. The patient- and disease-related risk factors, including hepatic, are often diffcult or impossible to change, but the transplant-related risk factors should be carefully considered in the pre-transplant setting.

No proven medical prophylaxis exists, but sodium heparin, prostaglandin E1, ursodeoxycholic acid and low-molecular-weight heparin have been tried, although data about effectiveness remains inconclusive (Carreras 2012, 2015). Defbrotide, approved for treatment of severe SOS/VOD, has also been used as prophylaxis (Dignan et al. 2013), and one randomised study in children has shown a reduction in SOS/VOD incidence (Corbacioglu et al. 2012).

# **10.4.7 Treatment**

As soon as SOS/VOD is suspected, supportive therapy should be initiated. In mild cases of SOS/ VOD, close monitoring to detect progression and supportive management is often suffcient.

The monitoring should include:

The supportive management consists of:

Defbrotide is licenced for the treatment of severe hepatic SOS/VOD. Defbrotide protects the endothelial cells, reduces infammation and restores thrombo-fbrinolytic balance (Richardson et al. 2013). The recommended dose is 6.25 mg/kg body weight administered as a 2 h, IV infusion every 6 h (to a total dose of 25 mg/kg/ day). Recommendation for treatment duration is at least 21 days but should continue until the symptoms and signs of VOD resolve. Defbrotide is generally well tolerated (Keating 2014) but should not be used with products that affect platelet aggregation, e.g. non-steroidal antiinfammatory drugs (NSAIDs), anticoagulant therapy or other products that increase the risk of bleeding.

# **10.4.8 Nursing Aspects**

It is important to perform an assessment of each new patient considering the risk factors mentioned above and to take baseline measurements including defning a threshold of >5% for weight gain. Most baseline measurements will be standard for HSCT patients, but in patients at high risk for SOS/VOD, assessments of abdominal girth and right upper quadrant (RUQ) pain and inspection of sclera may be added.

Standard daily monitoring should include temperature, pulse, blood pressure, respiration rate and saturation. One of the most important daily monitoring aspects is an accurate fuid balance including intake, output and weight since fuid imbalance is one of the earliest signs of SOS/VOD. A fuid retention that does not respond to diuretics represents an early sign of endothelial damage.

When performing abdominal girth measurement, it is advised to use a marked line for placement of the measuring tape and to choose one position (i.e. sitting/standing/lying) for the patient, to be used for each subsequent measure. Abdominal discomfort, tenderness, pain (in particular RUQ pain) and inspection for collateral circulation and/or spiders should always be included in abdominal assessment. For nurses trained in palpation and percussion for ascites, bulkiness, liver margins and size, these assessments should also be performed.

The sclera and skin should be assessed for bleeding/bruising and discoloration (jaundice).

Knowledge of the relevant reference ranges of daily laboratory values, particularly liver enzymes, serum bilirubin, blood count, electrolytes, urea and serum creatinine, will enable early detection of signifcant change or trend in values since nurses are likely to take blood samples and see the results frst and can alert medical colleagues.

All fndings should be precisely documented and any changes promptly reported. This is especially important in patients identifed as high risk as early detection of SOS/VOD may affect the overall outcome.

If SOS/VOD is suspected, the monitoring should be intensifed and adequate vascular access established. In addition to standard lab tests, coagulation parameters should be performed daily. If possible, hepatotoxic drugs should be avoided and diuretics and pain medication administered as needed. Electrolyte replacement may be necessary, and in case of thrombocytopenia or bleeding, blood products will be administered. If fuid restriction is enforced, it is important to know the smallest volumes that can be safely delivered.

The patient may also need assistance to be comfortably positioned.

When SOS/VOD has been diagnosed, the supportive care and monitoring will be further intensifed including assessing for failure in respiratory, cardiac and renal function. Defbrotide treatment will most likely be started, and patients in need for ventilatory support should be prepared for transfer to the intensive care unit (ICU).

Patients should be informed and educated to notify the staff of any signs and symptoms that may need closer monitoring or intervention. In case SOS/VOD is diagnosed, both patient and family will need reassurance and support.

# **10.5 Other Early Complications of Endothelial Origin**

# **10.5.1 Introduction**

A number of early HSCT complications seem to be initiated by damage to the vascular endothelium. The most well defned and well described of these complications is sinusoidal obstruction syndrome (SOS)/veno-occlusive disease (VOD) described in the previous section of this chapter. Other syndromes in this group have been named engraftment syndrome (ES), diffuse alveolar haemorrhage (DAH), idiopathic pneumonia syndrome (IPS) and transplant-associated microangiopathy (TMA). The similarities in their clinical manifestations and the lack of established diagnostic criteria often make determination of incidence and differential diagnosis diffcult (Soubani and Pandya 2010; Afessa et al. 2012). Although many times mild and with spontaneous recovery, these complications also share the risk for progression to multi-organ failure (MOF)/multi-organ damage (MOD), resulting in a poor outcome.

Ongoing research and efforts for better characterisation and treatment indicate that there will be future changes in terminology and diagnostic criteria, as well as interventions, for the early HSCT complications mentioned here.

# **10.5.2 Pathogenesis**

Several factors in the HSCT setting activate the endothelial cells that line the blood vessels. Contributing factors are the conditioning treatment and use of other drugs such as granulocyte colony-stimulating factor (G-CSF) and calcineurin inhibitors (CNI), e.g. cyclosporine-A, and microbial products translocated through mucosal barriers. The result is that fuid and proteins leak out of tiny blood vessels and fow into surrounding tissues. If unrecognised, this may lead to dangerously low blood pressure and subsequently MOF and shock. The symptoms often appear around the time of neutrophil recovery, i.e. when the absolute neutrophil count (ANC) increases to ≥0.5 × 109 /L, which is why the complex process of engraftment may also play a role in activation of endothelial cell damage. The activation of the endothelial cells leads to further damage and infammation by the release of pro-infammatory cytokines. Since the incidence of vascular endothelial syndromes is higher after allogeneic transplantation, alloreactivity (the immune response to non-self cells) is considered to play a role in activation and damage of endothelial cells.

# **10.6 Engraftment Syndrome (ES)**

# **10.6.1 Defnition**

ES usually occurs after auto-HSCT although described in allo-HSCT as well, in particular when reduced intensity conditioning (RIC) and cord blood (CB) have been used.

Due to lack of diagnostic criteria, the term ES has been used as synonymous with capillary leak syndrome (CLS), auto-aggression syndrome, peri-engraftment respiratory distress syndrome (PERDS), aseptic shock syndrome and autologous graft-versus-host disease (AGVHD). Although there are differences, their common denominator is that they share some or all symptoms that have been attributed to ES.

Engraftment is defned as when the number of neutrophils in the patient's blood rises to an absolute neutrophil count (ANC) of ≥0.5 × 109 /L.

Peri-engraftment can be defned as the period within 5 days of neutrophil engraftment.

# **10.6.2 Incidence and Prognosis**

Due to the diagnosis diffculties, no reliable incidence fgures are published although fgures between 10% and 70% have been reported. There is also a lack of survival data. Most cases are mild and respond well to corticosteroid therapy, but ES may progress and lead to transplant-related mortality and decrease in overall survival. Patients requiring mechanical ventilation have a poor prognosis.

# **10.6.3 Risk Factors**

There are a number of potential risk factors related to patient characteristics, disease, previous treatment, conditioning treatment, stem cell source and supportive drug treatment, but there is a lack of consensus, which can in part be contributed to the lack of diagnostic criteria. Changes in HSCT practices with new drugs and alternate stem cell sources may impact the risk factors in the future.

Among the risk factors described are:

# **10.6.4 Diagnosis**

There are two tools to aid diagnosis of ES: the Spitzer (2001) and the Maiolino et al. (2003) diagnostic criteria. The clinical manifestations are divided into major or minor clinical criteria (Table 10.8), but Maiolino only has one major criteria, non-infectious fever. The timing of symptoms relative to engraftment also differs

between the two, where Maiolino has a stricter time frame from 24 h before to any time after neutrophil recovery compared to Spitzer's 96 h after (Table 10.9). However, in some patients, others have described onset of symptoms from 7 days before (for patients with POEMS) to 7 days after engraftment, and in cases with more severe symptoms, the early symptoms may have been overlooked, why the clinical criteria sometimes could be used regardless of appearance of symptoms in relation to time for engraftment (Chang et al. 2014). C-reactive protein (CRP) is not used for diagnosis in either criteria, but a sudden and signifcant increase in the CRP level has been found to support the diagnosis.

# **10.6.5 Prevention**

Early recognition of signs and symptoms is the most important aspect since there is no standard prophylaxis for ES, although there is evidence that corticosteroids may prevent this complication.

# **10.6.6 Treatment**

Before treatment is initiated, other diagnoses such as infection, drug rash, diarrhoea associated with infection or medication and intravenous (IV)-related fuid overload should be excluded. Broad-spectrum antibiotics should be used until infection is ruled out (Cornell et al. 2015). If cultures are negative, symptoms remain after 48–72 h of antibiotic treatment and other aetiologies can be excluded, corticosteroid treatment can be initiated.

Methylprednisolone in doses of 1–3 mg/kg/ day IV are recommended until symptoms begin to subside. Response to treatment is usually seen within 2–3 days. Corticosteroids could then be switched to oral administration and should be slowly tapered. Early intervention with steroids prevents progression to more severe manifestations, and in the vast majority (80%) of patients, there is then complete resolution in less than 6 days. In cases with no response to steroid treatment after 72 h, biopsies of affected organs may be necessary. If biopsies are performed for evaluation of diarrhoea, the fndings may not be able to distinguish from GvHD. This does however not exclude ES since overlap and coexistence with GvHD is possible. If a biopsy supports the ES diagnosis, treatment with additional immune suppressants should be started and continued until response. If the result of the biopsy is an alternative diagnosis, the patient should be treated accordingly.

In addition to pharmacological treatment, supportive care with IV fuids, with electrolyte supplement as needed, and oxygen therapy may be necessary depending on the symptoms.

In cases of encephalopathy or severe ES with MOF, plasma exchange may be considered (Yeoung-Hau and Syed 2014).

# **10.6.7 Nursing Aspects**

Daily nursing assessments are critical in early detection and diagnosis of all complications to HSCT. The patient's general well-being should be assessed. Listed in Table 10.10 are the nursing

Thoele (2014)

assessments that should be carried out frequently, the fndings that could indicate ES and actions that can be taken in order to detect or rule out the ES diagnosis. All fndings should be documented and any abnormalities promptly reported to the treating physician.

If steroid treatment is started, the patient should be assessed for possible side effects such as hyperglycaemia and insomnia. Blood glucose should be monitored daily.

# **10.7 Idiopathic Pneumonia Syndrome**

# **10.7.1 Defnition**

Pulmonary complications (PCs) are the leading cause of patients' admission to intensive care unit (ICU) after HSCT. PC can be divided into infectious or non-infectious. One of the noninfectious PCs is idiopathic pneumonia syndrome (IPS).

For the purpose of this chapter, IPS will be defned and described according to the defnition by the American Thoracic Society (Panoskaltsis-Mortari et al. 2011):

An idiopathic syndrome of pneumopathy after HSCT, with evidence of widespread alveolar injury and in which an infectious etiology and cardiac dysfunction, acute renal failure or iatrogenic fuid overload have been excluded.

The alveolar injury is a result from the release of proinfammatory cytokines during engraftment, increasing alveolar permeability and causing diffuse alveolar or interstitial infltrates.

IPS also includes a subset of diagnoses of primary lung injuries classified according to the anatomical sites of inflammation. They can either be related to the pulmonary parenchyma (e.g. acute interstitial pneumonitis and acute respiratory distress syndrome (ARDS)), the airway endothelium (e.g. bronchiolitis obliterans syndrome (BO)), the vascular endothelium (e.g. different forms of ES (PERDS, CLS)) or be unclassifiable. Other less frequent non-infectious PCs have also been identified. None of these entities will be described here.

# **10.7.2 Incidence and Prognosis**

PCs are common in HSCT recipients and a major cause of morbidity and mortality. IPS is more often seen in patients undergoing allogeneic HSCT, with a mean estimated incidence of 1–10% (6% in auto-HSCT) (Chi et al. 2013). The overall outcome is different between auto- and allo-HSCT recipients, and where IPS in patients who have undergone auto-HSCT usually has a favourable prognosis, the mortality is 60–80% in the allo-setting (Carreras 2012). IPS has a progressive nature, and patients with progression to respiratory failure and need for mechanical ventilation have a very poor prognosis with 95% mortality.

# **10.7.3 Risk Factors**

For IPS, the following risk factors have been identifed (Diab et al. 2016):

Pre-transplant pulmonary function abnormalities have also been associated with early respiratory failure and mortality (Chien et al. 2005).

# **10.7.4 Diagnosis**

The most common signs and symptoms are fever, non-productive cough, rales, dyspnoea, tachypnoea and low saturation, with an increasing need for oxygen support.

The diagnosis will be based on alveolar injury confrmed clinically, radiologically and/or functionally. X-ray will reveal diffuse pulmonary infltrates. Infection must have been ruled out by negative cultures and tests in bronchoalveolar lavage (BAL) or lung biopsies (Zhu et al. 2008), and there should be no evidence of cardiac dysfunction, acute renal failure or treatment-related fuid overload. It is however considered possible that some cases of IPS may be caused by an unidentifed underlying infection since infections may lack typical signs and symptoms in the neutropenic patient. The IPS diagnosis can thus be supported by lack of improvement despite broad-spectrum antibiotics and other antimicrobial drugs.

The typical onset will be around day +20, but IPS may also present later after HSCT, which is why it is important to be on alert for this complication, also after discharge from the hospital, in the outpatient setting.

There are no standard guidelines for diagnosis and evaluation of PC after HSCT, but the course of illness should be considered when differential diagnoses are to be excluded. When symptoms occur, IPS may rapidly progress to pulmonary dysfunction requiring mechanical ventilation.

# **10.7.5 Prevention**

For patients at risk for IPS, careful consideration of treatment options pre- and post-transplant such as avoiding conditioning with TBI or highintensity regimens and choice of GvHD prophylaxis may be benefcial. Monitoring of pulmonary function and symptoms after transplantation will enable prompt intervention.

In patients with decreased lung function prior to HSCT and suspected lung injury in the posttransplant setting, close collaboration with pulmonary specialist or the intensive care team may prevent progression of pulmonary dysfunction (Elbahlawan et al. 2016).

# **10.7.6 Treatment**

Beyond supportive care, there is no proven treatment for IPS. In auto-HSCT patients, corticosteroids can be effective, but this is usually not the case for allo-transplanted patients, irrespective of steroid dose. Studies with etanercept, a TNF-αbinding protein, given in combination with corticosteroids, have reported improved pulmonary function in patients with IPS following allogeneic HSCT and may be considered (Carreras 2012), although a small but later study (Yanik et al. 2014) could not confrm the beneft of this treatment.

# **10.7.7 Nursing Aspects**

The close monitoring and daily nursing assessments that apply for all HSCT patients should be employed. Depending on risk factors, extra attention may be needed to early and subtle symptoms of pulmonary dysfunction, such as decrease in saturation, shortness of breath and cough. Monitoring of daily weight and fuid balance, with administration of diuretics if necessary, will prevent and rule out fuid overload. Several different tests and examinations may be performed to establish or rule out the diagnosis of IPS. Sputum cultures and laboratory tests, such as polymerase chain reaction (PCR) for mycoplasma, and serum galactomannan for *Aspergillus* may need to be obtained and chest X-ray or computed tomography (CT) scan performed to rule out infection. In case a BAL, with or without transbronchial biopsy, will be performed, information to the patient and preparation prior to the procedure as well as support both before and after and post procedure monitoring is important. The BAL may add substantial discomfort, in particular to an already seriously ill patient. Other lung function tests may also be repeated, for comparison with pre-transplant results.

When corticosteroids are administered, the blood glucose levels should be followed daily, and the patient should be informed of and assessed for other side effects, e.g. insomnia. Oxygen therapy may need to be administered and non-invasive positive-pressure ventilation necessary. Respiratory diffculties generate anxiety, and the patient should be offered psychological support as well as assistance with positioning and breathing techniques and exercises. Medication for anxiety may be necessary. Referral to a physiotherapist, respiratory therapist or other staff with expertise in pulmonary diseases should be made for advice on tools and exercises that may help the patient maintain pulmonary function and prevent worsening of the condition.

If the condition shows no signs of improving, the patient should be prepared for transfer to the ICU.

Identifcation of patients at risk, prompt intervention to signs and symptoms of pulmonary dysfunction and close collaboration within the team will increase the chances of a positive outcome.

# **10.8 Difuse Alveolar Haemorrhage**

# **10.8.1 Defnition**

Diffuse alveolar haemorrhage (DAH) is a lifethreatening pulmonary complication occurring after allogeneic HCST without an explicit aetiology or a standard treatment (Park 2013; Wu et al. 2021). It is differentiated from idiopathic pneumonia syndrome (IPS) through confrmation of pulmonary haemorrhage by bronchoscopy and bronchoalveolar lavage (BAL). The bleeding can be either insidious, causing a gradual pulmonary dysfunction, or a more acute bleeding into the alveolar space. Damage to the alveolar-capillary barrier from conditioning treatment and the engraftment process with recovery of neutrophils leads to entry of blood into the alveolar space.

# **10.8.2 Incidence and Prognosis**

An approximate incidence of around 2% up to 20%, with a mortality rate ranging between 50% and 100%, has been reported for DAH in HSCT recipients (Afessa et al. 2002; Majhail et al. 2006; Carreras 2012; Wu et al. 2021). The incidence is similar between auto- and allo-HSCT.

The implication of prognostic factors has not been well studied, but early-onset DAH (within the frst 30 days after transplant) in patients undergoing auto-HSCT has a favourable prognosis.

# **10.8.3 Risk Factors**

Risk factors for the development of DAH in HSCT recipients include:

# **10.8.4 Diagnosis**

Among the initial symptoms of DAH, dyspnoea (90.2%) comes frst, followed by haemoptysis (45.7%) and fever in 29.3% of patients (Wu et al. 2021). Hypoxemia may be present, and diffuse or focal interstitial or alveolar infltrates can be found on chest X-ray or computed tomography (CT) scan. With such fndings, bronchoscopy with BAL and transbronchial biopsy is indicated, although performing these invasive tests in patients with severe illness and unstable respiratory status is a challenge.

The diagnosis is based on BAL fndings, which become progressively more blood stained, indicating blood in the alveoli. Other causes, such as heart failure and fuid overload, should be excluded. Infection needs to be ruled out by obtaining relevant cultures. Presence of hemosiderin-laden macrophages in BAL fuid is not diagnostic for DAH but may support the diagnosis.

It is often very diffcult to differentiate DAH from IPS and the ES form of respiratory distress (PERDS). IPS is more common in allo-HSCT, after engraftment, and does not respond to corticosteroids and has a more progressive nature. In PERDS, the majority of patients do not have BAL fndings, becoming progressively bloodier.

The mean onset of DAH has been reported on day 24 after transplant and 6 days after absolute neutrophil count (ANC) recovery.

# **10.8.5 Prevention**

Reversal of some risk factors, e.g. choice of conditioning treatment, may be possible, but otherwise no prophylaxis exists.

# **10.8.6 Treatment**

Corticosteroids, using methylprednisolone followed by slow tapering, is considered frst-line treatment even if effcacy can be questioned. With early diagnosis and treatment with steroid therapy, respiratory failure can often be prevented. Non-invasive ventilation may decrease mortality although the majority of patients with DAH require mechanical ventilation, and sepsis and MOF/MOD will cause death in a large proportion of patients (Rabe et al. 2010).

Other pharmacological therapies, as well as plasma exchange, have been tried for treatment of DAH. Recombinant factor VIIa (rFVIIa) has been administered and achieved temporary control of bleeding. Tranexamic acid or the TNFα-inhibitor etanercept has been used in addition to corticosteroids but have not proved to be effective.

Transfusion of platelets and red blood cells (RBC) may be necessary.

# **10.8.7 Nursing Aspects**

Patients need frequent monitoring for early detection of any pulmonary symptoms. Respiration rate and saturation should be assessed together with temperature and other standard assessments. If cough is noted, this should be reported to the team and the treating physician. Cultures and blood tests may be necessary to rule out infection. Cultures should be performed according to signs and symptoms, but screening cultures can be collected to possibly enable detection of occult infection. The patient's circulatory status and fuid balance should be controlled by monitoring pulse, blood pressure, weight and input and output.

The patient should be instructed to report all symptoms, and if BAL and lung biopsy will be performed, patient information and support throughout the whole procedure is vital. Administration of transfusions, oxygen therapy and non-invasive ventilation should be performed as ordered, and since dyspnoea and other breathing diffculties are associated with a great deal of anxiety, patient support, sometimes with pharmacological treatment, is crucial. Proper positioning together with breathing exercises using appropriate breathing technique may alleviate some discomfort.

During high-dose corticosteroid treatment, blood glucose should be monitored, and it is important to be alert to steroid-related changes in the patient's mental status.

# **10.9 Transplant-Associated Thrombotic Microangiopathy (TA-TMA)**

# **10.9.1 Defnition**

Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognised complication of hematopoietic stem cell transplant (HSCT) with high morbidity and mortality (Young et al. 2021). It is characterised by a triad of endothelial cell activation, complement dysregulation and microvascular haemolytic anaemia and has the potential to cause end organ dysfunction, multiple organ dysfunction syndrome and death, but clinical features mimic other disorders following HSCT, delaying diagnosis.

# **10.9.2 Incidence**

The incidence will vary with the criteria used to diagnose TMA. In retrospective data, the incidence is approximately 4% in auto-HSCT, and 7% has been reported in allo-HSCT (Carreras 2012), whereas one prospective study has shown an incidence close to 40% (Jodele et al. 2015). Conditioning intensity, myeloablative (MAC) versus reduced (RIC), has not shown any difference in incidence in allo-HSCT. The gold standard for diagnosis of TA-TMA is based on characteristic histologic fndings, although bleeding risk often precludes tissue diagnosis (Young et al. 2021).

# **10.9.3 Prognosis**

As with many early complications in HSCT, prompt recognition of early signs and symptoms with early diagnosis and intervention will increase the chances of a positive outcome. Cases of mild TMA where calcineurin inhibitor (CNI), e.g. cyclosporine, tacrolimus and sirolimus, is the cause generally have a good prognosis if CNI can be discontinued. If TMA is not related to CNI treatment, the prognosis is worse due to lack of effective treatment options. Exact fgures for mortality rate are diffcult to establish, but in patients with TMA and multi-organ involvement, the mortality could be as high as >90%.

# **10.9.4 Risk Factors**

Use of total body irradiation (TBI) in conditioning treatment, CNI, graft-versus-host disease (GvHD), infections (e.g. cytomegalovirus (CMV) and fungal infections) and unrelated donor transplant (in particular if mismatched) are all considered risk factors or triggers for TMA, although reported data is conficting (Nadir and Brenner 2012; Rosenthal 2016).

# **10.9.5 Diagnosis**

TMA usually has an onset between 1 and 2 months after HSCT but can be seen both earlier and later.

Several slightly different criteria for diagnosis of TMA are being used (Sahin et al. 2016). See adapted Table 10.11. The diagnosis is diffcult but

**Table 10.11** TMA diagnostic criteria

a Ho et al. (2005)

b Ruutu et al. (2007)

c Cho et al. (2010)

d Jodele et al. (2015) can be confrmed with a biopsy tissue sample although this invasive test may not always be an option for the seriously ill HSCT recipient. TMA has clinical similarities with idiopathic thrombotic thrombocytopenic purpura (TTP), and laboratory testing for the von Willebrand factor regulator ADAMTS13 can be performed to support the diagnosis. In classical TTP, there is a severe defciency, while no signifcant decrease of ADAMTS13 is seen in TMA (Graf and Stern 2012).

Renal TMA should be suspected if the patient requires higher doses of antihypertensives than would be expected considering the situation and concomitant and/or nephrotoxic medication. Example of a differential diagnosis is virusrelated nephropathy.

Symptoms such as tachycardia, chest pain and hypoxemia should lead to suspicion of lung involvement and pulmonary hypertension. The diagnosis can be supported by fndings of cardiomegaly on chest X-ray, pericardial effusion on transthoracic echocardiography and blood tests.

Intestinal TMA presents with the same symptoms as acute GvHD (aGvHD), abdominal pain, diarrhoea, vomiting and gastrointestinal bleeding. The symptoms can also be mistaken for infectious colitis, but in TMA, the cause of the bleeding is ischemia in the bowels due to microangiopathy. In addition to the general diagnostic criteria, specifc criteria for gastrointestinal TMA have been proposed. Besides the clinical symptoms, X-ray fndings with signs of ileus and thick mucosal wall and endoscopy with mucosal erosions and haemorrhages are included in the gastrointestinal TMA diagnostic criteria, but the only defnite diagnostic test is a biopsy tissue sample.

As a result of generalised vascular injury in TMA, polyserositis with pericardial and pleural effusion and ascites can occur. It can easily be mistaken for GvHD, but where GvHD is more seldom associated with microangiopathic anaemia, proteinuria and hypertension, these symptoms are common in TMA.

# **10.9.6 Prevention**

No specifc prophylaxis exists, so vigilant monitoring of clinical signs and symptoms is necessary. CNI concentration in blood, lactate dehydrogenase (LD or LDH) and serum creatinine should be closely followed, i.e. two to three times/week, with laboratory testing. Additional blood tests with peripheral blood smear, haptoglobin and direct and indirect antiglobulin tests (DAT and IAT) should be performed if an increase is seen in CNI, LD and creatinine levels.

# **10.9.7 Treatment**

There is currently no established treatment for TMA, but supportive measures should always be taken. Traditionally, the frst step is to discontinue CNI, despite paucity of evidence for this action. It is also important to treat infections, GvHD and hypertension. Changing to other GvHD prophylaxis and use of antimicrobial drugs should be based on a risk-beneft assessment where, for example, nephrotoxicity is considered. Administration of diuretics may be necessary to treat fuid and sodium retention due to steroid treatment. Vasodilators and renin-angiotensin antagonists may also be used to treat hypertension.

It is recommended to restrict platelet transfusion in microangiopathic disease, but this is often impossible due to the need to prevent bleeding complications.

A potential treatment for TMA is eculizumab. Eculizumab stops the complement-activating cascade preventing formation of C5b-9. This leads to hampering of the intravascular haemolysis. Eculizumab has shown effect when started early after diagnosis (Jodele et al. 2015). Monitoring for effect by following serum concentration levels is important, and dose adjustments may be necessary to reach and maintain the desired therapeutic levels and effect.

In a small number of cases, successful treatment with rituximab and other monoclonal antibodies has been reported.

Treatment attempts have also been made with defbrotide at the same dosing as approved for treatment of severe sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) but with variable results.

Total plasma exchange (TPE) has been tried due to the clinical similarities between TMA and TTP, but where TTP can be successfully treated with TPE, it is not recommended for TMA due to poor response rates.

# **10.9.8 Nursing Aspects**

Careful assessments will facilitate early diagnosis of, or ruling out, TMA and thus improve the outcome. Close monitoring of vital signs and being alert to any changes or trends is standard. Keeping track of fuid balance and weight is equally important. Blood pressure should be kept below 140/90 in adult patients (Jodele et al. 2015). The patient's urine should be monitored for proteinuria and the patient instructed about what abnormal fndings and symptoms to look for and to notify staff of any discomfort including signs of gastrointestinal bleeding. If invasive tests such as biopsies are to be performed, proper preparation and support is vital.

If pharmacological treatment with eculizumab is started, serum level concentration needs to be followed. Treatment with rituximab and defbrotide should be administered as ordered, and the patient should be monitored accordingly for effect and side effects.

Since the onset of TMA can occur after discharge from the transplant unit, it is important to be observant to symptoms and consider this diagnosis even in the outpatient setting.

**Acknowledgements** Nordic Oral Care in Cancer Group, United Kingdom Oral Management in Cancer Group, European Oral Care in Cancer Group.

# **References**

Stringer AM, Yazbeck R, Elad S, Lalla RV. Emerging evidence of the pathology of mucositis. Support Care Cancer. 2013;21:3233–41.

incidence and predisposing factors. Hepatology. 1984;4:116–22.

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# **Supportive Care 11**

S. J. van der Linden, M. E. G. Harinck, H. T. Speksnijder, Teija Schröder, Ien Schlösser, Vera Verkerk, Michaela van Bohemen, A. M. Rusman-Vergunst, J. C. Veldhuijzen, and W. J. A. Quak

#### **Abstract**

Hematopoietic stem cell transplantation (HSCT) care is highly complex. This chapter focuses on the aspects of supportive care required following HSCT.

Assessment tools are key component of nursing practice and are necessary for planning and providing patient-centered care. HSCT care must be planned, implemented, and evaluated and is underpinned by collaboration with the entire multidisciplinary healthcare team.

e-mail<EMAIL_ADDRESS><EMAIL_ADDRESS><EMAIL_ADDRESS><EMAIL_ADDRESS><EMAIL_ADDRESS><EMAIL_ADDRESS><EMAIL_ADDRESS><EMAIL_ADDRESS>
H. T. Speksnijder Rotterdam University of Applied Sciences, Rotterdam, The Netherlands e-mail<EMAIL_ADDRESS>
T. Schröder Helsinki University Hospital for Children and Adolescents, Helsinki, Finland e-mail<EMAIL_ADDRESS>
With supportive care following HSCT, we ultimately aim to improve the quality of life of our patients in the posttransplant period.

Supportive care extends beyond symptom management and includes social, psychological, and spiritual care. The needs of the patient are multifactorial and can be complex, considering multiple issues at the same time and involving multiple disciplines.

Throughout supportive nursing care, our clinical competence is critical and is complemented by experience, knowledge, and awareness.

#### **Keywords**

Supportive care · Assessment · Early warning scores · Oral care · Nutrition · Allied health professionals · Transfusion · Physiotherapy · Spiritual care · Complementary therapies · Music · Touch · Massage · Pediatric

# **11.1 Nursing Assessment**

Highly specialized and complex nursing care is essential for the disease- and treatment-related health problems of patients with hematological diagnoses (Kluin-Nelemans and Tanasale-Huisman 2013). The diagnoses within hematology are diverse but generally associated with a specifc set of symptoms. Hematological diseases

S. J. van der Linden (\*) · M. E. G. Harinck ·

I. Schlösser · V. Verkerk · M. van Bohemen ·

A. M. Rusman-Vergunst · J. C. Veldhuijzen · W. J. A. Quak Erasmus MC, Rotterdam, The Netherlands

can be broadly divided into malignant and nonmalignant hematological diseases. The underlying hematological disease and cumulative effects of previous therapy can infuence the degree and range of side effects and symptoms experienced following HSCT conditioning therapy. These effects can manifest as physical complaints such as fatigue, fever, infection, and bleeding and can result in complex illness necessitating specialist care and treatment. Psychological concerns are common and can frequently manifest as lowlevel anxiety and depression and less often as features of signifcant trauma. As a key element of the multidisciplinary team, nurses are ideally placed to identify and assess symptoms due to illness or treatment at an early stage. HSCT nurses have extensive knowledge that contributes to treatment optimization. Assessment is undertaken frequently to refect the dynamic nature and rapidly changing clinical picture and will take into account the patient's vital signs, blood results, and symptoms as well as knowledge of their baseline physical function. By taking the medical and social history of the patient into consideration, we can increase our awareness of the potential care problems that may arise. The understanding and assimilation of information derived from these sources in conjunction with standardized assessment tools and instruments enable measurable and objective care delivery.

# **11.2 Pain Assessment**

In certain hematological diseases such as lymphoma or multiple myeloma, patients experience pain as a result of the compression of the lymph nodes or bone destruction. In some cases, patients are reluctant to report symptoms of pain to their attending physicians in case this is interpreted as a poor treatment response. It is imperative to consider both verbal and nonverbal signs and symptoms of pain to complete a comprehensive assessment.

The bedside nurse is well placed to assess their patient and explain the importance of adequate pain management using pharmacological and supportive measures. Improving the patient's comfort will enable them to better tolerate treatment and improve their experience.

In the HSCT setting, pain is most commonly experienced as a result of mucositis, but patients will also report other pain such as bone pain associated with GCSF, abdominal pain due to diarrhea, or general discomfort with fuid accumulation.

Not all reported pain symptoms or discomfort is treated in the same way. By explaining to our patients the possible cause of the pain and the treatment for it, we can also help manage their expectations of the analgesia and other supportive interventions. We should inform our patients of the common side effects of analgesia like drowsiness and constipation and ways of reducing these effects.

When assessing pain, a standardized tool should be applied to ensure consistency across patients and between assessments. A comprehensive evaluation of the pain, location, characteristics, onset, duration, frequency, severity of pain, and exacerbating and relieving factors should be included. This assessment should be supported by the patient's nonverbal reactions such as facial expression, pallor, tempo of speech, body position, etc. as well as their vital signs.

According to Kluin-Nelemans and Tanasale-Huisman (2013), a nurse can give the patient information and tips and tricks in the feld of pain relief:

# **11.3 The Role of Early Warning Scores**

# **11.3.1 Early Warning Scores in the Adult Setting**

Observing vital signs is a crucial task in the care of the HSCT patient. The patient's condition can change dramatically in a short period of time due to treatment and illness. Various measuring instruments allow us to monitor vital functions. Early warning scores are used as a prediction model of adverse events. When a patient shows signs of deteriorating, the early warning score is supposed to identify this and warn the nurse (Morgan et al. 1997). The Modifed Early Warning Score (MEWS), one of the most cited models (Subbe et al. 2001), shows when values of vital functions deviate and indicates when intervention is required.

The MEWS (Subbe et al. 2001) scores various items (Table 11.1):

In addition, decreased urine production, SaO2 < 90% with adequate O2 therapy, and the nurse's awareness or "gut feeling" give increased value to existing scores (Ludikhuizen et al. 2012). If the score is moderately elevated, it is advisable to monitor the vitals more often and to inform the attending physician. When the score increases, continuous monitoring is necessary, and evaluation from an emergency intervention team or a medical emergency team should be requested. These teams are available in most HSCT centers and usually consist of a doctor and an intensive care unit (ICU) nurse/emergency nurse. Compared to the traditional MEWS, a MEWS-SF score was studied to identify deteriorating patients with hematological malignancies even better. In the MEWS-SF, the SpO2/ FiO2 (SF) ratio has been added to identify the oxygenation index as indication of lung functioning (Lee et al. 2020).

Standardized, structured communication techniques may help the nurses give an adequate and clear overview of the current state of a patient (Dayton and Henriksen 2007). The mnemonic SBAR (Situation, Background, Assessment, Recommendation) is the most well-known technique used in healthcare (Riesenberg et al. 2009). However, in a recent systematic review (Lo et al. 2021), the measured communication improvement using the SBAR in clinical settings had small-tomoderate effects. When SBAR was used together with multi-face interventions like early warning scores or rapid response systems, improvements in patients outcomes were measured.

**Table 11.1** Modifed early warning score

Subbe (2001)

# **11.3.2 HSCT and Intensive Care**

The outcomes of HSCT patients have been greatly improved over recent decades due to new therapies and improvements in supportive care (Saillard et al. 2016). An ICU admission is sometimes necessary to treat life-threatening situations that can arise following HSCT.

Reasons for admission might include:

Treatment in the ICU consists of:

Both short-term and long-term survival of critical ill HSCT patients have improved signifcantly in recent years (Lueck et al. 2018; Netters et al. 2010; Ven van der et al. 2009). When a hematological patient is admitted to ICU early in their course, the chance of survival is greater (Peigne et al. 2009). Early admission reduces further organ dysfunction and increases the probability of reversing existing organ failure by delivering timely and appropriate organ support. The modifed early warning score (MEWS) may contribute to this early recognition and prompt referral to ICU.

When the patient is well enough to return to the HSCT unit, fear of relocation may occur. This can happen because the continuous monitoring of vital functions ceases and the ward environment is very different from that of the intensive care. The patient may experience stress and anxiety and should be prepared at ICU for the transfer to the HSCT unit, taking into account the psychological effect of relocation to both patient and family (Coyle 2001).

# **11.3.3 Early Warning Scores in the Pediatric Setting**

As noted by Agulnik et al. (2016), hospitalized oncology and HSCT patients are a high-risk population with frequent clinical decline requiring unplanned PICU transfer and high mortality rates. Complications developed by these patients, such as sepsis and respiratory failure, are known to have better outcomes with earlier identifcation and management.

It is important to know the normal vital signs in children in different ages. That is the basis which helps recognize the early warning signs in children. The use of PEWS scores as an assessment tool has the potential to quantify the severity of illness in children (Murray et al. 2015).

In reference to Agulnik et al. (2016), PEWS has been implemented in many pediatric institutions. Their study demonstrates that the PEWS tool is valid in identifying pediatric oncology and HSCT patients requiring unplanned PICU transfer. In a recent study, they concluded that hospitalized pediatric hematology-oncology and post-HCT patients have frequent deterioration resulting in a high mortality (Agulnik et al. 2022). Critical deterioration is preceded by a long duration of abnormal vital signs. This implicates the use of the PEWS to early predict critical deterioration.

The use of PEWS scores as an assessment tool has the potential to quantify the severity of illness in children. It is hoped that this results in facilitating early identifcation of patients at risk for clinical deterioration and prompt intervention to avoid the need to transfer to a higher level of care (Murray et al. 2015).

# **11.4 Nutritional Assessment**

The malnutrition universal screening tool (MUST) is a validated screening tool for recognition and treatment of malnutrition (Elia 2003). The MUST form must be flled in accurately upon admission, asking for length/height, weight, and weight loss and whether the patient has no food intake for several days.

**Fig. 11.2** Bioelectrical impedance analysis (BIA)

**Fig. 11.1** Hand dynamometer

The HSCT patient often has a reduced dietary intake during and following conditioning therapy, but this is often not considered at the time of admission.

Sometimes weight loss is diffcult to assess due to fuid gain. It is not always possible to determine what proportion of muscle or fat components account for the weight loss using conventional methods.

The measuring instruments deployed to obtain information about muscle function and muscle mass are the hand clamp and the bioelectrical impedance analysis (BIA).

The hand clamping force gauge (see Fig. 11.1) can be used to measure the maximum crushing force. The maximal squeezing force of the hand gives a good estimate of the peripheral muscle function and is related to the total amount of muscle mass in the body. Hand force depends on age and gender. It can also be infuenced by other factors, such as disease. By obtaining different hand tightness measurements during the course of treatment, it can be determined whether the patient's muscle function increases or decreases (Norman et al. 2011).

A bioelectrical impedance analysis (BIA) (see Figs. 11.2 and 11.3) is a tool measuring the resis-

**Fig. 11.3** BIA resistance. (Photo credit http://www. nutritionalassessment.azm.nl/algoritme+na/onderzoek/ lichaamssamenstelling/bia.htm)

tance that the body provides for an alternating current of 50 kHz (Ursula 2004). The fat-free mass is calculated using a formula incorporating the resistance, length, weight, gender, and age. With this measurement, we can assess whether a patient with weight loss has lost muscle mass and/or fat mass. Determining the fat-free mass with the BIA is not reliable if there is an abnormal hydration status (Kylea et al. 2004).

# **11.5 The Role of Allied Health Professionals**

In the care of the HSCT patient, collaboration between different supporting disciplines is of

# **11.6 Principles of Nutritional Support**

Patients undergoing HSCT experience intensive treatment with chemotherapy, sometimes in combination with total body irradiation (TBI), increasing their risk of weight loss and malnutrition. Furthermore, some recipients may already be malnourished prior to transplant as a consequence of induction therapy or infection and are at risk of further signifcant nutritional compromise during and following transplant.

# **11.6.1 Nutritional Problems in Intensive Chemotherapy Treatment**

# **<IP_ADDRESS> Reduced Resistance to Infection**

Following intensive chemotherapy, the patient has reduced tolerance due to neutropenia and/or increased intestinal permeability. In neutropenia, the number of white blood cells decreases signifcantly, resulting in the so-called aplasia with an increased risk of infection. The patient is neutropenic if the neutrophil granulocytes (subdivision of the leukocytes) are less than 0.5 × 109 /L. An increased permeability of the intestinal wall is caused by intensive chemotherapy damaging the gastrointestinal mucosa. As a result, pathogenic bacteria (bodily bacteria or bacteria from the diet) can enter the bloodstream (sepsis or blood poisoning). The patient has an increased risk of infection due to the reduced resistance. If the patient is expected to be neutropenic for longer than 7–10 days after chemotherapy, antimicrobial prophylaxis may be given because of the high risk of infection. In some centers, the patient may commence this prophylaxis (selective intestinal contamination, SDD) at the time of conditioning therapy. These specifc antibiotics select out the patient's own aerobic, potentially pathogenic intestinal fora and remove them (Bouakline et al. 2014).

To prevent food-mediated infections, the Hygiene Nutrition Directive or "neutropenic diet" or "clean diet" guidelines are implemented (Sonbol et al. 2019). This directive is usually followed from the start of conditioning therapy until discontinuation of the SDD or neutrophil recovery. The National Consultation Dietitian Hematology and Stem Cell Transplantation in the Netherlands has written the Hygiene Nutrition Directive, which is the basis for all hospitals in the Netherlands. There are small differences between several hospitals (LODHS 2020).

# **<IP_ADDRESS> Food Aversion, Taste and Smell Changes, and Bad Taste in the Mouth**

Intensive chemotherapy, as well as other medications such as antibiotics and antifungal agents, adversely affects the senses of taste and smell. The infuence of the disease itself can also affect taste, and taste may be reduced, and/or there may be increased sensitivity to all favors and smells. Aversions to specifc foods, enhanced favor or taste sensation, or a bad taste (metal, cardboard, or sand favor) is frequently reported. Sometimes, the taste perception does not match with the taste memory. Patients may also be more sensitive to odors and can fnd that many foods or products like perfume or cleaning agents smell unpleasant.

#### **<IP_ADDRESS> Nausea and Vomiting**

Cytotoxic treatment is often associated with complaints of nausea and vomiting. Medication to reduce nausea and vomiting (antiemetics) and hydration infusions are given and often adjusted. Nausea and vomiting after chemotherapy can occur acutely (4–24 h) and is often severe. The symptoms may also occur later (2 or several days to sometimes a few weeks after the chemotherapy) (Hesketh et al. 2018). There is usually no association between vomiting and the type of diet used. As the patient undergoes multiple chemotherapy cycles, anticipatory vomiting may occur. In this case, vomiting occurs prior to the treatment in response to previous chemotherapies and is triggered by memory, experience, smell, taste, and sometimes visual cues.

# **<IP_ADDRESS> Reduced Appetite and Early Satiety (Full Feeling)**

Intensive chemotherapy, as well as other medications, infections, and fever, can cause a reduced appetite and feeling of early satiety or fullness. As a result, a reduced dietary intake may occur, which may adversely affect the nutritional state.

# **<IP_ADDRESS> Mucositis (See Oral Complications Section for Further Information)**

Mucositis (oral and gastrointestinal) frequently occurs after conditioning therapy. The grade depends on the type and intensity of chemotherapy. Chemotherapies that are associated with mucositis are busulfan, etoposide, melphalan, and methotrexate (van Sebille et al. 2015). Mucositis can occur in the mouth and throat (orally) and in the rest of the gastrointestinal tract (gastrointestinal).

Oral mucositis can vary widely starting with sensitive gums (mucositis grade 1); the patient is often able to eat everything, until blisters and ulcerations appear in the mouth, and then the patient has even diffculty drinking sips of water (mucositis grade 4, according to the WHO scale) (Özlem and Sümeyye 2021). Good oral hygiene is very important to limit complications associated with oral mucositis. Mucositis usually occurs 4–10 days after the conditioning and lasts about 2–3 weeks. As soon as the leukocytes start to rise to normal values, the mucositis heals rapidly.

In severe mucositis, oral nutritional intake is usually inadequate, and the patient is recommended for nutritional intervention. Gastric feeding with a tube through the nose (tube or nasogastric feeding) is preferred over parenteral nutrition, because it is physiologically more natural and reduces the risk for intestinal atrophy (Lieshout et al. 2020). The main contraindication of tube feeding is the risk of bleeding due to ulcerations in the gastrointestinal tract.

Insertion of a nasogastric feeding tube is safe when there is mucositis grade 1 or 2 and if there are suffcient platelets (at least 40 × 109 /L). Otherwise, the patient frst needs platelet transfusion for placement of the tube. When the severity of the mucositis is too great to introduce a tube, parenteral nutrition is the remaining option.

Diarrhea, due to gastrointestinal mucositis, is a common complaint following conditioning therapy. It is important to pay attention to dietary fber, electrolytes, and hydration. Patients with severe watery diarrhea have reduced nutritional absorption through the gut, and parenteral nutrition may be indicated.

When the patient is discharged from the hospital after HSCT, dietary intake is often still not optimal and particularly after allogeneic myeloablative conditioned (MAC) stem cell transplantation. The patient often reports a dry mouth, nausea, vomiting, and early satiety. These patients beneft from ongoing nutritional monitoring and support for some time in the outpatient setting. Additionally, these patients can have increased energy demands due to the treatment, and further interventions may need to be considered such as tube feeding at home to limit further weight loss and restore nutrition.

In general, following autologous HSCT, there are less complications and infection-related problems. However, following allogeneic HSCT, it takes several months for the immune system to recover; hence, these patients are susceptible to infections for quite some time. In addition, the immune system is suppressed with medication to prevent graft rejection and to prevent or treat GvHD.

# **11.7 Transfusion**

# **11.7.1 Introduction**

Blood transfusion is an essential element of supportive care for many hematological disorders, and HSCT recipients will almost always require transfusion support during aplasia. Importantly, HSCT recipients will usually require product irradiation to prevent transfusion-associated GvHD (tGvHD). This section covers general information on blood transfusion. Please refer to your local and national transfusion directive or policy for further details.

# **11.7.2 Blood Products and Indication**

Different types of blood products can be transfused: erythrocyte concentrate, platelet concentrate, and plasma. The most commonly used blood product is erythrocyte concentrate (Sanquin 2016). Erythrocyte concentrate is administered in severe anemia, where insuffcient hemoglobin reduces oxygen transport capacity. There may be acute anemia, for example, due to bleeding, or chronic anemia, for example, due to a chronic disease.

Platelet concentrate is administered to correct thrombocytopenia to prevent or treat bleeding. The indication for administration of prophylactic platelets depends on the patient's condition and whether the patient requires a higher circulating platelet count to treat, limit, or prevent bleeding. For the correct transfusion threshold, see the local transfusion guideline. Different transfusion thresholds are used internationally.

Plasma is administered to help correct coagulation factors. The indication for plasma transfusion is usually based on PT/APTT and fbrinogen content in the blood.

In summary, the indication for transfusion is based on the clinical situation of the patient and laboratory diagnostics.

# **11.7.3 Blood Groups and Pretransfusion Investigations**

In order to select the correct blood product for a patient, the determination of the ABO and Rhesus blood group is necessary. For transfusion of platelet concentrates and plasma, this is suffcient. In addition to the ABO and Rhesus blood group systems, there are many more systems such as *Duffy*, *Kidd*, and *MNS*. For the administration of erythrocytes, it is important to screen the patient prior to transfusion for irregular antibodies in addition to the ABO and Rhesus blood groups. These antibodies are usually not naturally present in the blood but can be acquired at each pregnancy and may increase with chronic transfusion need. Depending on the number and type of antibody, it may be diffcult to fnd the appropriate erythrocyte concentrate. Following allogeneic stem cell or cord blood transplantation, the stem cell donor blood group(s) as well as recipient blood group should also be taken into account. For example, in case of double cord blood transplantation, up to three different ABO blood groups may need to be taken into account. In case of emergency and if there is no time for determining a blood group, erythrocytes with blood group "O negative" must be administered. Blood group O negative is the universal donor for erythrocytes (Table 11.2).

Platelet antibodies such as HLA (human leukocyte antigen) antibodies may also need to be considered. These antibodies may develop after prior transfusions and/or pregnancy. Sometimes HLA antibodies result in no or low increment after platelet transfusion. For these patients, platelet donors are selected as the best possible match at HLA level. This is an intensive process, and sometimes, only a very small number of platelet donors are identifed for a particular patient. In these cases, it may take longer than usual to obtain platelets for the patient, and in an emergency, "random donor" platelets may be prescribed until the matched platelets become available. For plasma transfusion, only the ABO blood group is important (Table 11.3). Note: Blood group AB is the universal donor. In plasma, the Rhesus blood group does not need to be considered since the Rhesus blood group is on the membrane of the erythrocyte.

**Table 11.2** Blood group compatibility for erythrocytes

**Table 11.3** Blood group compatibility for plasma

It is known that some drugs can interfere with the accuracy of pre-transfusion investigations in the laboratory. An example of this is daratumumab (monoclonal Ab anti-CD38). It is therefore important, upon request of serological testing, to provide the laboratory with all relevant medical information and transfusion history, including transplantation, pregnancy, previous serious transfusion reactions, and the use of relevant medication such as fudarabine (purine analog).

# **11.7.4 Processed Blood Products**

Sometimes, blood products need to be processed. In addition, erythrocytes and platelet concentrates need to be irradiated and may be washed in some cases. Erythrocytes and platelets are washed in the case of previous severe anaphylactic transfusion reaction or in a patient with IgA defciency. When washing blood products, the plasma proteins are removed as far as possible. In plasma, this operation is not possible. Erythrocytes and platelets are irradiated to damage the T cells in the blood product, preventing these T cells from causing transfusion-associated graft-versus-host disease in patients with risk factors such as HSCT, antithymocyte globulin (ATG), alemtuzumab, and fudarabine. Only thrombocyte and erythrocyte blood products can be irradiated.

# **11.7.5 Transfusion Reactions**

Although today's blood products are very safe, a patient sometimes experiences side effects from transfusion. Table 11.4 shows the symptoms of a possible transfusion reaction that may occur during and up to several hours after transfusion.

Acute transfusion reactions may be caused by administration of an incorrect blood product, volume overload, or bacterial or viral contamination of the transfused product. In addition, there may be an unexpected reaction from the patient. If transfusion symptoms are observed during a transfusion reaction, the transfusion should be discontinued immediately, and the doctor should be alerted. Always leave intravenous access in situ and then follow the instructions of the physician. It is very important to inform the blood transfusion laboratory about the possible transfusion reaction so that the cause can be investigated. This may prevent a transfusion reaction at a subsequent transfusion (Federatie Medisch Specialisten 2022).

In addition to acute reactions, blood transfusions can create long-term effects. For example, if a patient gets a lot of erythrocyte concentrates over a longer period of time, developing iron overload can lead to increased iron stores in organs such as the heart, liver, and kidneys, causing severe damage. This process occurs because erythrocyte concentrate contains iron, and the body does not have a system to break this excess iron down and remove it. However, this can be treated by monthly venesection when the blood counts have normalized after HSCT and if the hemoglobin is not suffcient, by medication such as Exjade or Desferal.

**Table 11.4** Symptoms that may indicate possible transfusion reaction

Vademecum (2020)

# **11.7.6 Hemovigilance**

Hemovigilance is the systematic monitoring of side effects and adverse incidents throughout the donor-to-patient transfusion chain, as well as anything that contributes to safer and more effective use of blood products (Tripnet 2017). In this context, hospitals report transfusion reactions and incidents to their National Hemovigilance Organization. Annually, serious transfusion actions are reported to the EU by the National Hemovigilance Organization.

# **11.7.7 Conclusion**

For a safe blood transfusion, it is important that the correct indication is stated. The laboratory must have all relevant medical information to select the correct blood product. The nurse must verify:

In addition, the patient must be observed closely during transfusion and the doctor notifed immediately of symptoms of possible transfusion reaction. The blood is an organ, and blood transfusion is an organ transplant, which requires maximum care.

# **11.8 Physiotherapy and Exercise**

Over the last years, several clinical trials have contributed to the growing body of evidence showing the benefcial effects of exercise in cancer patients and also in the feld of HSCT. Exercise interventions at different time points during and after HSCT can improve physical performance, quality of life, symptom control, and fatigue. However, it is still not possible to give a clear advice regarding the best type, intensity, start, and duration of an exercise program (Steinberg et al. 2015; Wiskemann et al. 2015; Wiskemann and Huber 2008; Cramp and Byron-Daniel 2012; Knols et al. 2005; Spence et al. 2010; Speck et al. 2010).

In the time period before and after HSCT, a specialized oncology physical therapist can be useful to advise, coach, and support exercise (under supervision). By remaining mobile, complications can be prevented, and the effects of the treatment can be optimized. Depending on the phase that the patient is in, the physical therapist will set goals (by using the "shared decision model" with the patients). The goal can be to stay at the same level during the treatment or improve condition before, during, or after treatment.

Due to the long hospitalization in isolation and the side effects from treatment, exercise can be a challenge. Most patients are not permitted to leave their room, so providing apparatus such as light weights, exercise bands, or static bikes can be helpful. The patient's condition changes day to day, so the physical therapist will need to adjust the expectations to ensure they remain realistic. It is important not to force exercise to maintain safety and prevent strain or injury.

# **11.9 Psychological/Spiritual Care**

# **11.9.1 Introduction**

Psychosocial issues can lead to such a loss of energy that patients become dependent on their partner or caregivers. This is further compounded by fatigue. In addition, physical symptoms such as pain can enhance the sense of dependence. Reduced appetite, insomnia, and side effects of medication can cause depressive feelings, while anxiety and fear can contribute to restlessness, forgetfulness, nausea, and tension. It is important to regularly evaluate these patient's care needs and any additional care or aftercare requirements.

tance) and react in their own way to their diagnosis. They may also experience these emotions during their transplant. Anxiety, sadness, powerlessness, and/or a disturbed body image can cause dysfunction, and it is essential to support the patient to reduce fear and/or discuss their feelings. Enabling a social network around the patient will provide a vital source of support both during and after hospitalization. Prompt referral to a psychologist or possibly a consultative psychiatric nurse (CPN) or a psychiatrist may be necessary for those patients with a history of psychological issues, in those who appear unable to cope emotionally, or where there are any concerns for psychological well-being.

# **11.9.2 Basic Information of Psychological Care for the HSCT Recipient**

Beside the physical impact of the HSCT treatment, there is great impact on the whole psychosocial well-being of the patient (and their relatives). Physical problems continuously interact with the psychological state. The enduring nature of many physical problems demands a huge amount of resilience. This section describes the emotional impact of HSCT therapy and the importance of integrated care, with a focus on the role of the psychologist or consultative psychiatric nurse (CPN) and on the role of the bedside HSCT nurse.

Emotional problems such as depression and fear of relapse may occur and impact adversely on the patients' quality of life (QOL) (Syrjala et al. 2012). Emotional concerns are frequently referred to as psychological distress, which has been defned in Distress Management Version I (Practice Guideline Oncology of National Comprehensive Cancer Network (NCCN) 2002) as "a multi-determined unpleasant emotional experience of a psychological (cognitive, behavioral, emotional), social, and/or spiritual nature that may interfere with the ability to cope effectively with cancer, its physical symptoms, and its treatment."

Distress extends along a continuum, ranging from common feelings of vulnerability, sadness, and fears to problems that may become disabling such as depression, anxiety, panic, social isolation, and spiritual crisis (NCCN 2002).

This description gives suffcient reason to organize an interdisciplinary team of caregivers around this special patient group. "Meeting the needs of a patient requires the multiple competences that many caregivers from different professions will have to share in order to offer the best quality of comfort and care. It is a common practice in which each team member will inculcate his own competencies. This is the essence of interdisciplinary" (Porchet 2006). Braamse, psychologist at Vrije Universiteit, Amsterdam (VUmc), wrote her doctoral thesis about psychological aspects of HSCT in patients with hematological malignancies (2015). Hematological malignancies as well as treatment procedures are associated with impairment in patients' QOL. According to the World Health Organization (WHO), QOL refects a subjective concept, defned as an "individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns" (WHO 2017). Impairments are caused by the original disease, prior treatment, and intensive conditioning therapy. Certain subgroups of patients have more diffculties adjusting to their disease and treatment and consequently experience a more impaired health-related QOL posttransplant compared with other patient subgroups. Suffering from (chronic) GvHD leads to problems with overall QOL and physical well-being. Braamse states (2015): "Other subgroups that are at risk for worse psychological and social functioning are female patients, patients receiving low social support and patients experiencing pretransplant psychological distress." This is consistent with other research (Hill et al. 2011; Nordin et al. 2001) on psychological and social functioning in cancer patients. Receiving low social support had been shown to increase the risk of depression and anxiety. Braamse (2015) indicates that most HSCT patients were not in need of active interventions to improve psychological distress: most patients chose watchful waiting instead of a special online intervention program or additional psychological care. Braamse (2015) concluded that a discrepancy appears to exist between symptoms patients report in the year after transplantation and their need for additional care: it seems that a substantial number of patients who report emotional problems after auto-SCT do not engage in help-seeking behavior. This highlights the great resilience of patients going through all different aspects related to undergoing a HSCT and their strength to cope with it without additional professional help.

# **11.9.3 Role of the Consultative Psychiatric Nurse for the HSCT Patient**

A consultative psychiatric nurse (CPN) visits the HSCT patients in the outpatient clinic, during the "waiting zone" before admission. The patients are screened by protocol, which asks them to share their experiences about:

The CPN gives psychoeducation on various topics, for example, coping, loss of control, and loss of social roles. The screening includes some questions, which indicate if there is a risk of psychiatric decompensation or other increasing problems. The CPN discusses the assessment outcome and possible needs with the patient as well as helpful resources. Extra support by the allied health professionals or other disciplines may also be suggested.

When there is preexistent psychopathology, a special care plan will be described in collaboration with the physician, the psychiatrist, and nurses from the ward. The CPN writes the conclusions and advice in the patient record.

During the hospitalization of these patients, the CPN visits them for a brief consultation and observes how the patient is coping. This is an informal way of counseling. CPNs take part of the weekly interdisciplinary meeting to discuss the complex cases with the nurses and other disciplines. The main goal of the meeting is to give practical advice about the communication and structuring the daily nursing care. The meeting also functions as a mechanism for supporting each other in our work with this patient group, which has great impact on all caregivers.

The experience of the CPN is that many HSCT patients, after hearing the news about their diagnosis, have a "rollercoaster experience." At this point, there is often less time to think about the impact of therapy options due to the pressure to commence therapy. In the weeks between chemotherapy with its (side) effects and waiting for HSCT, patients often begin to consider their dilemma and contemplate their situation. Meanwhile, their physical condition is improving, and they are afraid of losing this as they begin their HSCT journey. Most patients share their experience (while they visit the CPN in the out-clinic setting) about the two emotional pathways: realizing that it is a possibility that they can die and trying to stay strong and positive toward the treatment. They lose their innocence toward staying in isolation and dealing with lots of physical problems. Last but not least, they struggle with their social role and how to manage the loss of or changes to it.

Patients report many examples of when they felt understood by their doctors and nurses. But many patients also report experience of misunderstandings and diffcult and complicated communication with caregivers.

Deweirdt and Vincke (2008) stated how patients report the importance of a family member being allowed to stay for rooming-in while the patient was anxious. For the patient, it is important that their caregivers provide basic, personal attention, inserting in their experience, their concerns, and their irritations.

The phase of recovery varies between patients. Some of them have the feeling of being elderly or aged. Others use their frst energy to spend time at work or with friends, which can affect home relationships and partner interaction.

HSCT patients are frequently readmitted because of infections, GvHD, or other complications. After a long stay in the hospital, each new readmission can add an enormous psychological burden. It is understandable that patients sometimes lose courage. In some cases, patients speak about their boundaries being further threatened by the treatment. They fnd it diffcult to discuss because the doctor did so much good work and can mean that they don't want to refuse further treatment. It can be the role of the CPN to help patients communicate their wishes.

# **The Collaboration Between a CPN and Hematology Nurses on the HSCT Wards**

*Case Examples for This Population*

Case 1

Patient A, male, 21 years old, non-Hodgkin lymphoma (NHL).

Relapsed NHL (initially diagnosed aged 16). He is a student and living independent near the campus. He has a steady relationship for a year, but because of his treatment and functional decline, he has moved back home to live with his mother. His parents are divorced and don't communicate well. He enjoys online gaming until late at night and subsequently wakes up late in the morning.

During his hospitalization, he had some diffculty with the ward routine such as waking up early in the morning and was unfriendly toward the nurses. His mother was very concerned, so she stopped working. She visited her son daily and remained by his bedside for the entire visit even when his girlfriend arrives.

He had fever for several days and mucositis requiring opioid administration, and he experienced nightmares due to analgesia. His thoughts and reactions were slower, and at night, he became more anxious. He couldn't eat normally.

In this case, the CPN can help the nurses with coordinating the communication and the daily routine and to observe for the signs of confusion or hallucinations that might occur despite his young age.

Case 2

Women B, 44 years old, acute myeloid leukemia (AML).

She has a known bipolar personality diagnosis for which she is prescribed lithium. Lithium has a specifc therapeutic range and must be closely monitored through lithium blood levels. Nurses on general wards are often uncertain about the care of patients with a psychiatric diagnosis and about their own (communication) tools and skills. It is understandable that they are unsure about their observations because behavior change can occur as a result of the HSCT and existing psychopathology. The patient and the CPN can work together to process this and support the ward team in the care of these patients.

In these cases, the patterns of reaction on the changed psychosocial situations are very understandable. Patients are not doing things wrong, but sometimes, their reactions or behavior may not have a positive effect on recovery. For each case, it is important that the HSCT nurses use their own observations to contribute to patient care.

In the nursing practice, it can be helpful to consider the following:

Nurses understand that body and mind continually interact, and they need to develop skills to structure and interpret their observations. They should discuss this in multidisciplinary meetings and consider appropriate interventions. Nurses need to be taught how to use evidence-based tools that assess and address this aspect of care.

The patient is the best source of information about the impact of their concerns, coping in normal healthy life, and what might help them at that moment. To promote self-management and shared decision-making, it is necessary that nurses are aware of the diverse resources and how to use them in their own work setting. Even when there are many professionals involved in a patient's care, it does not necessarily follow that they will work in a multidisciplinary manner. Interdisciplinary working is time demanding: time for meetings, dialogue, and questioning teamwork (Porchet 2006).

Coolbrandt (2005) wrote a thesis about keeping and losing courage, a qualitative research in HSCT patients at Gent University Hospital. Coolbrandt (2005) noticed the active role of the nurses in the recovery story of HSCT patients. Like their medical counterparts, nurses contribute to the positive story and support patients in their therapy. Nurses protect the positive story by advising what the patient might expect. When things are going badly, they intervene by explaining the situation. Sometimes, it is appropriate to normalize a situation, and the patients feel less panic. Nurses give positive feedback; patients told that it helped them when the nurses are optimistic. Nurses give comfort when they reassure that symptoms will resolve, and they identify solutions improve symptoms. Nurses are often searching for the balance between "realistic hope and hopeful realism." This study of Coolbrandt (2005) is followed by a study in the same ward about the way hematology nurses care for HSCT patients through the most diffcult part of treatment (Deweirdt and Vincke 2008). We already know, but this study confrms the great importance of an empathic attitude and expertise. This empathic attitude is characterized by understanding what the patient is going through, willingness to adjust the schedule if necessary for the patient, and paying attention to the person behind the patient. The shown expertise, that nurses can normalize concerns and complications, creates confdence in the collaboration between patient and caregivers.

Psychologist Braamse (2015) learns that for some patients, there's often no immediate solution for the problems. Patients have to go through the situation—and they know that very well. They don't expect their nurses and relatives to wear their burden. Patients know that the isolation is inherent of their illness and treatment. But they still need the presence from caregivers and close relatives or to feel them nearby. In this way, they can feel the autonomy to choose their own way of coping with the situation. That autonomy is often affected by the disease and treatment.

Nurses can always refect on themselves with the following basic questions (derived from the authors experience):

These questions can help you go back to your nursing base when the complexity of the cases makes you problematize things too much. When you feel powerless because of the multiple problems, you don't have to forget that your presence is also an intervention.

# **11.10 Therapeutic Interventions, e.g., Complementary Therapies, Music, Touch, and Massage**

In some countries, there are well-being and relaxation departments for the oncologic patients. The goal is to provide the patients with a wide range of recreational activities and with that maximize their well-being during the treatment. Most of the time, such teams consist of a coordinator, an art therapist, a music therapist, and a group of volunteers. In the hospital, they can make a "living room" where patients and their family can come to relax and optionally can partake in a creative activity or a workshop. It consists of four different subdivisions: activity therapies, art therapies, music therapies, and complementary therapies/care. Each division will be specifed below.

# **11.10.1 Activity Therapies**

Activity therapies consist of three different pillars: creative activities, social activities, and a rental service.

# **<IP_ADDRESS> Creative Activities**

Patients can choose from a wide range of creative activities. They can do this on their own, with a volunteer, or with other patients (workshop). For this patient group, most activities take place in the patient room.

Some of the creative activities that we offer include mosaic, jewelry making, painting, drawing, mandala, knitting, and crochet. Special creative volunteers help and provide the patient with creative material. Also workshops can provide special creative activities like (dry)fower arranging and seasonal workshops.

A creative activity provides the patient with a welcome distraction to get through the day. It also helps keep the mind of negative things, and it is a way to make something nice for their loved ones.

#### **<IP_ADDRESS> Social Activities**

Patients regularly stay for long periods of time during their treatment. Some of the patients don't have a big social network and are at risk of becoming lonely during their stay. An initiative "life well-being and relaxation" has special "social" volunteers that visit the patients on a regular basis. The volunteers work with a cart that is flled with all kinds of magazines. With that cart, the volunteer visits every patient on the ward. They make contact with new patients, hand out magazines, and tell what can be offered to them during their stay. They make extra time to visit and talk to lonely patients. Most patients really look forward to the weekly meetings with the volunteers.

# **<IP_ADDRESS> Rental Service (in Some Hospitals/Organizations)**

Patients have the possibility to rent items that will make their stay more pleasant. They can get laptops, game consoles, e-readers, tablets, and audiobook players. Patients can rent DVDs directly from a webpage. Offering board games, puzzles, and handy tools like a book seat (a handy device that makes it possible to put a book or a tablet on the bed without the need of holding it) is some of the special offers you can give to the patient.

# **11.10.2 Art Therapies**

Art therapy focuses on the power of the image, where color and form play an important role. Art therapy can give support when the body, mind, and soul are out of balance because of the physical and mental pressure that comes with being ill. With art therapies, a guiding question or a specifc theme forms the basis for the therapy. Some possible themes are acceptance, coming closer to your inner self, enlightenment, relaxation, and how to handle emotions. With art therapies, the process is the most important aspect. It does not matter if the patient is creative or not; it only matters that the patient is willing and open for the therapy.

There are many different creative forms a patient can choose from: drawing, painting, felting, and molding. A combination of said techniques is also possible. Making a collage or writing poetry can also be offered. The materials that can be used are diverse: pastel chalk, aquarelle pencil, and aquarelle and acrylic paint. The art therapist decides together with the patient what material and technique to use.

Patients make regular use of art therapies. Because of their long stay in the hospital, the art therapist can offer lots of therapeutic sessions to the patients, which make it easier to work on a certain set goal.

# **11.10.3 Music Therapies**

Music therapy focuses on the power of melody, harmony, and rhythm. Music therapy can give support when the body, mind, and soul are out of balance because of the physical and mental pressure that comes with being ill. With music therapies, a guiding question or a specifc theme forms the basis for the therapy. Some possible themes are acceptance, coming closer to your inner self, enlightenment, relaxation, and how to handle emotions. With music therapies, the process is the most important aspect. It does not matter if the patient is creative or not; it only matters that the patient is willing and open for the therapy.

There are many different musical forms a patient can choose from, both in an active form and the recipient. The music therapist can play alongside the bed of the patient; the patient can choose to just listen, but he/she can also sing or play along with an instrument. It is possible for the patient to borrow an instrument, so that they can enjoy playing their own music during the stay in the hospital. Listening to music alongside the music therapist is also a possibility (the therapist has a Bluetooth speaker box for these occasions), and the patient can compose and then record his/her own song on CD. This is a great opportunity because the music not only is benefcial for the moment but also acts as a nice memory for a later time.

The musical instruments the patients can choose from are as follows: guitar, keyboard, sound bars, and a lyre (a kind of harp).

Patients make regular use of the music therapies. A lot of patients fnd the music that the art therapist plays very soothing, and they can let their emotions run free. Some patients even request that the music therapist plays music on their deathbed or at their funeral.

# **11.10.4 Complementary Therapies/ Care**

Because of the side effects of the disease or HSCT treatment, some complementary therapies like massage, manicure, and pedicure are limited or not possible for the patient group. The complementary therapies that can be used by the patients are discussed below.

#### **<IP_ADDRESS> Aromatherapy**

With the use of aromatherapy, the patient can experience a wide range of different aromas. Every aroma has its own use. Some will sooth or calm, while others will activate the patient. The use of electric scent streamers in the patient room distributes the aromas.

#### **<IP_ADDRESS> Therapeutic Touch**

Therapeutic touch is a technique to help people relax, relieve their pain, and heal faster. It is sometimes called a "laying on of hands" and is based on ancient healing practices. Therapeutic touch is thought to promote healing through balance in the body.

#### **<IP_ADDRESS> Living Color Lamp**

The living color lamp can change the color of the room to match the mood of the patient. Patients can change the colors with a remote, so that they can alternate between colors. Just like aromatherapy, colors can also infuence the well-being of the patients.

# **11.11 Skin Care (See Also Chap. 11 GvHD About Skin Care)**

# **11.11.1 Introduction**

Our skin is important in many ways. Grégoire (1999) stated that the skin is the frst line of defense against harmful infuences of our environment. The skin prevents us from overheating, undercooling, or drying out. The skin has a sense of touch, so we can feel things and also perform complex actions, for example, with our hands and face. Our skin is unique to us and who we are as a person, recognizable to the people around us or through identifcation by fngerprints and scars.

The skin exists of three layers:

Grégoire (1999) wrote in his book about pathology and physiology of the layers of the skin. The epidermis is the outer layer. This consists for the most part of horn cells. These cells are constantly newly formed in the lower layer of the epidermis. The cells multiply by division. The newly formed horn cells always move slightly to the surface of the skin because they are pushed upward by the continuous production of new cells. When the cells reach the top of the epidermis, they die. Our skin will form a very strong layer (like an armor), which is diffcult to penetrate for pathogens and, in addition, counteracts dehydration of the skin. This dead horn layer is extra thick on some areas of the body, such as on the soles of the feet and on the palms of our hand.

There are also other cells in the lower layer of the epidermis between the horn cells: the melanocytes. The pigment cells make small pigment pellets that they pass on to the horn cells to place the pigment like an umbrella above their core nucleus. Vulnerable hereditary material in the nucleus is shielded against the damaging effect of ultraviolet radiation in the sunlight.

The Grégoire (1999) wrote about the leather skin (dermis) as a solid construction of connective tissue and is much different in content than the epidermis, which consists of a few types of cells. The leather skin is also the most important part of the active defense system of the skin: through which special white blood cells play an important role, viruses and bacteria can be recognized and directed harmlessly. The leather skin also ensures the elasticity and tensile strength of the skin. When the skin ages or is damaged by sunlight, the elasticity and resilience decrease. The leather skin is not constantly renewed, as happens with the epidermis. Damage to the leather skin will therefore always be visible as a scar. However, if only the epidermis becomes damaged, it will heal completely.

The subcutaneous connective tissue is the layer that separates the skin of the muscles and tendons in our body. There are blood vessels (food and oxygen supply), lymph vessels (drainage of waste), and nerves (touch sensation, pipeline, temperature sensation). The blood supply is ingenious and precisely regulates the supply of nutrients and oxygen to the leather skin and the lower layers of the epidermis. The blood vessels in the skin also play an important role in the body's temperature control. By dilating the blood vessels, extra heat can be delivered to the outside, and with vasoconstriction, the release of heat can be reduced so that no energy is lost.

# **11.11.2 Skin and Chemotherapy**

When a patient receives chemotherapy, problems of the skin are common. The skin contains many fast-growing cells, which will be affected by chemotherapy.

Possible complaints are:

Usually, after the end of chemotherapy, the skin will recover quickly.

Basic advices for chemotherapy patients (Erasmus MC (Care guide) 2009):

# **11.11.3 Skin Responding at the Treatment**

The skin changes depend on the type of chemotherapy the patient receives. For example, the skin is drier and darker (= pigmentation problem) or look dusky or gray. Also, the nails can change in structure. This is due to the effects of chemotherapy. It is good to advise the patient to adjust the daily care of the skin to the changes that have occurred.

You can advise the patient (Erasmus MC (Care guide) 2009):

# **11.11.4 Skin and Rash**

If the patient endures itching, scaling, splitting, and burning, you can advise the following:

# **11.11.5 Skin and Acne**

Chemotherapy can cause acne. This is a side effect that creates uncertainty in our patients. You can advise the following:

# **11.11.6 Advice on Itching**

Because of the treatment, the skin can dry out it which can cause itching or a prickling sensation that can be uncomfortable. You can advise the following:

# **11.11.7 Skin and Risks of Bleeding and Infections**

Chemotherapy may (temporarily) increase the risk of infection and bleeding. Observe the patient for wounds, blisters, or discolorations. In case of sudden redness of the skin or the occurrence of blisters, contact the attending physician. A little extra care for the skin is recommended.

# **11.11.8 Skin and the Sun**

Advise caution with sun exposure and encourage the application of high SPF sunscreen (30–50). The patient needs to be careful with direct sun exposure and also if they are under the shade due to refected light. During the periods the patients undergo chemotherapy, they can take a walk or work in the garden but advise them against sunbathing. They should avoid the sun between 12 and 15 o'clock. Chemotherapy can cause the loss of hair and thinning of the hair on the scalp. The scalp is more at the risk for sunburn. After chemotherapy, the sun can cause more discoloration of the skin. Our patients must always protect their skin. Wearing a (sun) hat or cap and covering the arms are recommended. Using a sunscreen with a protection factor of 30 or more is extremely important.

# **11.12 Discharge from Inpatient Care**

When a patient is discharged following HSCT, this is often an anxious time. They are now leaving the "safe" environment of doctors and nurses. Some of the patients feel that they don't have any trust in their own body to let them know when they are not well.

It is advisable to inform the patient about the general aspects/living rules so that they can pick up their daily routine at home: housework or social events.

# **11.12.1 School, Study, and Work**

• Patients who are no longer neutropenic and when their physical condition allows may slowly take up their studies or activities.

# **11.12.2 Domestic Work**

# **11.12.3 Social**

# **11.12.4 Driving**

• The patient should consult with their attending physician when to resume driving. Some medications or having anemia can affect the ability to concentrate so that driving is not safe.

# **11.12.5 Sports Activities**

• Give the patient information about building up their physical strength and condition. Some rehabilitation sports programs can be given in the living area of the patient. The patient can also seek information from a physiotherapist in the area to improve their physical condition.

# **11.13 Readmissions to Hospital**

Patients are often unsure about the rules of life and their physical condition during and after HSCT. It is important that patients from the outpatient clinic receive clear information when they can resume certain activities in their social and general life. It is important to inform the patient fully about the rules of life so that they can become independent more quickly after this intensive treatment period.

In the home situation, side effects or problems may occur after HSCT. The patient should contact the hospital or attending physician. In many HSCT centers, emergency call procedures are well established. The patient should be aware of these. According to the Erasmus MC (2009) Zorggids (care guide), the contact moments should be as follows.

# **11.13.1 Urgent Complaints**

Following HSCT, they should contact immediately (inside and outside offce hours) with the following complaints:

# **11.13.2 Complaints**

Following HSCT, the patient should contact (within offce hours) at:

# **11.14 Pediatric Considerations**

Advances in treatment and improved prognosis increase the number of children and families living through the experience of childhood cancer. Increased survival rates come at the cost of aggressive combinations of chemotherapy, radiotherapy, and surgery, each of which may be associated with adverse effects and psychosocial diffculties for families (Meyler et al. 2010).

Hematopoietic stem cell transplantation (HSCT) may affect children and their families, inducing depression, anxiety, burnout symptoms, and posttraumatic stress symptoms, as well as posttraumatic growth (PTG), which includes feelings of inner strength, closer relationships with family members and friends, and a greater appreciation for life, factors that might lead to a general feeling of growth (Riva et al. 2014). Furthermore, these treatments can lead to physical late effects, which may also have psychosocial consequences to the patient and the family long after treatment has ended (Meyler et al. 2010).

It is important to understand the general impact of childhood cancer on families, like the emotional impact, the specifc impacts for individual family members and extended family, and the disruption to family life. How the illness impacts on the social lives and networks of the family and the social implications for families needs to be taken into consideration (Meyler et al. 2010).

There are many specifc psychological interventions to help children deal with cancer treatment. As quoted by Weinstein and Henrich (2013) in their research, the interventions that are mostly used to help children before they undergo a painful or anxiety-inducing procedure are educating children by explaining the procedure, providing emotional support to children by listening and answering children's fears and worries or holding their hands, and distracting children through passive forms such as music, television, and books or through active forms such as playing, telling stories, singing, and using bubbles. Weinstein and Henrich (2013) explain the least commonly reported strategies that nurses used were breathing exercises to relax the child using books, tapes, and videos to educate children on their treatment and hypnosis. All these psychological interventions are effective in reducing pain and anxiety, along with enhancing acceptance of medical treatments (Weinstein and Henrich 2013).

Also, Weinstein and Henrich (2013) stated that one of the primary benefts of these psychological interventions is that children shift from a passive and helpless state of pain and anxiety to a state of control and empowerment with an active adaptive attitude toward life. Through these interventions, children are considered an active participant within their own care. By preparing children psychologically for medical procedures and teaching them coping strategies, nurses may help reduce the risk of developing maladaptive behaviors and psychopathologies. (Meyler et al. 2010) indicate that physicians and nurses working in pediatric oncology are in a unique position to identify and manage psychosocial issues in childhood.

In order to prevent feelings of isolation and helplessness, children's rights in hospital (EACH 2016) stresses that steps should be taken to mitigate physical and emotional stress. The staff should avoid or reduce situations or actions described by the child as stressful. The staff should learn to recognize and act upon the fears or concerns of the child and families whether or not explicitly expressed. To mitigate emotional stress, the child and family should be offered emotional support.

It is important to work together with multidisciplinary team members like child life therapists, psychologists, and social workers who all can help provide psychological support to the child and their families (Weinstein and Henrich 2013). Contacts should be offered to social services, psychologists, and therapeutic healthcare professionals as well as religious support or counseling when requested, taking into account the family's cultural background and contact with self-help groups, relevant support groups, and patient or consumer organizations (EACH 2016).

For children, it is important to try to make the life in hospitals as close to normal life as possible. School is an important part of it for schoolaged children. School is also an important part of adolescents' and young adults' lives, and being diagnosed with cancer in childhood may affect perceptions of school. Cancer and its treatment have a negative impact on mental and physical health and often lead to an increased absence from school. Furthermore, treatments with radiation and chemotherapy, especially among patients diagnosed with a central nervous system (CNS) tumor, may signifcantly affect neurocognitive function and levels of education (Winterling et al. 2015).

Results from Winterling et al.'s (2015) studies show that survivors appear to achieve education levels comparable to those of control groups although some studies indicate that survivors more often repeat a school year and receive additional academic support.

Furthermore, worry over missing school is a great concern for adolescents starting chemotherapy.

# **References**

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# **Graft-Versus-Host Disease (GvHD) 12**

John Murray, Jacqui Stringer, and Daphna Hutt

#### **Abstract**

Acute and chronic graft-versus-host disease (GvHD) is a major cause of morbidity and mortality in patients who undergo allogeneic haematopoietic cell transplantation (HCT) and affects approximately 30–40% of recipients. Prevention remains the goal, and the recent introduction of post-transplant cyclophosphamide in the haploidentical transplant setting is changing the landscape. GvHD diagnosis is complicated, and grading and staging vary depending upon the tool and transplant centre involved. For the majority of patients who go on to develop GvHD, corticosteroids remain the frst-line treatment for both acute and chronic forms of the disease. Recipients that are refractory to systemic steroids have a plethora of second- and third-line options available to them. A 'standard of care' approach has not yet become agreed globally due to poor evidence from small and limited randomised control trials. However, the recent REACH (Zeiser et al. N Engl J Med. 382(19):1800–10, 2020; Zeiser et al. N Engl J Med. 385(3):228–38, 2021) and ROCKstar trials (Cutler et al. Blood. 38(22):2278–89, 2021) have armed clinicians with new and effective therapies. Supportive care is paramount, and the nurse is at the centre of the patient's care and in the best position to guide and advise the patient and family through this often-long-term complication.

#### **Keywords**

Acute graft-versus-host disease · Chronic graft-versus-host disease

# **12.1 What Is Graft Versus Host Disease (aGvHD)?**

# **12.1.1 Defnitions**

*Acute graft* versus *host disease* (aGvHD) is a reaction of donor immune cells against host tissues. The three main tissues that acute GvHD affects are the skin, liver and gastrointestinal tract (Zeiser 2019).

*Chronic graft* versus *host disease* (cGvHD) is a syndrome of variable clinical features resembling autoimmune and other immunologic disorders. Manifestations of chronic GvHD may be restricted to a single organ or site or may be

© The Author(s) 2023

J. Murray (\*) · J. Stringer

The Christie NHS Foundation Trust & The University of Manchester, School of Medical Sciences, Manchester, UK

e-mail<EMAIL_ADDRESS><EMAIL_ADDRESS>
D. Hutt

Department of Paediatric Haematology-Oncology and BMT, Edmond and Lily Safra Children Hospital, Sheba Medical Center, Tel-Hashomer, Israel e-mail<EMAIL_ADDRESS>
M. Kenyon, A. Babic (eds.), *The European Blood and Marrow Transplantation Textbook for Nurses*, https://doi.org/10.1007/978-3-031-23394-4\_12

widespread, with profound impact on quality of life (Jagasia et al. 2015).

# **12.2 Background to GvHD**

The *New England Journal of Medicine* reported the infusion of bone marrow into patients by E. D. Thomas and colleagues in 1957, following radio- or chemotherapy. Pre-clinical animal studies revealed that transplantation of splenocytes from non-oncogenic donor strains facilitated haematopoietic recovery but led to a severe illness characterised by anorexia, reduced weight, diarrhoea, ruffed fur and eventual death. It was labelled at the time 'secondary' or 'runt's disease' and later became known as graft-versushost disease (GvHD). It was clear that the effect was not one of the conditioning therapies but was associated with an immune-mediated syndrome (Wolff et al. 2012).

GvHD, both acute and chronic, is the leading cause of non-relapse mortality and is associated with a high morbidity that increasingly affects quality of life (Gooptu and Antin 2021). However, the success of allogeneic haematopoietic stem cell transplant (HSCT) depends on simultaneous graft-versus-tumour (GvT) effects. There is a fne line with aGvHD. The symptoms and side effects can be unpleasant and sometimes harmful and, in severe cases, life-threatening. However, it is well documented that some level of aGvHD is benefcial. It has been found that relapse rates post allograft were lowest in patients with aGvHD versus those without (Baron et al. 2012). Therefore, broad-based immunosuppressive strategies are less attractive as these may dampen the GvT beneft. Relapse accounts for a signifcant proportion of treatment failures after HSCT; thus, strategies for GvHD prevention with minimal impact on GvT are the holy grail of transplantation (Magenau and Reddy 2014). The introduction of post-transplant cyclophosphamide may well be a step toward better prophylaxis and prevention of GvHD in several protocols (Gooptu and Antin 2021).

Historically, GvHD is termed 'acute' before day 100 and 'chronic' any time after day 100. However, it has since been recognised that there can sometimes be 'overlap' between the types, so signs and symptoms are used to aid and determine the diagnosis. The skin is the most common organ affected followed by the gastrointestinal (GI) tract and then the liver. Typically, the skin develops a rash, which often but not always appears on the palms of hands and soles of the feet frst and can rapidly spread to the rest of the body. GI and liver GvHD symptoms such as nausea, vomiting, diarrhoea, abnormal liver enzymes and jaundice are similar in both acute and chronic forms of GvHD.

According to the 2014 NIH consensus, aGvHD includes classic aGvHD (maculopapular erythematous rash, gastrointestinal symptoms or cholestatic hepatitis), occurring within 100 days after HCT or donor leukocyte infusion. The broad category of aGvHD also includes persistent, recurrent or late-onset aGvHD, occurring more than 100 days after transplantation or donor leukocyte infusion. The presence of GvHD without diagnostic or distinctive cGvHD manifestations defnes the broad category of aGvHD (Vigorito et al. 2009; Jagasia et al. 2015).

# **12.3 Acute GvHD**

*Overview*: aGvHD occurs following an allogeneic haematopoietic stem cell transplant and is a reaction of donor immune cells against host tissues and remains a major cause of morbidity and mortality (Greinix 2008). High-dose chemotherapy +/− radiotherapy inficts cellular damage, and this leads to an infammatory process; the activated donor T-cells interact with the host epithelial cells. Approximately 35–50% of HSCT recipients will develop aGvHD (Dignan et al. 2012). There are several factors that can infuence the development of aGvHD: the stem cell source, age of the patient, conditioning regimen and GvHD prophylaxis used. All aGvHD can be associated with culture-negative fever. Biopsies of skin and GI tissue (more rarely liver) are often obtained, although the diagnosis of aGvHD is regularly made based upon clinical signs and symptoms. A biopsy is useful to help differentiate from other diagnoses, which may mimic GvHD, such as viral infection (hepatitis, colitis) or drug reaction (causing skin rash). The modifed Glucksberg-Seattle criteria (Przepiorka et al. 1995), International Bone Marrow Transplant Registry (IBMTR) (Rowlings et al. 1997) and Mount Sinai aGVHD International Consortium (MAGIC) criteria (Harris et al. 2016) are widely used and give a stage and grade (grade 0–IV) for each organ and its degree of involvement. The lack of standardisation of grading has led to diffculties comparing patient groups at different centres.

# **12.4 Pathophysiology of GvHD**

In the 1960s, Billingham (1966) proposed three central tenets for the development of GvHD. These are:

Donor T-cells are now recognised as occupying a central role in mediating GvHD following interactions with activated host and donor antigen-presenting cells (APC). A complex network of cytokines, chemokines, cellular receptors and immune cell subsets then modulates T-cell/APC interactions that result in the initiation and maintenance of GvHD (Magenau and Reddy 2014).

The three-phase process for aGvHD comprises:

initial tissue damage from the conditioning therapy

Activation and then proliferation of donor T cells

Finally, infammatory cytokines are released such as interleukin-1 and tissue necrosis factor alpha that produce tissue necrosis.

Acute GvHD is modulated in part by the presence of cells capable of inhibiting immune responses, most notably regulatory T-cells (Magenau and Reddy 2014) (Fig. 12.1).

Both prevention and treatment of aGvHD attempt to disrupt the three-step pathophysiological cycle. Most current treatment options of aGvHD affect more than one event in this cycle through relatively non-specifc immunosuppressive and anti-infammatory mechanisms (Greinix 2008).

Reduced intensity conditioning will usually contain drugs that deplete T-cells, such as Campath-1H or ATG. This reduces the initial risk of aGvHD but increases the risk of infective complications such as CMV and also the risk of lateonset aGvHD and cGvHD. Up to 50% of patients will develop some aGvHD despite prophylaxis (Mohty et al. 2020).

# **12.4.1 Risk Factors**

Factors that can increase the likelihood of aGvHD include older recipient/donor, sex mismatch and specifcally a multiparous female donor into a male donor. Furthermore, the intensity of the preparative regimen does appear to correlate with increased incidence of aGvHD. This effect may occur due to greater tissue damage from the preparative regimen, predisposing these tissues to more infammation from the alloreactive cells. Higher doses of radiation also give rise to more GvHD. Equally, more recent use of nonmyeloablative preparative regimens has led to lower incidence of aGvHD in some studies (Jacobsohn and Vogelsang 2007).

# **12.4.2 Signs and Symptoms of aGvHD**

#### **<IP_ADDRESS> Skin**

Acute GvHD can cause a rash which is usually fat and red and often occurs on the hands, feet and around the ears and upper chest, at frst. This

**Fig. 12.1** The three phases of acute GVHD, as described by Ferrara and colleagues (From Hill and Ferrara 2000. Reproduced with permission)

can quickly spread to cover the whole body. It is often, but not always, itchy and sore and can feel like sunburn. A biopsy may be taken but is not always diagnostic. On examination, the features may include apoptosis at the base of epidermal rete pegs, dyskeratosis, exocytosis of lymphocytes, satellite lymphocytes adjacent to dyskeratotic epidermal keratinocytes and perivascular lymphocytic infltration in the dermis (Ferrara and Deeg 1991).

#### **<IP_ADDRESS> Gastrointestinal**

Signs and symptoms include weight loss, stomach discomfort and pain, nausea, vomiting and diarrhoea. The diarrhoea can be profuse with secretions and may also result in bleeding from ulceration of the mucosa. The effects of highdose therapies and infection need to be excluded. Biopsy in this group of patients is more informative and may show apoptotic bodies at crypt bases, crypt ulceration and fattening of surface epithelium (Dignan et al. 2012).

#### **<IP_ADDRESS> Liver**

Jaundice from hyperbilirubinaemia is the hallmark of advanced liver GvHD with a cholestatic pattern of elevated conjugated bilirubin, alkaline phosphatase and gamma-glutamyl transpeptidase (GGT) and may be associated with pruritis. There is a wide range of differential diagnoses, which should be considered and excluded such as venoocclusive disease, drug toxicity and infection. It is often extremely diffcult to perform biopsy due to the increased risk of bleeding, but, if taken, histology shows endothelialitis, lymphocytic infltration of the portal areas, pericholangitis and bile duct destruction (Dignan et al. 2012).

# **12.4.3 Classifcation of Acute GvHD: Grades I–IV**

Acute GvHD carries a signifcant transplantrelated mortality (TRM) with grades 0–I (mild) having a TRM of approx. 28% and grades II, III and IV (very severe) TRM of 43%, 68% and 92%, respectively (Greinix 2008).

# **12.4.4 Prevention of GvHD**

*Prophylaxis*: GvHD prophylaxis for full-intensity allografting is based around calcineurin inhibitors (CNI) along with short-course methotrexate (MTX) (Gooptu and Antin 2021). This works by interfering with calcium-dependent interleukin-2 (IL-2) gene activation and de novo purine metabolism, respectively. CNI and MTX act synergistically to non-selectively inhibit lymphocyte activation and proliferation. The combination of ciclosporin and MTX or tacrolimus and MTX as prophylaxis for aGvHD compared to any singleagent treatment has been shown to be superior (Greinix 2008).

# **12.4.5 GvHD Prophylaxis Medications**

The standard medications used across the transplant community are listed below.

*Ciclosporin* (*CsA*) is given as an intravenous infusion commencing usually 1–2 days prior to HSCT infusion to load the bloodstream and is eventually converted to an oral preparation when the patient is able to tolerate tablets again. Ciclosporin binds to cyclophilin and prevents generation of nuclear factor of activated T-cells (NF-AT), which is a nuclear factor for initiating gene transcription for lymphokines including interleukin-2 and interferon gamma. This action leads to suppression of cytokine production and subsequent inhibition of T-cell activation (Greinix 2008).

*Methotrexate* (*MTX*) is an anti-proliferative agent given intravenously on days 1, 3, 6 and 11 after HSCT for those patients receiving a fullintensity transplant. It prevents the division and clonal expansion of T-cells. It is important to receive all four doses, but severe mucositis (grade IV) often prohibits administration of the fourth and fnal dose and is given at the clinician's discretion.

*Mycophenolate mofetil* (*MMF*), used mainly in reduced-intensity transplant conditioning regimens, is an anti-metabolite that results in noncompetitive reversible inhibition of inosine monophosphate dehydrogenase. This leads to selective inhibition of lymphocytes, purine synthesis and proliferation. Patients have less mucositis and faster neutrophil recovery compared to methotrexate (Greinix 2008).

*Tacrolimus* binds to FK506 protein 12, a different protein to the one that CsA does, but their fnal common pathway is identical (Greinix 2008).

*Sirolimus* is a natural macrolide antibiotic that exerts its immunosuppressive effect by inhibiting cytokine-driven signalling pathways of the T- and B-cell via mTOR blockade and specifcally inhibiting the progression of cells from the G1 phase to the S phase. The advantage is that sirolimus has a completely different toxicity profle to calcineurin inhibitors and can be used in combination with them (Dignan et al. 2012).

*Campath-1H or alemtuzumab* is given in a variety of doses from 30 to 90 mg and is dependent upon the cell source and degree of mismatch between donor and recipient. It is an unconjugated humanised IgG1 kappa monoclonal antibody that targets the CD52 antigen on the T and B lymphocytes as well as on monocytes, macrophages, eosinophils and dendritic cells. The major disadvantage of this drug is the increase of infections due to the extended period of lymphopenia. CMV reactivations and infections are particularly troublesome in this patient cohort, necessitating strict surveillance (Dignan et al. 2012).

*Anti-thymocyte globulin* (*ATG*) decreases T-cells and also leads to viral infections. Epstein-Barr virus (EBV) reactivations can be problematic and can result in post-transplant lymphoproliferative disease (PTLD).

*Post-transplant cyclophosphamide* (*PT-Cy*) used in haploidentical transplants and allows mismatched transplantation to occur, addressing both host rejection and GvHD.

*Abatacept* is a fusion protein that selectively inhibits T-cell co-stimulation and is effective as aGvHD prophylaxis (Ngwube et al. 2020).