# **7.3 The Role of Cellular Therapy in Solid Tumours: TCR/TILS**

In the setting of solid tumour cancers immune effector cell products known as TCRs (engineered T cell receptors) and TILs (tumour infltrating lymphocytes) are more commonly used (Li et al. 2019).

**Engineered T Cell Receptors** Similar to CAR-T cell therapy, TCRs are genetically engineered with a viral vector to produce an extracellular receptor which recognises molecules on the surface of cancerous cells. To do this TCR therapy utilises the cell's human leukocyte antigen (HLA), as cancers in the solid tumour setting do not have cell surface 'CDs', as seen in haematological cancers. Engineered T cell receptors will be manufactured to recognise a specifc combination of cell surface HLA and neoantigens, specifc to the tumour they are targeting (Zhao and Cao 2019). T cells are collected for this product in the same way as that for CAR-Ts, through the process of apheresis. Currently TCR therapy has been used in the clinical trial setting in lung, melanoma and synovial sarcomas (Clinical Trials 2022a).

**Tumour Infltrating Lymphocyte (TIL)** TIL therapy utilises naturally occurring lymphocytes already found in the tumour itself and are expanded in the manufacturing laboratory to develop a product specifc to that tumour and patient. As TILs come directly from the patient's tumour they are already equipped to recognise many of its surface targets (Boldt 2021).

TILs are manufactured quite differently to the products previously discussed. Initially samples of tumour tissue will be extracted and sent to the manufacturing lab. In the lab the tumour will be cut into many pieces and broken down to release the lymphocytes. These lymphocytes are then grown and expanded over time, in a medium called interleukin-2 (IL-2), with the result being an infusible product (Boldt 2021). Currently TILs have been used in the clinical trial setting in melanoma, lung and breast cancers (Clinical Trials 2022b).

Both the above products will be returned to the treatment site frozen, and after thawing are infused back to patients in the same way as CAR-T or a stem cell infusion. The toxicity profle, inclusive of cytokine release syndrome and immune cell associated neurotoxicity syndrome, is expected to be similar, and in some cases milder, to that of CAR-T cell therapy.

Currently, CAR-T cells are not used in the setting of solid tumour cancers, other than in clinical trials, due to various factors negating their success. These have been seen to include the inability to successfully navigate the complex tumour microenvironment, increased evidence of 'on target off tumour' toxicities and also, traffcking and infltration into tumour tissue. Although many clinical trials are working to overcome these obstacles, through the blocking of cytokines and immunosuppressive cells, they are still in the early stages (Zhao and Cao 2019).

# **7.4 The Role of Clinical Trials/ Academic Products**

The commissioning of commercial CAR-T cell products would not have been possible without the promising clinical data demonstrated in early phase trials. Many of the treatments given daily in haematology and cell therapy transplant all have a rooting in clinical trials.

Clinical trials are important for a variety of reasons. Initially their main aim is to establish if a treatment works in the way it is intended to, and what side effects it may cause. This is done through progressing phases, starting from animal model trials to Phase 1, 2 and 3 in human clinical trials. Following this, some treatments will also be tested in a randomised control trial to establish if they work better than currently available treatments.

Aside from this, trials also play an important role in establishing the logistics of a new treatment, for example, if medicines are administered to patients in a new way, how feasible is this for both the patient and the treating team (HealthTalk. org 2019).

Currently there are over 2000 clinical trials running worldwide for the three most common products in the feld of IECs (1051 for CAR-Ts, 606 for TILs and 652 for TCRs), and this isn't counting various other products under investigation, such as CAR-NK cells (Clinical Trials 2022b). TILs have the longest running history of trial activity, with their clinical signifcance being established as early as 1994 (Rohaan et al. 2019).

The current and future aim of IEC clinical trials is to continue to develop a solely personalised cell therapy product for a wide application of malignancies, whilst negating the known toxicity profle and obstacles of the individual products effcacy. The current landscape of clinical trials shows a range of development opportunities, which can be seen in the genetic engineering of TIL therapy to improve its functionality, the continued development of 4th Generation CARs to improve their in vivo durability, and also randomised control trials, used to establish if IECs products are more effective than currently available treatments (Rohaan et al. 2019). Additionally, research is also focused on access to "off-the-shelf" allogeneic CAR-T products, simplifying the manufacturing process and mitigating side effects, among other aims (Kröger et al. 2022).

Clinical trials have supplied a vast amount of important data, both scientifcally and holistically, on the improving effcacy of IEC products. However, this data has also been able to highlight the areas in which signifcant progression is still required.

# **7.5 Patient Selection and Referral:**

Patients who are considered eligible for CAR-T therapy should be assessed and discussed at local multi-disciplinary team meetings and a referral made to the CAR-T treatment centre. A National screening board may also sit to determine if the patient is suitable, review images and histology and approve that the patient is able to enter the program. Health insurance considerations may need to be satisfed in some countries. Criteria to go ahead are outlined by EBMT/EHA/JACIE (Hayden et al. 2022) and include the physical condition which should be an ECOG<2, Karnofsky or Lansky >60%. Have a life expectancy of more than 6–8 weeks, the absence of an active malignancy and not be on immunosuppressive treatment. Be free from infection, particularly viral infections.

Once accepted onto the program this triggers referral to the apheresis team with manufacturing slots booked, laboratory informed and the provisional booking of an infusion date.

# **7.6 Apheresis/Manufacturing/ Laboratory/Chain of Identity**

# **7.6.1 Apheresis**

The production of autologous CAR-T cells requires collection of non-mobilized mature lymphocytes through apheresis of mononuclear cells (MNCs) (Tuazon et al. 2019; Mahadeo et al. 2019). Absolute lymphocyte count (ALC) thresholds to proceed with leukapheresis can vary between different CAR-T products (Mahadeo et al. 2019). The leukapheresis is similar to apheresis for extracorporeal photopheresis or for the collection of allogeneic mononuclear cells intended for post-transplant immunotherapy (donor lymphocyte infusions); no specifc apheresis protocols have so far been proposed by cell processor manufacturers or by the CAR-T cell manufacturers (Yakoub-Agha et al. 2018).The apheresis procedure might be technically challenging, as patients are heavily pre-treated with multiple lines of previous therapy and often have low leukocyte and lymphocyte counts (Ceppi et al. 2018). The targeted cell dose for leukapheresis can vary depending on the specifc product and manufacturing process (Mahadeo et al. 2019).

Timing for apheresis is critical in most patients and should be closely coordinated with the primary physicians and CAR-T cell team, as it should be when patients recover but prior to the need for additional chemotherapy and after an appropriate washout period. This is especially challenging for patients with relapsed disease and a high blast count. The apheresis must be coordinated with the pharmaceutical company to ensure the availability of the production slot. Some products are sent fresh to the production facility where others are sent frozen.

Paediatric apheresis procedures are considered safe but challenging as it has potentially more side effects than in adults due to the small body mass and unique physiology of children. The main problems are the extracorporeal volume of the cell separator device, poor venous access and metabolic complications due to citrate toxicity (Del Fantea et al. 2018).

nal pain and restlessness may be the frst signs. Children need Ca supplement IV or PO throughout the procedure.

#### **Pre-apheresis Consultation**

# **7.6.2 Manufacturing/Laboratory/ Pharmacy/Chain of Identity**

The Memorial Sloan Kettering Cancer centre in New York describes how to build a CAR-T cell program, having eight essential tasks to success: Patient intake; CAR-T cell consultation service; collection, ordering, shipping and receiving; Bridging strategy; Cell infusion; Post infusion care day 0–30; Post infusion care day 30 onwards; Financing, regulatory and reporting requirements (Perica et al. 2018). This process may differ across countries and continents, but broadly speaking following this outline would result in a positive outcome for the patient and the institution.

Defned procedures aid the tracking and verifcation of the product identity from the point of harvest via any manipulation on site and storage prior to shipping for production. Once the T cells have been delivered to the commercial facility the product is manipulated, expanded, cryopreserved and delivered back to the host institution for infusion into the patient. Manufacturers work very closely with each centre to ensure that a chain of identity is maintained and accurate; this requires an extensive quality program and engagement from multiple MDT members (Perica et al. 2018).

CAR-T cell manufacture occurs following leukapheresis. The T cells once isolated are transduced with the CAR gene. The cells are treated, expanded in culture over approx. 1 month and sent back to the transplant centre for re-infusion. During the processing stages the cells are monitored for viability and are screened for bacterial contamination. The process may sometimes fail to produce enough product and the apheresis may need to be performed again. Once CAR-T cells are manufactured and genetically modifed they become an advanced therapy medicinal product (ATMP), and the responsibility of the hospital pharmacy. Under current European Union regulations, CAR-T cell therapies fall under the advanced therapy medicinal products (ATMPs) framework. ATMPs represent a category of medicinal products defned in EU Regulation 1394/2007 (Kröger et al. 2022). Therefore, the process has tightly regulated coordination between the medical and nursing team, cellular therapy laboratory, manufacturing site and pharmacy.

# **7.7 Patient Preparation and Consent**

All eligible patients should be counselled in clinic and provided with written and verbal information regarding the procedure. Opportunities for questions are important and the input from the specialist nursing team is vital. Prior to apheresis patients require a series of tests and assessments, the 'Work-up'. These will include a thorough examination of treatment history, physical assessment, imaging, bone marrow examination and routine blood tests, including virology. A COVID-19 screen which will need to be valid within 30 days of harvest. An absolute lymphocyte count of >0.2 × 109 /L is recommended to ensure an adequate collection. Nursing staff will perform a vein assessment and potentially the patient may require the insertion of a central venous catheter if peripheral access is poor. Once all pre-assessment tests have been satisfed the patient will be passed as eligible and suitable for treatment and then consented in clinic.

# **7.8 Bridging Therapy**

From apheresis to infusion of CAR-T is approx. 4–6 weeks. This has obvious problems for patients, especially those with rapidly progressive and aggressive disease. In order that patients can receive CAR-T therapy they may require bridging therapy following apheresis and prior to the lymphodepleting conditioning treatment. Ideally bridging therapy should be commenced within 3 days of apheresis. The choice of therapy is determined by the MDT and considers the overall tumour burden and anatomical site of disease. The aim is for disease and symptom control rather than remission induction. Bridging therapy can be split into four categories; high dose chemotherapy; low dose chemotherapy; radiotherapy; novel agents. There should be a focus on minimal organ toxicity and infection (Hayden et al. 2022). These therapies may all be employed and each institution will have a preference, please refer to your own SOP. Examples of bridging therapy; in high grade lymphoma frequently used bridging therapies include radiotherapy to bulky disease and Polatuzumab with Rituximab and Bendamustine; in mantle cell lymphoma frequently used bridging therapies including a BTK inhibitor with radiotherapy to bulk; in acute leukaemia frequently used bridging therapies include Inotuzumab or a Tyrosine Kinase Inhibitors. CD19 targeted bridging therapy should, however, be avoided.

# **7.9 Product Receipt**

Once the CAR-T products are genetically modifed there will be coordination between the manufacturing facility and cellular therapy centre. The unit receiving the CAR-T cell products will need to have suitable storage containers and facilities for genetically manipulated material; depending on national legislation, a storage site may need regulatory approval as gene therapy medicinal products are also genetically modifed organisms (Yakoub-Agha et al. 2018). On receipt of the cells from the manufacturing facility the laboratory will need to ensure the following: (1) inspection of the dry shipper seal for breaches; (2) review of the temperature log throughout transportation; (3) inspection of product integrity; (4) CAR-T identity label checks, prior to completion of receipt forms (Hayden et al. 2022).

# **7.10 Lymphodepleting Chemotherapy (LD), Product Thawing and Infusion**

# **7.10.1 Lymphodepleting Chemotherapy (LD)**

The patient will be admitted to either an ambulatory care or ward setting in a qualifed cellular therapy unit. If the centre does not have established policies and infrastructure to allow for safe outpatient-based administration, hospitalization is recommended during this period to ensure close monitoring and optimal hydration (Yakoub-Agha et al. 2018).

The patient will receive lymphodepleting chemotherapy (also known as conditioning chemotherapy) which is used prior to product infusion. The purpose of LD is to help create space in the immune system for the infused CAR-T cells to expand and proliferate. Patients in most protocols will receive lymphodepleting chemotherapy, which creates a favourable immune environment for adoptively transferred CAR-T cells, improving their in vivo expansion, subsequent persistence, and clinical activity (Hay and Turtle 2017).

The choice of LD is dependent on the CAR-T product or clinical trial protocol. Fludarabine and cyclophosphamide are the two main chemotherapy drugs used in combination. Fludarabine dosing is consistent between products and indications (25–30 mg/m2 /day ×3 days) whilst cyclophosphamide schedules differ. Other chemotherapy agents can be used depending on the product or trial, these include drugs such as Bendamustine, or Cytarabine & Etoposide. LD conditioning is usually administered on a 3-to-5 days schedule prior to the infusion of the CAR-T cells (Yakoub-Agha et al. 2018), allowing two rest days prior to product infusion.

The medical and nursing team should ensure the patient has received all appropriate investigations that are required on admission before commencing LD. Considerations prior to commencing LD are set out in the Management of Adults and Children receiving CAR-T cell therapy EBMT guidelines (Hayden et al. 2022) these cover blood parameters, disease status, cardiac function, clinical condition and receipt of CAR-T product.

# **7.10.2 Product Thawing and Infusion**

The patient will receive a medical review and need to be deemed ft to proceed. Complications following LD can develop; The EBMT guidelines (Hayden et al. 2022) outline complications which should be ruled out prior to infusion.

There will be coordination between the laboratory, pharmacy and the clinical area, agreeing a time for infusion. Patients will have been informed and consented prior to admission. However further preparation of the patient and reconfrmation of information prior to product infusion is considered good practice. The patient will have appropriate intravenous access (a central line or peripheral cannula), written, verbal information and confrmation of consent and an explanation of the procedure ensuring any questions are answered.

Product infusion has some differences to stem cell infusion; these should be outlined in the local standard operating procedure. Centres will have a thawing device and an agreed process on where thawing takes place, and which staff are responsible and competent for this. Product thawing is performed in a pharmacy clean room, cell therapy unit or patient bedside, double wrapped in a watertight plastic bag, using thawing devices according to manufacturer's instructions and local regulations (automated thawing device, 37 ± 2 °C water bath, or dry-thaw method) (Hayden et al. 2022). The current licensed products are in bags; however clinical trials may differ with the use of vials requiring syringing. The trial protocol needs to be followed ensuring that thawing and infusion meet the requirements of the trial.

**Table 7.3** Process of product infusion

Confrmation of infusion time, ideally in daytime hours Premedication with paracetamol and antihistamines (avoiding corticosteroids)

Attach appropriate giving set to central line or cannula (standard blood transfusion 170–200 microns sets are acceptable). There should not be a leucocyte depletion flter, and fuid infusion sets are not suitable

Check if patient identifers match with the prescription and product documentation

Remove the product and verify if it matches the patient, prescription and documentation

The product should be inspected prior to thawing to ensure bag integrity and placed in sterile outer bag If thawing is conducted in a water bath, the spike ports that protrude out of the water must be carefully massaged to ensure that they thaw in synchrony with the rest of the product. Additionally the much smaller volumes of CAR-T cell products only require very short thawing times. (Yakoub-Agha et al. 2018)

Once the product is thawed the bag should be carefully be connected to the giving, using aseptic non-touch technique ANTT

The patient should have observations recorded before, during and after the infusion, with care taken to the recognition of reactions. Documentation of timings are recorded, this includes removal of product from the shipper, thawing start and end time, infusion start and end time

Following infusion, the vial/bag and giving set should be disposed of as a GMO biohazard in compliance with institutional policies and country-specifc regulations (Hayden et al. 2022)

Confrmation of infusion time, ideally in daytime hours

#### **Product Infusion**

The process of product infusion is outlined, see Table 7.3.

# **7.11 Potential Complications and Nursing Implications**

Patients are at risk post CAR-T infusion of complications; there are short term (up to 30 days) and long term (post 30 days). The nurse requires knowledge and understanding of when these may occur, what monitoring is required, appropriate interventions and escalation, playing an essential role in patient education and management.

#### **Short-Term Effects**

During the immediate phase following infusion there are clear documented toxicities that nurses need to be aware of. These include tumour lysis syndrome, infection, neutropenia, anaemia, thrombocytopenia, cytokine release syndrome (CRS), immune effector cell associated neurological syndrome (ICANS) and haemophagocytic lymphohistiocytosis (HLH)/ Macrophage Activation Syndrome (MAS). It is recommended that patients are admitted to hospital during the early post-infusion period unless high-level ambulatory care and rapid readmission pathways are already well established, as in centres already providing ambulatory haematopoietic cell transplantation (Yakoub-Agha et al. 2018).

# **7.11.1 Tumour Lysis Syndrome (TLS)**

There were some cases of TLS reported in the pivotal CAR-T trials (Maude et al. 2018; Neelapu et al. 2017; Schuster et al. 2019). For patients with signifcant disease burden, especially ALL with extensive marrow infltration or Non-Hodgkin's Lymphoma with bulky adenopathy, many groups start allopurinol for TLS prophylaxis prior to chemotherapy or cell infusion (Brudno and Kochenderfer 2016). There should be careful monitoring of the patient for TLS following CAR-T infusion utilising standard protocols.

# **7.11.2 Infection Risk, Neutropenia, Anaemia and Thrombocytopenia**

Most patients who present for CD19 CAR-T cell immunotherapy have poor immune function due to both the effects of their malignancy and prior cytotoxic treatments (Hill et al. 2017).

Patients will have received lymphodepleting chemotherapy and therefore develop neutropenia, anaemia and thrombocytopenia. Their risk factors should be assessed and appropriate management and supportive treatment commenced during this phase. During the period of neutropenia the patient is at most risk of bacterial infections, or respiratory viral infection. Invasive fungal infections are rare; however there are increased risk factors for B-ALL with prior allo-HCT; prior fungal infection and prior long-term/ high-dose steroid exposure (Gudiol et al. 2021). Prophylaxis medication will be commenced on admission as per the cellular therapy centres local policy and should include Antiviral (Aciclovir), anti-pneumocystis (Co-trimoxazole or Pentamidine). Systemic anti-fungal prophylaxis if the patient has risk factors for developing a fungal infection. Recommendations for prophylaxis and timings are set further detailed in the EBMT best practice guidelines (Hayden et al. 2022).

The nurse needs to respond promptly to the development of a fever or other signs of infection, ensuring that appropriate intravenous antibiotics are commenced. This is particularly important given the overlap in some of the cellular therapy related toxicities.

# **7.11.3 Cytokine Release Syndrome (CRS)**

The nurse has a fundamental role in understanding, recognising and the management of CRS. CRS is the most common acute adverse event associated with CAR-T cell therapy. It's a systemic infammatory response triggered by the release of cytokines by CAR-T cells following their activation upon tumour recognition in vivo (Lee et al. 2018). The cytokines implicated in CRS may be directly produced by the infused CAR-T cells, or other immune cells such as macrophages that might produce cytokines in response to cytokines produced by the infused CAR-T cells (Brudno and Kochenderfer 2016). There are many cytokines which can be released in CRS; one of the notable ones is interleukin 6, which has been shown to correlate to severe CRS. Other cytokines and chemokines such as IL-8, IL-10, IL-15, IFN-g, and MCP-1 have also been shown to associate with severe CRS (Neelapu 2019), additionally CRS can lead to increased C-reactive protein (CRP) and hyperferritinemia are useful laboratory markers. CRS can progress to life-threatening vasodilatory shock, capillary leak, hypoxia and end-organ dysfunction (Frey and Porter 2019).

The cases of CRS varies dependent on the product, the disease characteristics and the grading system which has been used, the reported incidence has ranged from 30–100% and for CRS grade 3 or 4 from 10–30% (Frey and Porter 2019). These variations will continue due to more clinical trials and potential future licensed products.

There have been varying grading systems used to recognise and grade CRS. The ASTCT consensus grading (2018) modifed other grading systems and is widely used across cellular therapy centres; however other grading systems may be used in clinical trials for example. The ASTCT guidelines for the diagnosis of CRS are applicable to adults and children alike; however, high vigilance for diagnosis might be especially important among children and AYAs (Ragoonanan et al. 2021).

The Common Terminology Criteria for Adverse Events CTCAE. Nurses caring for cellular therapy patients will need to know how to use the grading system, and necessary interventions and escalation.

CRS is characterised by fever ≥38 °C, haemodynamic instability and hypoxemia. Severity is graded according to the ASTCT consensus criteria (below) and the differential diagnosis includes neutropenic sepsis. Empiric, broad-spectrum IV antibiotics should be commenced (Hayden et al. 2022). Local standard operating procedures will outline the management, intervention and appropriate escalation. The common symptoms of CRS are not unique to CRS. Practitioners must be cautious and exclude other causes of fever, hypotension, hemodynamic instability, and/or respiratory distress, such as an overwhelming infection (Lee et al. 2018).

**Fig. 7.2** Algorithm outlining the grading and management of cytokine release syndrome (CRS) (adapted from Hayden et al. 2022)

CRS can either be self-limited (requiring only supportive care with antipyretics and intravenous fuids) or it may require intervention with anticytokine-directed therapy such as corticosteroids or tocilizumab (Frey and Porter 2019).

Tocilizumab is licensed for frst line use and is a monoclonal antibody treatment against IL6 receptor. It has been shown to be effective for most patients; those who do not respond to an initial dose often clinically improve with a second administration and/or the addition of corticosteroids. In addition to being an effective tool to manage CRS, tocilizumab is attractive because blocking the IL-6 receptor may provide toxicity management without impacting the antitumor effect of the CAR-Ts (Frey and Porter 2019).

Cellular therapy centres should have doses of Tocilizumab readily available for patients at risk of developing CRS. Corticosteroids are used for second line treatment. In early CAR-T studies, they reported reduced expansion and lacking persistence of CAR-T cells in patients who received corticosteroids (Davila et al. 2014). However, in subsequent studies early steroid use has not been associated with detrimental effects on clinical remission rates or CAR-T cell persistence (Topp et al. 2019; Liu et al. 2020). Figure 7.2 is an algorithm outlining the grading and management of cytokine release syndrome (CRS) (EBMT/EHA/ JACIE best practice guidelines; Hayden et al. 2022)

**Grade 1** The patient will have a temperature >38 °C, and no hypotension or hypoxia.

Nursing management will consist of blood cultures and infection management starting broad spectrum antibiotics, regular recording of vital signs, CRS grading, fuid balance monitoring. Patient will have their bloods monitored for full blood count, urea and electrolytes, and liver function, C-reactive protein, ferritin and coagulation.

**Grade 2** The patient will have a temperature >38 °C, and hypotension (not requiring vasopressors) and/or hypoxia requiring low fow nasal cannula at <6 l/min or blow by.

Nursing management will be the same as grade 1, with rationale for increasing the frequency of vital signs and fuid monitoring. Hypotension can be supported with careful fuid replacement which should be monitored cautiously given the risk of vasodilatation, capillary leak and consequent oedema in patients with progressive CRS (Schuster et al. 2019). In children hypotension should be accounting to age and the patient's individual baseline. Indications for Tocilizumab are met at grade 2. The patient can be managed on the CAR-T unit; however, there should be discussions with critical care colleagues and careful monitoring to assess for deterioration. When two doses of tocilizumab (8 mg/kg) fail to control CRS, dexamethasone should be administered (Hayden et al. 2022).

**Grade 3** The patient will have a temperature >38 °C, and hypotension requiring vasopressors and/or hypoxia requiring high fow nasal cannula at >6 l/min, facemask, non-rebreather mask or venturi mask. The patient should be managed in a critical care unit, where there is support to deliver vasopressors and or high fow oxygen.

**Grade 4** The patient will have a temperature >38 °C, and hypotension requiring multiple vasopressors (excluding vasopressin) and/or hypoxia requiring positive pressure (e.g. CPAP, BiPAP intubation and mechanical ventilation). The patient will be on critical care for further intervention, due to capillary leak leading to pulmonary oedema and impairment of ventilation in addition to oxygenation. These patients tend to respond to positive pressure ventilation, which may be accomplished in several ways, up to and including intubation and mechanical ventilation (Lee et al. 2018).

If CRS does not respond to tocilizumab/corticosteroids, alternative therapeutic options include siltuximab and anakinra, but limited clinical data is available (Maus et al. 2020). Corticosteroids should be subject to rapid taper once CRS is controlled (Hayden et al. 2022).

The ASTCT consensus states that the resolution of CRS has less clarity than the onset this is because temperature often normalizes within a few hours after tocilizumab administration, whereas the other components of CRS take longer to resolve. Once such therapies are used, the patient is considered to still have CRS, even in the absence of fever, until all signs and symptoms leading to the diagnosis of CRS have resolved (Lee et al. 2018). Most patient have had resolution of CRS within 14 days.

# **7.11.4 Haemophagocytic Lymphohistiocytosis or Macrophage Activation Syndrome (HLH/MAS)**

HLH/MAS is a life-threatening hyperinfammatory syndrome that can occur in patients with severe infections, malignancy or autoimmune diseases. It is also a rare complication of haematopoietic stem cell transplantation (HSCT), with high mortality and has additional been observed in CAR-T therapy (Sandler et al. 2020).

Patients may have symptoms which overlap meaning there is a differential diagnosis. HLH/ MAS are a syndrome which can overlap with CRS. HLH is also an infammatory syndrome which occurs from pathological T cell and macrophage activation. Hence, the CAR-T cell CRS picture overlaps the commonly known clinical scenario of HLH including elevated ferritin levels (peak ferritin levels of >10,000 ng/ml), coagulopathy, liver dysfunction, and other end organ involvement (Shalabi et al. 2021). It may occur at the same time as CRS or after it has resolved. Patients should be monitored closely with an increase in blood test including full blood count, liver function, ferritin, CRP and coagulation. HLH/MAS can be seen in severe CRS and the patient and likely to be in intensive care if organ support is required.

A survey in EBMT centres reported an absence of standard protocols (Sandler et al. 2020). Neelapu et al. (2019) also reported there are no formal guidelines for the management of CAR-T-associated HLH/MAS which currently exist. Throughout the literature the general recommendations are for anakinra) a recombinant humanised IL-1 receptor antagonist) and corticosteroids. The EBMT best practice guidelines outline a table from expert opinion based on a literature review with timings and dosage detailed. The nurse's role is fundamental for vigilance in monitoring and prompt escalation to the medical team.

# **7.11.5 Immune Efector Cell-Associated Neurotoxicity Syndrome (ICANS):**

Neurological toxicity is the second most reported toxicity following CAR-T treatment (Neelapu et al. 2017). The incidences vary depending on the clinical trial reporting and ranges from 20–60% of CD19 CAR-T patients (grade ≥3, 12–30%). Onset is typically 3 to 5 days after CAR-T but can occur concurrently with/shortly after CRS, and 10% of patients develop 'delayed ICANS' more than 3 weeks after infusion (Hayden et al. 2022). Patients that have early and severe CRS are at risk for ICANS, showing that the severity and early onset of CRS as measured by the extent of fever within 36 h of the infusion, hemodynamic instability, tachypnea and hypoalbuminemia refecting loss of vascular integrity and capillary leakage (Yakoub-Agha et al. 2018). Therefore careful monitoring and vigilance of patients is essential in nursing care.

Initially neurological toxicity was named CAR-T cell-related encephalopathy syndrome (CRES); however, the ASTCT consensus grading 2018 renamed the syndrome immune effector cell-associated neurotoxicity syndrome (ICANS). This was more inclusive of other symptoms, as well as to acknowledge other cellular immunotherapies and therapeutics, such as bispecifc antibodies, that may have similar neurologic side effects (Lee et al. 2018).

ICANS is less well understood and the pathophysiology is likely to be due to the combination of infammatory cytokines increasing vascular permeability; endothelial activation leading to blood-brain barrier breakdown (Hayden et al. 2022).

ICANS can present with a subtle onset. The utilisation of the ASTCT immune effector cell encephalopathy (ICE) score is an essential tool for nurses to effectively grade ICANS. Similar to CRS grading, it consists of a grade 1–4. This grading consists of a series of nine questions and a written sentence, with 1 point for every question the patient answers correctly. The patient will be asked these usually twice a day, or more frequent if they deteriorate. An example of assessment is below (Table 7.4):

The grade will be calculated based on the patients score. The frst signs for example could be diffculty in word fnding in changes in their writing. The nurse has a fundamental role in ensuring clear documentation and effective communication between each shift and to the medical team.

Grade 1: This constitutes an ICE score of 7–9, meaning the patient has at between 1–3 questions wrong. The patient requires close monitoring, and investigations such as MRI, EEG and LP as clinically indicated.

Grade 2: The ICE score is 3–6. Investigations will be as grade 1. Medications should be reviewed in case there are any diffculties in swallowing or increased confusion. Corticosteroid therapy with a rapid taper is indicated for grade ≥2 ICANS (Hayden et al. 2022). There will need

to be discussion with a neurologist and also intensive care.

Grade 3: The ICE score is 0–2. The patient should be managed in intensive care, due to altered level of consciousness and potential seizures. Patients with grade 3 ICANS have severe global aphasia and do not speak or follow commands even when wide awake and thus may be unable to answer any of the ICE questions (Lee et al. 2018). Imaging may show local/focal oedema. Steroids are indicated at grade 2 and the patient should be commenced on levetiracetam if seizures clinically or on EEG and status epilepticus with benzodiazepines (Hayden et al. 2022).

Grade 4: The ICE score is 0 on the ICE assessment due to being unarousable and unable to perform the ICE assessment. This depressed level of consciousness should be attributable to no other causes, for example, no sedating medication (Lee et al. 2018). Seizures are described as lifethreatening prolonged seizure (>5 min); or repetitive clinical or electrical seizures without return to baseline in between. The may be deep focal motor weakness such as hemiparesis or paraparesis. There is also potential for elevated ICP/ Diffuse cerebral oedema on neuroimaging; Decerebrate or decorticate posturing; or Cranial nerve VI palsy; or Papilledema; or Cushing's triad (Lee et al. 2018). The patient should be managed in intensive care and may require mechanical ventilation for airway management and seizures.

Whilst Tocilizumab is effective for CRS, there is limited effcacy for ICANS due to not crossing the blood brain barrier (Schubert et al. 2020) and should only be administered if the patient has concurrent CRS. Corticosteroids are the main recommended treatment, with agents such as Siltuximab and Anakinra but clinical data on their utility in ICANS is limited (Hayden et al. 2022).

ICANS is a complex and challenging toxicity and patients can deteriorate rapidly. Most patients, however, do respond to treatment and it is considered a reversible toxicity. Due to the possibility of late ICANS, patients should be advised not to drive for up to 8 weeks post product infusion, this is recommended by all the current licensed products.

The EBMT best practice guidelines (Hayden et al. 2022) illustrated in Fig. 7.3 outlines management of the patient with ICANS.

The use of ICE in children may be limited to those age ≥12 years with suffcient cognitive ability to perform it. In children age <12 years,

**Fig. 7.3** The EBMT best practice guidelines (adapted from Hayden et al. 2022)

**Fig. 7.4** Cornell assessment of pediatric delirium (CAPD) to assess encephalopathy in children <12 years. Adapted from Lee et al. (2018)

the Cornell Assessment of Pediatric Delirium (CAPD) is recommended to aid in the overall grading of ICANS (Lee et al. 2018) (see Fig. 7.4).

# **7.12 Discharge**

Discharging the patient can be arranged when they are deemed medically ft and has recovered from any toxicities. The patient and family should be appropriately prepared and supported with information to go home with.

# **7.13 Follow Up Process**

Follow up for CAR-T recipients can be considered in three phases

The process for admission to D+28 is described in previous sections.

# **7.13.1 Medium-Term Follow-Up**

Information provided to the patient and carers at discharge should include complications, signs to report and to who and advice on delayed TLS/ CRS and ICANS. While rare, these can occur at this stage and should be managed according to standard unit protocols.

Testing can vary according to disease, product and unit, however the table, patient monitoring during medium-term follow-up (Hayden et al. 2022) offers a standardised approach in line with EBMT/EHA recommendations.

# **7.13.2 Infectious Complications**

Prior treatment with HCT, bridging and CRS/ ICANS therapy contribute to infection risks. Prolonged neutropenia beyond D+30 affects approximately a third of patients while lymphopenia can take as long as 2 years to resolve (Burstein et al. 2018) and even then, only in 86% of patients.

Most infections in the frst 30 days are bacterial and respiratory viruses with viral infections predominating beyond D+30 (Strati et al. 2021).

Anti-viral and anti-pneumocystis prophylaxis are routinely recommended while anti-bacterial is only considered in cases of prolonged neutropenia.

Prolonged Cytopenias: Patients receiving cellular therapy treatments may have issues with prolonged cytopenias. Haematological recovery after lymphodepletion and CAR-T cell infusion varies across CAR-T cell products; however, haematological recovery for CD19-directed CAR-T cell therapies may be more delayed (Maus et al. 2020). Early cytopenias can be attributed to LD chemotherapy; however, the pathophysiology remains poorly understood and there may be product-intrinsic and/or disease-specifc factors. Bone marrow biopsy may be useful beyond day 28 to exclude recurrent disease, hemophagocytosis and, rarely, myelodysplasia (Hayden et al. 2022)

Reports of cytopenias lasting more than 30 days have been reported in both patients receiving both axicabtagene ciloleucel and tisagenlecleucel (Neelapu et al. 2017; Schuster et al. 2019). Therefore providing ongoing potential challenges for both the patient and clinical teams. Prophylactic antimicrobials against bacterial and/or fungal infections should be considered in patients with prolonged grade 4 neutropenia. In addition, if the conditioning therapy included fudarabine, prophylaxis against herpes zoster and *Pneumocystis jiroveci* pneumonia is recommended for at least 1 year (Neelapu 2019). Cellular therapy centres will a have local policy to support post CAR-T prophylactic medications.

Patient will continue to be supported in the outpatient setting requiring regular blood tests and assessment for toxicities. GCSF can be used in prolonged cytopenias, G-CSF can be used for severe neutropenia (<0.5 × 109 /L) from day +14 onwards, following as long as CRS/ICANS has resolved (Hayden et al. 2022). Local policy should be followed for support with anaemia and or thrombocytopenia. These cytopenias usually resolve in most patients, and they do not seem to place patients at a major risk of late-onset complications (Locke et al. 2019).

The patient should have regular follow -up support and information on risk factors of cytopenias such as infective complications. There may be shared care between the referring centre and cellular therapy centre, therefore clear lines of communication between both and the patient are required.

# **7.13.3 B Cell Aplasia and Hypogammaglobulinemia**

B cell aplasia is ongoing in about a quarter of responders at 12 months (Frigault et al. 2019) and hypogammaglobulinemia can result in serious or recurrent/chronic infections necessitating replacement therapy. Both B cell aplasia and hypogammaglobulinemia can be seen in patient post cellular therapy and is well documented in CAR-T therapy when CD-19 is the target. The on-target off-tumour effect of CD19-directed CAR-T cells on normal B cells, B cell aplasia and hypogammaglobulinemia are expected toxicities after CD19-directed CAR-T cell treatment (Schubert et al. 2020). This means the CAR-T cells are targeting normal B cells as well as malignant ones. It occurs in all responding patients and can persist for several years (Yakoub-Agha et al. 2018).

# **7.13.4 Vaccinations**

Vaccination guidance follows similar principles to that used following HSCT starting from 3 months after infusion with infuenza and SARS-COV-19, inactivated vaccines later from 6 months and live vaccines from 1 year or later depending on status of immune reconstitution or if allo-HSCT history or immunoglobulin replacement. Vaccine responses are likely to be lower in this group; however, the consensus view is that vaccination may reduce infection rates and improve clinical outcomes (Hayden et al. 2022).

# **7.14 Psychological Care**

Patient-reported outcomes from 40 patients 1–5 years after CAR-T therapy revealed depression, anxiety and cognitive diffculty in 19/40 with 7/19 reporting diffculty in two areas and 2/19 patient reporting diffculty in all three areas (Ruark et al. 2020). In this study, having more post-CAR-T cognitive diffculties appeared to be associated with worse global mental health and global physical health. Furthermore, that almost 50% of the patients in this cohort reported at least 1 clinically meaningful neuropsychiatric outcome, strongly indicates that a signifcant number of patients would likely beneft from some form of psychological support or mental health service following CAR-T therapy.

A multi-disciplinary team approach that takes a comprehensive clinical and holistic view of these patients is essential. This should include CAR-T physicians, disease-specifc physicians, specialist nurses, data managers and clinical trial staff as well as psychosocial health professionals to capture the range of needs that may be experienced by these patients in the long-term follow-up period.

Complementary and essential to this is the ongoing relationship and liaising with the referring centres which is just as critical to patient care as at the initial time of referral. Distributing protocols and policies and providing continued opportunities for referral staff education can help to sustain shared care arrangements which are especially important for those patients referred from a greater distance.

# **7.15 Post 30–100 Days: Relapse/ Non-response/Disease Progression/Therapy**

Post day 28 patients should be reviewed regularly. In contrast to post autologous and allogeneic transplant patients, little is known about the long-term effects of CAR-T cell therapy beyond 1–2 years. Only a small cohort of patients has been followed for more than 2 years. The identifed complications include prolonged cytopenias, hypogammaglobulinaemia and delayed B and T cell immune reconstitution with consequent atypical infection. Other longer term toxicities may emerge with longer term follow-up of larger cohorts of patients. Exact timing of discharge will be based on the clinical condition of the patient, availability of carers, pre-existing comorbidities, distance from home to hospital and suitability for ambulatory discharge care.

Routine blood tests will be taken at each follow-up clinic within the frst 100 days and should include, FBC, biochemistry, liver profle, fbrinogen, CRP and viral pcr of CMV and EBV, and immunoglobulin levels. Assessing immune recovery with Immunophenotyping monthly for 3 months followed by 3 monthly for 1 year is recommended alongside fow cytometry for CAR-T persistence (Hayden et al. 2022). Relapse of the original disease is the largest risk, but patients may develop new problems such as a second malignancy, neurological, immune or haematological disorders. Similar to allograft patients, CAR-T recipients also require lifelong irradiated blood products and they should be given patient information and an alert card upon discharge. Patients must be made aware of the potential symptoms of delayed neurological toxicity and advised that they should refrain from driving or operating heavy or potentially dangerous machines until at least 8 weeks post infusion or until resolution of neurologic adverse reactions if longer. Patients experiencing a seizure should inform their countries driving regulators and refrain from driving until authorised to do so.

To prevent opportunistic infections, prophylaxis with anti-viral, anti-biotics and anti-fungal medication common to the HCT patient is employed for at least 12 months or until lymphocyte count is consistently >1 and CD4 >200, whichever is longer. IV immunoglobulins are used routinely in children (for IgG levels <400) and are considered in adults with recurrent infections with encapsulated organisms and hypogammaglobulinaemia <4 g/L (Hayden et al. 2022).

Once clinically stable and having responded to treatment the patient can be referred back to their local teams for follow-up. Requirements for monitoring and follow-up must be shared with the referring team. Patients will also be followed up at the treating centre (in person or via remote consultation) every 6 months (in year 1) and then annually in order to monitor progress and to collect data required for EBMT. Additional follow-up appointments at the treating centre may be required in the event of complications arising from treatment, suspected relapse or as requested by the referring team.

An example of routine monitoring post D+30, this is not exhaustive, and centres will have local SOP and policies to follow, see Table 7.5.

**Table 7.5** Routine monitoring post day 30

Further specifc investigations may be undertaken as clinically indicated

*NHL* Non Hodgkin lymphoma, *ALL* acute lymphoblastic leukaemia

In patients who relapse, of which this occurs in approx. 40–60%, many have undetectable CD19 disease with CAR-T still present in the peripheral blood (Perica et al. 2018). There is no standard of treatment in the post-CAR-T relapsed setting. Patients should be enrolled in clinical trials if they are available. Other options may include salvage chemotherapies or check point inhibitors. A second treatment with CAR-T may be considered if relapse occurs more than 3 months later and tissue biopsy reveals a viable target is still evident.

# **7.16 Long-Term Follow-Up (LTFU):**

Unlike the HSCT setting, the LTFU period starts much earlier at D+100. Hypogammaglobulinemia, infection and prolonged cytopenia are common (Cordeiro et al. 2020). In the same late events paper, reporting patients who survived at least 1 year after treatment, subsequent malignancies occurred in 15% of patients including 5% with MDS.

Screening for second malignancies is recommended through the standard cancer screening programmes (cervical, breast, colorectal) with monitoring of full blood counts for late cytopenia and a low threshold for bone marrow biopsy to exclude secondary MDS/AML (Hayden et al. 2022).

# **7.17 JACIE**

Since the approval of CAR-T in Europe and the expanding role of immune effectors cells, the standards have changed to refect this. Chapter 1 covers JACIE and Quality Management in HSCT: Implications for Nursing.

# **7.18 EBMT/EHA/GoCART-Further Education**

Immune effector cells have seen progression in recent years. The complexity and rapid changes in the feld of cellular therapies demands wide collaboration to maintain up-to-date education on the entire pathway from collection to the manufacturer and back to the clinical unit. GoCART, a multistakeholder coalition launched by EBMT and EHA, offers a platform to provide the required diversifed and topic-specifc education on CAR-T cell therapies (Kröger et al. 2022). There are many resources available for nurses to learn more about this complex area. EBMT/EHA and GoCART provide excellent European educational opportunities of CAR-T and other immunotherapy treatments.

# **References**

chimeric antigen receptor modifed T cells. Biol Blood Marrow Transplant. 2020;26(1):26–33.

chimeric antigen receptor-modifed T-cell immunotherapy. Blood. 2017;131:121–30. https://doi. org/10.1182/blood-2017-07-793760.

Petropoulos D, Gill JB, Duncan CN, Lehmann LE, Hingorani S, Angelo JR, Swinford RD, Steiner ME, Hernandez Tejada FN, Martin PL, Auletta J, Choi SW, Bajwa R, Dailey Garnes N, Kebriaei P, Rezvani K, Wierda WG, Neelapu SS. Diagnosis, grading and management of toxicities from immunotherapies in children, adolescents and young adults with cancer. Nat Rev Clin Oncol. 2021;18(7):435–53.

**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

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# **BMT Settings, Infection and Infection Control 8**

John Murray, Emanuela Samarani, Chiara Renica, Iris Agreiter, Laura Orlando, and Daphna Hutt

#### **Abstract**

Despite improvements over the past several decades, infection remains a signifcant risk to all haematological patients receiving therapy. Those requiring allogeneic transplant and especially those that have HLA disparity or T-celldepleted grafts have an even higher risk of infective complications due to delayed recovery of T- and B-cell function. Patients receiving CAR-T therapy also present unique problems related to their B cell aplasia. Early identifcation with prompt effective treatment is paramount to improve all patients' survival. The recent pandemic has further highlighted patient safety through robust adherence to hand

J. Murray (\*)

E. Samarani · C. Renica Unit of Blood Diseases and Stem Cell Transplantation Department of Clinical Oncology, ASST Spedali Civili di Brescia, Brescia, Italy

I. Agreiter · L. Orlando Istituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland

D. Hutt

hygiene and maintenance of the environment with cleaning and disinfection as the backbone of an effective infection preventative program. Basic nursing care and a sound knowledge base of the risks, presentation, diagnosis and treatment will improve patient care.

#### **Keywords**

Viral infection · Bacterial infection · Fungal infection · Handwashing · Isolation

# **8.1 Introduction**

Infection is a major cause of mortality and morbidity in haematopoietic cell transplantation (HCT) and chimeric antigen receptor T-cell (CAR-T) recipients due to regimen-related toxicity. Improvements over the past couple of decades especially in supportive care have helped to reduce this risk. The development of neutropenic fever is a frequent occurrence, and centres have algorithms for identifying and treating infection promptly. In this chapter we discuss the common viral, bacterial and fungal infections that our patients develop.

Mackall et al. (2009) displays the variety of infections in Fig. 8.1 that may occur and the approximate timeframe for their development which aids the clinical team to refne and direct investigations and potential treatments appropriately.

<sup>©</sup> The Author(s) 2023

M. Kenyon, A. Babic (eds.), *The European Blood and Marrow Transplantation Textbook for Nurses*, https://doi.org/10.1007/978-3-031-23394-4\_8

Haematology and Transplant Unit, The Christie NHS Foundation Trust & The University of Manchester, School of Medical Sciences, Manchester, UK e-mail<EMAIL_ADDRESS>
Department of Pediatric Hematology-Oncology and BMT, Edmond and lily Safra Children Hospital, Sheba Medical Center, Tel-Hashomer, Israel e-mail<EMAIL_ADDRESS>
<sup>123</sup>

**Fig. 8.1** Phases of opportunistic infections among allogeneic HCT recipients. *HHV6* human herpesvirus 6, *NK* natural killer, *PTLD* post-transplant lymphoproliferative disease (Mackall et al. 2009)

# **8.2 Viral Infections**

Viral infection is spread by close contact with infectious secretions, either by large particle aerosols, formites or subsequent self-inoculation. Coughing and sneezing will produce aerosol particles, and a virus can also be picked up after contact with contaminated surfaces.

# **8.2.1 Cytomegalovirus**

#### **<IP_ADDRESS> Introduction**

Cytomegalovirus (CMV) disease is a serious potential complication of HCT leading to lifethreatening complications. CMV is usually acquired in childhood. It is a virus that is present worldwide, and whilst in developed countries approximately 50% of the population is seropositive, this rises to almost 100% in developing countries. CMV is shed intermittently from the oropharynx and from the genitourinary tract of both immunocompetent and immunosuppressed people. Prior to allograft the serostatus (IgG) of the patient and potential donors are assessed to gauge risk (Zaia et al. 2009).

CMV belongs to the human herpes virus family HHV5 and comes from the subfamily betaherpesvirinae. Betaherpesvirinae infects the mononuclear cells, establishes latency in the leukocytes and once reactivated replicates slowly. CMV is able to lie dormant for protracted lengths of time, and immunity to the CMV complex involves both the humoral and cell-mediated pathways. Patients treated with HSCT in the context of haematological malignancies can reactivate the latent virus, either from native host leucocytes, from those derived from the donor, or from both (Girmenia et al. 2019). The risk of reactivation varies dependent upon the patient and/or donor's previous exposure to CMV. CMV status can be shown as follows:

Risk factors for *CMV reactivation*

Risk factors for *primary CMV infection*

#### **<IP_ADDRESS> Presentation**

CMV can occur as a primary infection or as a reactivation of the previously latent virus. When a CMV IgG-negative patient develops CMV, this is termed a primary infection. When a patient, or donor, is known to be CMV antibody positive and then develops CMV, this is termed reactivation. The diagnosis of CMV disease requires the presence of symptoms and signs compatible with end-organ damage, together with the detection of CMV. If left untreated, asymptomatic CMV infection can progress to CMV disease.

#### **<IP_ADDRESS> Diagnosis**

It is important to diagnose reactivation early and institute timely treatment; therefore, regular monitoring of CMV levels is of paramount importance. Polymerase chain reaction (PCR) is the most sensitive and quantitative method of monitoring at-risk patients especially in the early post-transplant period (until at least day 100 post transplant) and longer in those on systemic immunosuppression.

CMV infection most commonly affects the lung, gastrointestinal tract, eye, liver or central nervous system, with CMV pneumonia being the most serious complication with >50% mortality (Tomblyn et al. 2009).

All HCT patients and donors will have their CMV status tested in clinic pre-transplant along with the CMV status of the donor.

#### **<IP_ADDRESS> Monitoring and Surveillance**

For disease monitoring post transplant, all patients who are seropositive themselves or whose graft is seropositive must receive at least weekly monitoring by whole blood (EDTA sample) PCR. This monitoring must continue whilst the patient is considered high risk of reactivation; the frst 100 days post transplant or until systemic immunosuppression has been discontinued, and there is no evidence of graft versus host disease (Girmenia et al. 2019).

#### **Prophylaxis**

#### **Letermovir**

In solid organ transplant, ganciclovir and valganciclovir are often used, however, due to high levels of myelosuppression in HCT this course of treatment is not followed. In a pivotal registration Phase 3 clinical trial, prophylaxis with letermovir signifcantly reduced the incidence of clinically signifcant CMV infection after allo-HCT and was approved for use as prophylaxis in adult CMV seropositive recipients in 2017 and is undergoing further studies in children (Marty et al. 2017). Letermovir has been adopted by many centres as prophylaxis https://www.medicines.org.uk/emc/product/11798/smpc#gref (accessed 25 October 2021).

#### **<IP_ADDRESS> Treatment**

Treatment of CMV reactivation will be undertaken following two consecutive positive CMV PCR levels at, or greater than, the limit of sensitivity, 500 copies/ml or one result of greater than 1000 copies/ml (or depending on local policy). Treatment will also be initiated regardless of PCR if signs of organ-specifc disease are identifed. Some centres may adopt a policy of preemptive treatment; please refer to your own institution guidelines for advice (Girmenia et al. 2019).

The treatment regimen is often undertaken as an in-patient. In which case, frst-line therapy is with intravenous ganciclovir. An outpatient oral alternative is valganciclovir, but can lead to signifcant bone marrow suppression (neutrophil count less than 1 × 109 /l) or treatment failure with rising viral levels or evidence of viral resistance after at least 1 week of treatment (Maffni et al. 2016).

Second- and third-line treatments are with foscarnet and cidofovir. Foscarnet may be adopted as a frst-line treatment if the patient reactivates within the frst month of transplant when blood counts have not fully recovered as it is less myelotoxic than ganciclovir. It does, however, have more renal complications, and regular electrolyte replacement is often required. Maribavir is a phase 3 trial drug that is waiting for approval but has shown to have less renal toxicity or marrow suppression and may be a substitute (Maffni et al. 2016).

Cidofovir leads to renal impairment, and a urine sample should be tested prior to infusion for the presence of protein. If proteinuria is greater than 2 on dipstick, or renal function has deteriorated (please refer to hospital/unit guidelines), then cidofovir should not be given.

# **Ganciclovir and Valganciclovir, Dosing and Administration for Nursing Staff**

For detailed instructions consult the summary of product information at these website addresses

# https://www.medicines.org.uk/emc/ product/10242#gref

# https://www.medicines.org.uk/emc/ medicine/9315#gref (accessed 15 October 2021)

Ganciclovir is an irritant; it is alkaline and may cause chemical phlebitis, so care should be taken to observe the cannula and ensure that it is functioning well prior to each use.

Valganciclovir is the oral prodrug of ganciclovir, so the same considerations should be made as when using ganciclovir.

Ganciclovir and valganciclovir treatment commonly results in cytopenias, and extreme caution should be applied when using it in patients with impaired bone marrow function (neutrophils <1 × 109 /l or platelets <50 × 109 /l), and the drug is contraindicated with severely impaired bone marrow function (neutrophils <0.5 × 109 /l or platelets <25 × 109 /l).

#### **Toxicity**

Teratogenicity has been shown in animal models and therefore care should be taken in handling the drug. It should not be administered by pregnant staff.

Gastrointestinal toxicity is common with nausea, vomiting and diarrhoea and should be recorded. Other drugs, e.g. ciclosporin, amphotericin B or MMF, may also potentiate the toxicity of ganciclovir; for further details consult the SmPC email link or discuss with your pharmacist or lead clinician.

# **Foscarnet Dosing and Administration for Nursing Staff**

For detailed instructions consult the summary of product characteristics at this website address

https://www.medicines.org.uk/emc/product/874/smpc#gref (accessed 15 October 2021)

Foscarnet is an irritant; it is alkaline and causes chemical phlebitis; therefore it must be diluted if administered via a peripheral vein; the undiluted solution may be used if administered via a central venous catheter.

#### **Toxicity**

Nephrotoxicity is a major side effect, with 12–30% of patients showing a signifcant decline in renal function. Electrolyte disturbance occurs frequently with low magnesium, calcium, phosphate and potassium most commonly requiring regular monitoring at least once daily whilst on treatment and following therapy. Local ulceration in the genital area may also occur in both men and women due to irritants excreted in the urine, and patients should be informed of this at the start of treatment and asked to be vigilant and inform staff if and when this occurs. Strict hygiene should be advised to reduce risk of skin ulceration.

# **Treatment with Cidofovir Dosing and Administration for Nursing Staff**

For detailed instructions consult the summary of product characteristics at this website address

https://www.medicines.org.uk/emc/product/11151/smpc#gref (accessed 15 October 2021)

Cidofovir is administered once weekly for two consecutive weeks then given as maintenance two weeks after the completion of induction treatment, administered once every 2 weeks.

#### **Toxicity**

Renal dysfunction is the major dose-limiting toxicity and may be irreversible, to minimize this, hydration and probenecid must be administered with each dose of cidofovir. In patients with hypersensitivity to probenecid or sulphacontaining drugs, cidofovir is likely to be contraindicated. Eighty percent of patients develop proteinuria due to tubular dysfunction whilst on therapy.

# **Treatment with Maribavir Dosing and Administration for Nursing Staff**

For detailed instructions consult the summary of product characteristics at this website address

https://www.sps.nhs.uk/medicines/maribavir/ (accessed 25 October 2021).

Maribavir inhibits DNA replication, maturation and nuclear egress a distinct mechanism of action. It is given as 400 mg twice daily oral medication. In a phase 3 Solstice trial, Maribavir was found to be superior compared to conventional antiviral therapies in refractory resistant CMV patients post transplant. At the time of writing, it is an investigational treatment waiting for approval (Marty 2021).

# **8.2.2 EBV**

#### **<IP_ADDRESS> Introduction**

Epstein-Barr virus (EBV) is a latent herpesvirus that is thought to infect as much as 95% of the adult population by the age of 40 years. It is an enveloped and double-stranded DNA virus human herpesvirus 4 (HHV4). Primary infection with EBV usually results in mild, self-limiting illness of the oropharynx in childhood and the clinical syndrome of infectious mononucleosis in adults and is often asymptomatic (Hamad et al. 2020).

During the primary infection, an immunocompetent individual will mount a vigorous response. Once the initial infection has cleared, the linear EBV genome becomes circular, forming an episome in the preferentially infected B cells and becomes established as a latent infection awaiting reactivation for life (Hamad et al. 2020). Antiviral agents such as ganciclovir inhibit the replication of the linear EBV-DNA but are ineffective against episomal DNA. These drugs therefore fail to prevent B-cell proliferation and are of no clinical use in treatment plans (Rasch et al. 2014).

Epstein-Barr virus post-transplant lymphoproliferative disease (EBV-PTLD) results from outgrowth of EBV-infected B cells (that are normally controlled by an effective EBV-specifc cytotoxic T-cell response) that occurs in the immunocompromised host (Deeg and Socie 1998; Heslop 2009). PTLD are classifed as either early-onset lesions which develop within 1 year or late onset occurring greater than a year post transplant (Ibrahim and Naresh 2012).

# **<IP_ADDRESS> Risk, Presentation and Manifestations**

Post-transplant lymphoproliferative disease (PTLD) is a rare but potentially life-threatening disease with an incidence of 0.5–17%. There are several risks that lead to increased likelihood of developing EBV-PTLD. These include over 50 years of age, splenectomy, reduced intensity conditioning, HLA mismatch, EBV donor and recipient serology mismatch, umbilical cord or haploidentical transplant, use of ATG or alemtuzumab, acute GvHD and CMV reactivation (Hamad et al. 2020).

The clinical manifestations of PTLD vary widely and may include nonspecifc symptoms such as fever, malaise, sweats, weight loss and in some cases obvious enlargement of lymphoid tissue (Ibrahim and Naresh 2012).

EBV viral load surveillance by PCR in whole blood is widely accepted as the preferred method of monitoring patients (Hamad et al. 2020). The European Conference on Infectious Diseases (ECIL-6) has no specifc recommendations. However, ECIL guidelines advise starting monitoring within 4 weeks of transplant until cellular reconstitution, approximately 4 months. This will be longer in those who received alemtuzumab or ATG and had haplo transplants or developed GvHD (Styczynski et al. 2016). It is presumed that EBV is transmitted from donor to recipient via the graft at a time of considerable immunosuppression for the recipient, or the patient develops primary EBV infection unrelated to donor EBV status. It is, therefore, advisable if possible to choose a seronegative donor if one is available. Reactivation is common but does not always lead to end-organ disease requiring treatment (Styczynski et al. 2009).

#### **<IP_ADDRESS> Diagnosis**

The pathological diagnosis of PTLD is based on the WHO classifcation and includes four main categories and is the basis for the UK BCSH guidelines (Swerdlow et al. 2008):

In practice, a clear separation between the different subtypes is not always possible, Styczynski et al. (2009) published defnitions of EBV that are in common use across Europe.

Early diagnosis is important so that treatment can be initiated promptly. The exact copy or log number to commence therapy has not yet been fully established. Action from a blood test alone is not indicated and should be in parallel with clinical symptoms such as fever and lymphadenopathy and imaging studies (Heslop 2009).

Whether PTLD presents as localized or disseminated disease, the tumours are aggressive and rapidly progressive and often are fatal if untreated in a timely manner (Deeg and Socie 1998).

#### **<IP_ADDRESS> Treatment**

Withdrawal of immunosuppression in the frst instance to allow recovery of the host's immune system to control the disease works in 0–73% of patients; an extremely variable response. This also may come at considerable risk of graft rejection or GvHD. An alternative option is to switch a calcineurin inhibitor to an m-TOR inhibitor. If patients are still positive then treatment with rituximab monoclonal antibody (anti-CD20) once a CT scan and if possible biopsy has been taken (Hamad et al. 2020).

Rituximab has been shown to improve outcome when initiated early as it targets B-cellspecifc surface antigens present on the EBV-transformed malignant cells. Rituximab is a chimeric murine/human monoclonal anti-CD20 antibody. As CD20 cells are expressed not only on malignant cells, normal B cells are destroyed in a patient who will already be immunocompromised and may lead to other viral infections. The effect of rituximab on the B-cell compartment can be up to 6 months following treatment and should, therefore, be used with caution and under strict surveillance in specialist centres. Rituximab used alone has response rates reported as 60–80%.

Adoptive T-cell therapy with CTLs has been used for several years and it shows good responses around 60%. There are trials ongoing to explore this further such as III MATCH. Failure to respond to removal of immunosuppression and single-agent rituximab as well as failure of adoptive cellular immunotherapy leads to the option of chemotherapy in the form of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone), although this is associated with a mortality of 27% in this setting (Hamad et al. 2020; Rasch et al. 2014).

# **8.2.3 HHV6**

#### **<IP_ADDRESS> Introduction**

There are two species of human herpes virus, HHV6, A and B. Human herpesvirus 6B (HHV6) is a ubiquitous virus, and more than 90% of the population over the age of 2 years are seropositive as it is easily passed person to person via saliva (Ward et al. 2019). Unlike other viruses, HHV6B can integrate into chromosomes as a mechanism of latency. This results in a condition referred to as inherited chromosomally integrated HHV-6 (iciHHV6-6). Almost all HHV6 reactivations post allograft are type B (Hill 2019).

#### **<IP_ADDRESS> Presentation**

HHV6B may be associated with the development of encephalitis (Ward et al. 2019). Clinically patients present 2–6 weeks post allograft with delirium, amnesia, confusion, ataxia and seizure. During the transplant process, HHV6 has been cited by Zerr et al. (2005) to cause a delay in engraftment with up to 60% more platelet requirements in those who become positive.

#### **<IP_ADDRESS> Diagnosis**

Diagnosis is made from PCR testing in symptomatic patients. On magnetic resonance imaging (MRI) of the head, there are hyperintense lesions noted, and these are referred to as post-transplant acute limbic encephalitis (PALE). Upon examination of the cerebrospinal fuid (CSF), HHV6 DNA is observed (Ward et al. 2019).

#### **<IP_ADDRESS> Treatment**

Foscarnet and ganciclovir are the recommended treatments and should be started as soon as possible following symptoms suggestive of HHV6 (Hill 2019).

# **8.2.4 Varicella Zoster Virus**

#### **<IP_ADDRESS> Introduction**

Varicella zoster virus (VZV) infection or chickenpox is usually a childhood disease, and transmission is either by inhalation of respiratory secretions or direct physical contact. Following exposure the virus remains latent in the dorsal root ganglion, and when it reactivates, it is referred to as "shingles" or herpes zoster. Herpes zoster is grouped painful vesicular lesions that can affect several dermatomes in immunocompetent people. In the setting of allogeneic HSCT, VZV carries a major risk of morbidity and mortality with 18–52% patients having clinically apparent infection related to reactivation of latent virus; however, with the use of aciclovir, this number has decreased (Thomson et al. 2005). Complications such as post-herpetic neuralgia, skin scarring and bacterial superadded infection are factors in morbidity (Steer et al. 2000; Boeckh et al. 2006).

#### **<IP_ADDRESS> Risk Factors**

All HSCT patients should receive prophylaxis for VZV with oral aciclovir or valaciclovir for 6 months to 1 year (according to local policy) or until immunosuppression is discontinued (Kanda et al. 2001). Transmission of VZV is diffcult to prevent as the period prior to symptoms where an individual is contagious can be up to 48 h before the appearance of a rash. The incubation period varies from 10 to 21 days, and an individual remains contagious until all of the vesicles have crusted over. If the immunocompromised patient is in contact with an individual with VZV infection (varicella or HZ), they are at signifcant risk of developing varicella themselves and will require prompt action from the transplant team (Styczynski et al. 2009).

HSCT will probably destroy any previous immunity to VZV. Immunization of family contacts especially children is advised to reduce risk.

#### **<IP_ADDRESS> Presentation**

VZV infection occurs in 40–50% if prophylaxis stopped at 6–12 months, with a peak incidence around 5 months and a spread of 2–10 months, usually occurring within 5 weeks of cessation of oral prophylaxis (Steer et al. 2000). Risk factors include unrelated donors, myeloablative conditioning, GvHD and the use of systemic corticosteroids. The rash may spread to more than 1–3 dermatomes in patients with visceral dissemination and is more diffcult to treat.

#### **<IP_ADDRESS> Diagnosis**

The best method for diagnosing VZV is by PCR testing of blood or a glass slide touched to a vesicle as the DNA is highly specifc and sensitive.

#### **<IP_ADDRESS> Treatment**

Treatment with high-dose aciclovir, valaciclovir or famciclovir (nucleoside analogues that interfere with viral thymidine kinase activity) can be employed.

Post treatment for VZV, it is advisable to restart prophylactic aciclovir if this was previously discontinued. The length of time prophylaxis should be continued will be guided by local policy and may range from 1 year to lifelong.

#### **<IP_ADDRESS> Vaccination**

Shingrix can be used in patients who are immunocompetent post transplant and are aged over 50 years, this is a non-live vaccine given as two doses, 2 months apart (Kamboj and Shah 2019). There is a non-live adjuvanted recombinant zoster vaccine (RZV) which has been developed to prevent herpes zoster, but there are no recommendations for use in allogeneic patients (Baumrin et al. 2021). EBMT guidelines from 2005 and CIBMTR in 2009 do allow the use of a live varicella vaccine in selected patient groups starting at 24 months post HCT (Chou et al. 2011).

# **8.2.5 Hepatitis B**

#### **<IP_ADDRESS> Background**

The hepatitis B virus (HBV) is a DNA virus classifed in the hepadna virus family. Patients infected by HBV prior to transplantation have a higher risk (70–86%) of HBV reactivation 5 years after HSCT transplantation. An active immunization of donors and early post-transplant vaccination of recipients have been suggested to avoid HBV reactivation. Donors should optimally receive more than one immunization, a rather high Ag dose and a highly immunogenic vaccine (Lindemann et al. 2016).

The use of chemotherapy and immunosuppression can reactivate latent hepatitis B. Further, HBV infection or reactivation contributes to liver-related morbidity and mortality; it occurs in 21–53% of patients. Transplantation of HBVnegative patients with stem cells from an infected donor (HBsAg positive) is associated with a high risk of transmission; some patients develop chronic hepatitis B. Donors with active HBV (DNA detection) should receive, if possible, antiviral treatment (Ullmann et al. 2016).

#### **<IP_ADDRESS> Clinical Features**

Post transplant at the time of immune reconstitution or during reduction of immunosuppressive drugs, there is a rise in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Other clinical symptoms are jaundice and fulminant liver failure as a result of HBV (liver-related mortality) (Lau et al. 2003).

#### **<IP_ADDRESS> Treatment**

Lamivudine (100 mg/day) is the frst choice for antiviral therapy for treatment, which should be continued for at least 6 months following discontinuation of immunosuppressive drugs (Tomblyn et al. 2009).

#### **<IP_ADDRESS> Prevention**

Patients who undergo HCT for haematological malignancy are an "at-risk" population because of the prolonged immunosuppression following the conditioning chemotherapy.

The nucleoside analogue antiviral drugs lamivudine, adefovir, telbivudine, entecavir and tenofovir may all be of potential use in the prevention of HBV reactivation in such patients. The majority of reports describe the use of lamivudine or entecavir, and both drugs appear to reduce the incidence of HBV reactivation. However, entecavir (and potentially tenofovir) may be superior to lamivudine because of more potent viral suppression and lower risk of antiviral resistance.

Prophylaxis for HBV reactivation with antiviral nucleoside analogues should be commenced in susceptible individuals before the initiation of chemotherapy (Pattullo 2016).

# **8.2.6 Hepatitis C**

#### **<IP_ADDRESS> Background**

The hepatitis C virus (HCV) is a double-stranded RNA virus classifed within the Flaviviridae. Six major genotypes have been identifed, from HCV1 to HCV6. It can be responsible for several systemic complications. The extrahepatic manifestations include vasculitis, fatigue, cryoglobulinemia and autoimmune disorders. HCV replication is signifcantly increased by immunosuppression and may cause a direct cytopathic effect in infected cells. The identifcation of pretransplant HCV infection appears clinically relevant. Being infected with HCV has been indicated as an independent risk factor for post-transplant veno-occlusive disease (VOD) of the liver. Reactivation of chronic HCV infection after tapering immunosuppressive therapy can sometimes lead to fulminant hepatic failure (Locasciulli et al. 2009).

#### **<IP_ADDRESS> Clinical Features**

HCV adversely impacts on platelet recovery, non-relapse mortality and overall survival. Sinusoidal obstruction syndrome (SOS), liver GvHD and hepatic problems are more likely to be severe and fatal in recipients with HCV. Pretransplant HCV infection is associated with a lower rate of platelet recovery.(Nakasone et al. 2013).

#### **<IP_ADDRESS> Treatment**

All HCT recipients with HCV infection should be evaluated for HCV therapy before the start of conditioning therapy. Whenever possible, HCVinfected HSCT candidates should commence and complete HCV therapy before transplant. If there is an oncologic imperative for moving quickly to transplant, a therapy with direct-acting antiviral agents (DAAs) should be able to clear extrahepatic HCV from donors more quickly than interferon and ribavirin.

Treatment of post-transplant HCV infection must be an urgent consideration for patients with fbrosing cholestatic HCV, patients with cirrhosis whose condition is deteriorating and patients who underwent HSCT for HCV-related lymphoproliferative disorders. Once HCV therapy is initiated, treatment interruption is not recommended because it is associated with increased risk of treatment failure.

#### **<IP_ADDRESS> Prevention**

A vaccination against HCV does not exist. However, to prevent the complication of coinfection, people with hepatitis C should be vaccinated against hepatitis A and B. Standard precautions are recommended for the care and treatment of all patients (ASHM 2012).

HCV-infected donors should be evaluated for HCV therapy and treated before cell harvest, in order to prevent transmission of HCV to uninfected recipients (Torres et al. 2015).

# **8.2.7 Hepatitis E**

#### **<IP_ADDRESS> Background**

Hepatitis E virus (HEV) is a single-stranded, non-enveloped RNA virus. In areas with poor sanitation, HEV 1 and 2 are spread orofaecally between humans, usually via contaminated water. In developed countries, HEV 3 and HEV 4 are transmitted from animal reservoirs. In Western Europe the food chain is the main source of infection, (Marano et al. 2015).

There are two types of infections: acute and chronic.

#### **Acute**

Acute HEV is mostly caused by genotypes 3 and 4. Jaundice occurs in about 75% of patients.

**Table 8.1** Extrahepatic manifestations of acute and chronic hepatitis E

#### **Chronic**

No studies have assessed the prevalence or incidence of HEV infection among haematological patients receiving chemotherapy. A small number have been found to have a chronic HEV infection and include a patient with untreated hairy cell leukaemia, a patient with idiopathic CD4 T lymphopenia and patients treated for lymphoma, chronic myelomonocytic leukaemia and B-cell chronic lymphocytic leukaemia.(Kamar et al. 2014).

# **<IP_ADDRESS> Clinical Features and Developing Countries**

The incubation period varies between 2 and 6 weeks; the most common symptom of HEV is jaundice(frequency of 40%). Extrahepatic manifestations of acute and chronic hepatitis E involve the following systems and organs (Dalton et al. 2015) (Table 8.1).

#### **<IP_ADDRESS> Treatment**

In haematological patients, pegylated interferon alone and ribavirin alone for 3 months have been used (Kamar et al. 2014).

#### **<IP_ADDRESS> Prevention**

Immunocompromised patients should be screened for HEV antibodies and RNA not only prior to transplantation but also post transplantation and during episodes of liver enzyme abnormalities (De Keukeleire and Reynders 2015).

# **8.3 Adenovirus**

# **8.3.1 Introduction**

Adenovirus (ADV) is a ubiquitous non-enveloped double-stranded DNA virus. It currently has more than 100 serotypes and is divided into six subgroups A–G (Lion 2019). Adenovirus is more prevalent in children but is becoming more prevalent in adults in the transplant population.

# **8.3.2 Risk Factors**

Adenovirus is spread by aerosolization or the faecal oral route with approx. 80% of children aged 1–5 years old seropositive. Risk factors include mismatched or unrelated donor, acute GvHD and isolation of ADV from multiple sites (Ljungman et al. 2003).

# **8.3.3 Presentation**

In healthy individuals, infection is self-limiting causing conjunctivitis and upper respiratory tract, urinary tract or gastrointestinal infections and remains latent in lymphocytes post exposure. Chakrabarti et al. (2002) report a 5–29% incidence of ADV after allogeneic HSCT. Occurrence post transplant can be associated with lifethreatening clinical manifestations, multi-organ failure leading to death (Lion 2019).

# **8.3.4 Diagnosis**

Samples taken from nasopharyngeal, rectal and corneal secretions, urine and unfxed biopsy tissue can be examined with PCR to assess viral load. Low level of ADV infection does not carry a high mortality. However, those patients that develop invasive disease, such as ADV colitis, have a signifcant mortality of 20–80% (Robin et al. 2007).

# **8.3.5 Treatment**

If possible immunosuppressive therapy should be tapered as the frst step (Lion 2019). Cidofovir is frst-line treatment and is a monophosphate nucleotide analogue of cytosine. Cidofovir inhibits viral DNA polymerase and has a low bioavailability with 90% of the drug excreted in the urine. Patients require hyper hydration and oral probenecid pre, during and post cidofovir to protect nephrons.

# **8.4 Coronavirus**

Coronaviruses (CoVs) primarily cause enzootic infections in birds and mammals. Humans have become infected in the last few decades. There was an outbreak of severe acute respiratory syndrome (SARS) in 2003 with 8000 cases and 700 deaths. Then in 2012, in Saudi Arabia there was an outbreak of Middle-East respiratory syndrome (MERS) that also claimed eight hundred deaths. Both of these infections were proven to be lethal when they crossed the species barrier and infected humans (Schoeman and Fielding 2019).

The infection in humans causes disease to varying degrees, from upper to lower respiratory tract infections that lead to symptoms of a cold, bronchitis, pneumonia and even SARS (Schoeman and Fielding 2019).

# **8.4.1 SARS-Cov-2 Virus**

#### **<IP_ADDRESS> Introduction**

A new coronavirus *SARS-CoV-2* was frst reported on 1 December 2019 from Wuhan in China and spread worldwide. The outbreak was possibly linked to a zoonotic transmission at a large seafood market and is also associated with bat-derived severe acute respiratory syndrome (Fei Zhou et al. 2020). It is the causative agent of Coronavirus Disease 2019 (COVID-19) (Orchard et al. 2021). By March 11, 2020, the World Health Organization (WHO) declared a SARS-CoV-2 pandemic (WHO Director General 2020). Most countries imposed restrictions on everyday life (Ljungman et al. 2020).

#### **<IP_ADDRESS> Risk Factors**

Risk factors include increasing age, deprivation and being from black and Asian minority groups. Comorbidities such as obesity, diabetes, cancer and poorly controlled asthma were associated with increased risk of death (NHS England Green Book 2021).

#### **<IP_ADDRESS> Presentation**

Transmission is via person to person spread through respiratory aerosols and direct human contact and fomites. There is a wide clinical picture described from asymptomatic to death (Fei Zhou et al. 2020). Estimates of the basic reproduction number [R] were initially between 2 and 3 although a recent estimate was as high as 5.7 (Orchard et al. 2021). In efforts to reduce infection, measures using active surveillance, physical distancing, early quarantine and contact tracing were employed to lesser and greater effect across the world, ideally avoidance in the frst place was the most effective strategy. Time from exposure to symptoms ranged from 2–14 days (Ljungman et al. 2020).

#### **<IP_ADDRESS> Diagnosis**

Typically symptoms occur within 5–6 days (incubation period) of exposure, although about 20% of patients remain asymptomatic throughout infection (NHS England Green Book 2021). Those with symptoms suggestive of COVID-19 require testing with PCR as per National guidelines. Isolation and the use of PPE are required until the test result is known (Orchard et al. 2021). Many individuals are likely to have mild symptoms and may be asymptomatic at the time of diagnosis. Symptoms include a new onset of cough and fever, headache, loss of smell, nasal obstruction, lethargy, myalgia, taste dysfunction, sore throat, diarrhoea, vomiting and confusion.

#### **<IP_ADDRESS> Treatment**

No antiviral drug has so far proven to have an impact on the death rate following multiple worldwide trials. Lower mortality has been shown in patients given corticosteroids (Ljungman et al. 2020). Of paramount importance is supportive care from the wider multidisciplinary team.

There are several vaccines targeting the S protein authorised for use; two use an mRNA platform (Pfzer BioNTech COVID-19 mRNA vaccine BNT162b2 or Comirnaty® and Moderna mRNA-1273 COVID-19 vaccine or Spikevax®) and two use an adenovirus vector (AstraZeneca COVID-19 vaccine/Vaxzevria® and COVID-19 vaccine Janssen Ad26 COV2-S [recombinant]). None of the studies have included HSCT or CAR-T recipients (BSBMT 2021).

NHS England has been working with the British Society of Blood and Marrow Transplantation and Cellular Therapy (BSBMTCT) and Anthony Nolan to ensure that those who have received a HCT or CAR-T therapy are offered COVID-19 re-vaccination. In patients who receive HSCT or CAR-T therapy, any protective antibodies from exposure or vaccination prior to transplantation are likely to be lost and it is unclear whether the recipient acquires the donor's immunity. Any previous COVID-19 vaccination is to be discounted and it is recommended that the individual is revaccinated as if they have never received a COVID-19 vaccine. Those that should receive a third primary dose are patients within 24 months of transplant at the time of their frst or second dose, ideally at least 8 weeks after the second dose. Patients over 24 months should receive a booster dose no earlier than 6 months after completion of the primary dose (EBMT 2021; NHS England Green Book 2021).

December 2021 saw the release of two novel agents aimed at the management of nonhospitalised patients using neutralising monoclonal antibodies or antivirals in adults and children >12 years. Data showed that sotrovimab when given to non-hospitalised patients with mild to moderate disease and at least one risk factor resulted in a relative risk reduction in hospitalisation or death by 85% (Gupta et al. 2021). MOVe-OUT a phase 3 trial from Merck and Ridgeback (2021) also revealed a reduction in relative risk of 30% in the composite primary outcome of hospitalisation or death by day 29. Sotrovimab a neutralising Mab that both blocks viral entry into healthy cells and clears infected cells is administered intravenously (500 mg once only) and Molnupiravir (800 mg 12 hourly for 5 days) an antiviral therapy is given orally if sotrovimab is contraindicated or not possible. Inclusion criteria are SARS-CoV-2 infection confrmed by PCR within 5 days. Onset of symptoms of COVID-19 within the last 5 days and a member of the highest risk group. This risk group includes autologous, allogeneic and CAR-T patients. Exclusion criteria are that the patient would require hospitalisation for their infection, or new supplemental oxygen requirement specifcally for the management of COVID-19 symptoms. Children under 12 years and less than 40 kg are also excluded (NHS England Green Book 2021).

#### **<IP_ADDRESS> Nurse Implication**

Globally, there are 43.5 million healthcare workers (HCW), 2 million of whom are nurses (World Health Organisation 2020).

During the pandemic period, HCW suffered physical and emotional stress. Diagnosis included moral distress (Turale et al. 2020), anxiety, depression and post-traumatic stress disorder (PTSD) (Morley et al. 2020). These conditions required psychological, emotional and physical support. Furthermore, the re-allocation of personnel has increased the state of anxiety, potentially due to the lack of familiarity in the new role (Centers for Disease Control and Prevention 2020). These factors may result in suppressing the natural process of grief and loss and, in the long term, may lead to faster professional burnout (Ayanian 2020).

During this period the International Code of Ethics (ICN 2012) states that within nursing;

there is a respect for human rights, including cultural rights, the right to life and choice, to dignity and to be treated with respect (Turale et al. 2020)

The HCW trying to balance their obligations of benefcence and duty to care for patients with rights and responsibilities to address inadequacies within their healthcare systems in ways that are consistent with rights and duties to protect themselves and their loved ones (Morley et al. 2020).

Nurse staffng is also a critical concern during a pandemic. While there is a need to be context specifc and fuid due to the inability to predict exactly how many nurses might become unwell or need to be quarantined, there is very little guidance regarding optimal or minimum staffng levels for preparation phases, for the initiation of triage, or for adequate provision of crisis care (Morley et al. 2020). The patient outcome is directly related to nurse staffng levels (Aiken 2011, 2017).

The healthcare systems and policy responses to COVID-19 are evolving rapidly, nurses and other HCW play an important role, taking a proactive approach with multidisciplinary teams to participate in the pandemic planning within their health organizations. It is critical that nurses regularly review and follow institutional, specialist college, state level and government recommendations. Measures should be subject to an ongoing review that will refect organizational, local, state-wide and national policies (including, criteria for COVID-19 testing, self-isolation, social distancing, quarantine and personal protective equipment [PPE]) (Paterson et al. 2020; Table 8.2).

The advent of the pandemic has caught many unprepared at an organisational level, but despite this, the management of patients has been optimal during this period, through a reorganization of activities and a management of available resources.

There are signifcant opportunities to learn from this pandemic situation, starting from improving nursing practice and contributing to policy-making through evidence-based research and empowerment strategies. We also "need to improve understanding of the ethically justifed expectations regarding what the public, employers, and co-workers can reasonably expect from nurses during public health emergencies". Nurses will continue to need strong moral courage and resilience to work during this COVID-19 pandemic, in hospitals, clinics, care homes and communities around the world, and across borders and cultures (Turale et al. 2020).

At the time of writing, SARS-CoV-2 remains a signifcant problem. All patients are screened prior to admission, local practices may differ with exact timeframes. If a patient tests PCR positive, the transplant will be placed on hold even if asymptomatic. In the general population, the infection is considered not infective after 10 days. Recommendations from the CDC in the USA suggest patients may continue to produce replication-competent SARS-CoV-2 beyond 20 days and recommend a test-based strategy for management including two negative tests at least 24 h apart after resolution of symptoms for at least 24 h and improvement of other symptoms and if a patient has been persistently PCR positive beyond 30 days consider additional testing (EBMT 2021).

# **8.5 Respiratory Complications**

Pulmonary complications are a leading cause of post-transplant complications and death in HSCT recipients (Alsharif 2009; Roychowdhury et al. 2005). Post-transplant pulmonary complications are classifed as either infectious or noninfectious. The rate of complications is signifcantly lower for autologous transplant recipients than for allogeneic transplant recipients. This is because of the absent risk of GvHD in autologous transplants, the infrequent use of immunosuppressive medications such as ciclosporin or tacrolimus and the absence of radiation therapy in the preconditioning regimen (Ho et al. 2001; Kotloff et al. 2004). Methods that healthcare professionals can use to improve patient outcomes in autologous and allogeneic recipients include raising clinical awareness, improving diagnostics, shortening time to medical intervention and continuing multidisciplinary research (Stephens 2013). The spectrum of pulmonary complications for transplant recipients will continue to change, due in part to rapid advances in supportive care, the increasing age of transplant recipients, new antiviral and antifungal agents and an increasing use of prophylactic broad-spectrum antibiotics post transplant (Sharma et al. 2005). The real key, however, to decreasing morbidity and mortality in adult and paediatric HSCT patient populations remains in effective diagnostic techniques (Stephens 2013).

\* For infection control and non-hazardous drugs.

Reprinted from Seminars in Oncology Nursing, Volume 36, Issue 3, C. Paterson, et al. Oncology Nursing During a Pandemic: Critical Refections in the Context of COVID-19, 151028, Copyright 2020, with permission from Elsevier

Pulmonary infections are the largest cause of post-HSCT infective morbidity and have been reported in most recipients, carrying a mortality rate of 20% (Cooke et al. 2008; Zuccotti et al. 2005). The principal cause of infection is the severe immunocompromised status of the patients from the disease process (malignant or non-malignant), conditioning regimens (nonmyeloablative and myeloablative) and immunosuppressive prophylaxis to prevent and treat GvHD. A study by Escuissato et al. (2005) reviewed CT fndings of transplant patients and found that viral infections (51%) were the most common in post-transplant recipients, followed by bacterial infections (23%), fungal infection (19%) and protozoal infections (less than 1%). In 5% of the cases examined, patients had two or more infectious agents concurrently.

# **8.5.1 Typical Onset of Pulmonary Complications Following Stem Cell Transplantation**

Typical onset of pulmonary complications following HSCT divided into three stages based on information from Antin and Raley (2009) Camus and Costabel (2005), Coomes et al. (2010), Polovich et al. (2009) and Soubani and Pandya (2010)

pulmonary toxicity

# **8.5.2 Diagnostics**

Diagnostic techniques for pulmonary disease in HCT patients are similar to that for non-transplant patients. Chest radiograph (X-ray) and thoracic computed tomography (CT) scan remain the most popular and less-invasive options. CT scans are particularly useful when compared with twodimensional X-rays because they can expose acute and chronic changes in the lung parenchyma. Respiratory CT scans involve taking pictures of cross-sections of lung tissue using high special-frequency reconstruction during inhalation and exhalation (Stephens 2013).

Changes such as nodules, "white out" and a "glassy" appearance signal the physician and radiology staff to consider additional diagnostics (Truong et al. 2010). This could include collecting sputum samples, bronchoscopy with or without bronchoalveolar lavage (BAL), open lung biopsy and needle biopsy (Kaplan et al. 2011; Truong et al. 2010).

Sputum samples can be collected by nurses, physicians or respiratory therapists according to transplant program protocols. Respiratory virus detection is highly dependent on the type of sample collected, the time of collection after the onset of clinical symptoms, the age of the patient and the transport and storage of the sample prior to testing. Several different upper respiratory tract specimens are applicable for testing, including nasopharyngeal (NP) washes, NP aspirates and NP swabs placed in virus transport media (Specter 2009; Storch 2000). Expectorations in the early morning or after a respiratory procedure can be the easiest for the patient to produce because of the natural accumulation of secretions at these times. About 15 ml of sputum is usually required for adequate laboratory analysis (Murray et al. 2010). Sputum can also be collected during a bronchoscopy. In some cases, bronchoalveolar lavage (BAL) will be performed during the bronchoscopy. BAL involves the fushing of fuid (usually a sterile normal saline solution) into a localized area of the lower respiratory tract and then immediately suctioning the fuid up the bronchoscope and into a sterile specimen container. BAL allows for the detection and characterization of several respiratory pathogens, including viral, fungal and bacterial agents, and is

**Table 8.3** Other virus that cause infections in allo-HCT patients

considered a major diagnostic mechanism for *Pneumocystis carinii* (now called *Pneumocystis jirovecii*) pneumonia (PJP) (Forslöw et al. 2010). In patients with focal pulmonary lesions, aspergillosis or pulmonary GvHD, fne-needle aspiration biopsy is considered the frst-line diagnostic method (Gupta et al. 2021).

In the patients after allo-HCT there are other common viruses that cause infections (listed in Table 8.3) that may lead to signifcant illness and ultimately hospitalisation. Many centres screen for these on a PCR panel when assessing an unwell patients with coryzal or respiratory symptoms. There are often limited treatments available with a lack of robust data to support usage.

# **8.6 Bacterial Infections**

# **8.6.1 Gram-Positive and Gram-Negative Bacteria**

In the frst phase post allo-HCT there are two main sources of bacterial infections: endogenous gastrointestinal fora (prevalently Gram**<sup>−</sup>**) and vascular catheters (prevalently Gram**<sup>+</sup>**).

In the early stages, antibacterial prophylaxis, as well as hand washing and oral hygiene plays a very important role.

The recommended strategies to prevent healthcare associated transmission of bacteria are prompt laboratory-based identifcation, adherence to contact precautions and strict hand hygiene. More expensive approaches include dedicated equipment and staff.

Bacterial infections most commonly occur in the frst month but can occur at any time. Both gram-negative and gram-positive organisms can cause pneumonia and have signifcant morbidity and mortality in HCT recipients (Tripathi and Sapra 2021). The most common being *Escherichia coli*, *Klebsiella*, *Pseudomonas*, *Enterobacter*, *Acinetobacter*, *Staphylococcus aureus*, coagulasenegative *Staphylococcus*, *Streptococcus pneumoniae*, *Streptococcus viridans* and *Enterococcus*. One also needs to recognize the risk of *Mycoplasma* and Chlamydia infections, although the common use of fuoroquinolones will empirically treat these organisms. Other causes of late pneumonia that should not be missed include *Nocardia*, *Listeria* and *Actinomyces*.

The group of Enterococci are gram-positive aerobes and include Vancomycin-resistant Enterococci (VRE), Coagulase-negative Staphylococcus (CNS), *Staphylococcus aureus*, Methicillinresistant *Staphylococcus aureus* (MRSA), *Streptococcus viridans* and *Streptococcus pneumoniae*. These are facultative anaerobes which are seen microscopically as single pairs and short chains and are part of the normal fora of the gastrointestinal tract. In transplant recipients, enterococcal infections are usually nosocomial and occur generally as invasive infections in the immediate post-transplant period, mostly as a consequence of endogenous gram-positive translocation.

Multi-drug Resistant Organism (MDRO), are an organism with resistance to antibacterial compounds and they represent an emerging problem in public health. Resistant *Escherichia coli* and *Klebsiella pneumoniae* bacteraemia and carbapenemase producing *K. pneumoniae* (KPC) are prevalent in haematology populations. There is an increase in the rates of vancomycin-resistant *Enterococci* that are responsible for up to 41% of all gram positive bacteraemias (Trubiano et al. 2013).

In 2020 the World Health Organization declared antimicrobial resistance a worldwide threat that requires urgent action.

Table 8.4 describes the main characteristics for each named bacteria and if it is a Gram+ or Gram− organism and if it is classed as an MDRO.

#### **Table 8.4** Bacterial characteristics

# **8.7 Infection Control Management**

Adapted from Weston (2013).

# **8.7.1 Isolation**

# **8.7.2 Equipment and Cleaning**

# **8.7.3 Hand Hygiene**

rubs or gels are not effective against *Clostridium diffcile* spores and MDRO.

# **8.7.4 Personal Protective Equipment (PPE)**

# **8.7.5 Waste and Linen**

• Any clinical waste and linen, including bedding and, if present, curtains, should be considered contaminated and managed properly.

# **8.7.6 Movement of Patients**

The combination of strict hand hygiene and contact precautions (gloves and apron) signifcantly reduces the incidence of CD (Dubberke and Riddle 2009).

Further treatments of recurrent CDI are fdaxomicin, probiotics, intravenous immunoglobulin and faecal transplants.

# **8.8 Faecal Microbiota Transplant**

Gut microbiota is a complex community of microorganisms that live in the digestive tract; over the past decade, the faecal Microbiota Transplant is gaining momentum (Gomaa 2020).

The treatment with faecal microbiota therapy is done by a technique that involves transfer of fresh stool from a healthy donor to the gastrointestinal tract.

In particular faecal microbiota transplantation (FMT) has emerged as a remarkably successful treatment for recurrent *Clostridioides diffcile* infection that cannot be cured with antibiotics alone (Khoruts et al. 2021).

# **8.9 Fungal Infections**

Invasive fungal diseases are a major obstacle to patients after transplant and are a major cause of pulmonary-related mortality (Ji et al. 2011). Patients are at risk at several points; in the neutropenic pre engraftment period, particularly when suffering with oral mucositis and the mucosal barrier is compromised. During engraftment when T cell immunity has not returned, and later if there is concomitant chronic GvHD leading to a delay in immune reconstitution. *Aspergillus* is the most common and most virulent fungal cause of pneumonia following HCT (Blaes et al. 2009; Wilson et al. 2009). Other fungal respiratory infections in post-HCT patients, particularly those receiving myeloablative conditioning, include *Malassezia*, *Zygomycetes* and *Candida* species (Wilson et al. 2009). Signs and symptoms may include fever, pleuritic chest discomfort and dyspnoea.

# **8.9.1 Diagnosis**

# **8.10 Mycobacteria**

Testing with purifed protein derivative (PPD) is often not helpful after allogeneic stem cell transplantation because of depressed delayed-type hypersensitivity reactions. Therefore a skin reaction with PPD will likely not occur.

# **8.10.1 Diagnosis**

Cultured sputum sample/BAL various indirect assays such as Quantiferon gold are helpful.

# **8.11** *Pneumocystis jirovecii*

# **8.11.1 Introduction**

*Pneumocystis jirovecii* (PJP) is an atypical fungus that causes severe pneumonia in immunocompromised patients. Recognized as a protozoan initially and reclassifed in 1988 as a fungus, pneumocystis cannot be propagated in culture, and few treatment options exist for those with PJP pneumonia. It is ubiquitous with almost universal seropositivity by 2 years of age (Thomas and Limper 2004).

# **8.11.2 Risk Factors**

It is recommended that all allograft patients are adequately covered with prophylaxis for PJP for at least 6 months and up to 1 year or more if on immunosuppression with combination trimethoprimsulfamethoxazole (TMP-SMX) as this has reduced incidence of infection to approximately 5% (Castro et al. 2005). Prophylaxis usually starts at the point of engraftment or upon discharge, as TMP-SMX can cause engraftment delay.

If the patient develops any sensitivity to TMP-SMX then alternatives are pentamidine nebulizer, atovaquone and oral dapsone. (Gea-Banacloch et al. 2009).

# **8.11.3 Presentation**

Those with PJP present with symptoms of subtle onset dyspnoea, a low-grade temperature and a nonproductive cough, and when examined, the chest is clear on auscultation. However, this may rapidly change with the onset of hypoxia requiring admission to a critical care unit. Imaging of the chest with X-ray reveals bilateral perihilar interstitial infltrates that become increasingly homogenous and diffuse as the disease progresses. Computed tomography (CT) scans show extensive ground-glass attenuation or cystic lesions (Thomas and Limper 2004).

# **8.11.4 Diagnosis**

Prompt diagnosis and treatment are warranted with adherence to prophylactic cover. Diagnosis should not rely only on clinical criteria or imaging. Due to the diffculties of culturing samples, the diagnosis of PJP is made through microscopic examination of sputum or bronchoalveolar fuid or by PCR (Alanio et al. 2016).

# **8.11.5 Treatment**

Treatment is with trimethoprim-sulfamethoxazole and the addition of systemic steroids to reduce the infammatory lung processes. For those that are intolerant to trimethoprim-sulfamethoxazole, atovaquone or a combination of clindamycin with primaquine is licenced for use (Chen et al. 2003; Alanio et al. 2016).

# **8.12 BMT Setting, Infection and Infection Control**

# **8.12.1 Introduction**

HCT using chemotherapy and radiotherapy leads to a reduced and compromised immune status. The administration of immunosuppressant to prevent graft rejection contributes also to the high risk of infections in this patient group (Brown 2010).

In recent years, improvement in HCT supportive care measures have decreased infectious morbidity and mortality. However, there is still scope for improvement since infection remains a leading cause of morbidity and mortality in patients undergoing HCT (Gratwohl et al. 2005).

# **8.12.2 Reverse Barrier Nursing and Protective Isolation**

It is crucial to have a skilled nursing team to assess, prevent, detect and treat infections. Delays in diagnosing an infection that results from a depressed infammatory response may lead to increased susceptibility to a broad range of potentially life-threatening organisms. For this reason, in addition to antimicrobial prophylaxis, there are other important strategies to prevent infections, for example, building a multi-professional network team specialized in infection control measures (Masszi and Mank 2012).

# **<IP_ADDRESS> Protective Isolation and Cleaning**

The large number of patients considered at risk requires an evaluation of all proposals of protective systems, in relation to the effectiveness, applicability and cost beneft (Pizzo 1981).

The Centres for Disease Control and Prevention (CDC) in 2009 made very specifc recommendations regarding precautions to be taken in HCT. These included measures such as protective isolation, the use of a single room and fltered air entering through a central or portable high-effciency flter (HEPA), capable of removing 99.97% of ≥0.3 uM in diameter particles.

For autologous HCT, there is no specifc indication other than the reference to "standard" precautions (as shown in Table 8.5) for each interaction with the patient. Protection with lab coat, gloves and mask is not indicated in the absence of suspected or confrmed infection of patients (Tomblyn et al. 2009). The effectiveness of specifc precautions in preventing infections in patients undergoing autologous HCT has not

**Table 8.5** Standard precautions of infection control (https://www.dhs.wisconsin.gov/ic/precautions.htm)

been evaluated but must follow the standard precautions for every patient contact.

Some centres use additional protection in an effort to reduce the risk of infection, but there are insuffcient data to recommend such behaviours (Tomblyn et al. 2009). Consistent with the organization of the department, it would be advisable to hospitalize the patient in a single room with attached bathroom. The ventilation system should ensure at least 12 air changes per hour; preferably with HEPA flters for prevention of airborne fungal infections, especially Aspergillus (Ifversen et al. 2021). The rooms, housing highly immunocompromised patients, need to be placed under positive pressure to prevent the entry into the room of airborne pathogens in the hallway or in adjacent spaces. In the rooms it is forbidden to keep fresh fowers and/or dried and potted plants (Tomblyn et al. 2009). Although it is unlikely that exposure to plants causes invasive fungal infections in patients undergoing HCT, it is recommended that plants and dried or fresh fowers do not enter the room during hospitalization (conditioning phase included) because of the *Aspergillus* sp., isolated from soil of ornamental plants and fowers. In addition it was found a high proportion of gramnegative bacteria is in the water of cut fower vases (*Pseudomonas*) (Tomblyn et al. 2009).

For the patient hospitalized in a protective environment, exits from the room should be restricted just for the execution of diagnostic tests and for a short period. If a construction site is present nearby the hospital, it is indicated to use a flter mask (N95) to prevent inhalation of spores. There are no recommendations regarding use of the mask with flter in the absence of the construction work (Tomblyn et al. 2009).

#### **<IP_ADDRESS> Handwashing**

The most important point in the prevention of infections in hospitalized patients, being in protective isolation, remains handwashing. Hand hygiene is a key element of the standard precautions for all types of patients (Tomblyn et al. 2009).

All staff and visitors must wash their hands before entering the patient's room in order to reduce the risk of cross infection.

Follow your institution's guidelines for hand hygiene. The fve moments of hand hygiene as defned by the World Health Organisation (2020) are:

It is also advisable not to wear false nails or extensions during direct contact with the patient and maintain the natural nails short. Furthermore hand hygiene cannot be done in a perfect way if you wear bulky rings. The experts' recommendation is to strongly discourage the use of rings during assistance (World Health Organisation 2020).

Nurses have an important role in educating the family, patient and visitors in effective handwashing and to provide all relevant information to reduce the risk of contracting infections.

#### **<IP_ADDRESS> Environmental Cleaning**

Environmental cleaning plays an important role in the prevention of nosocomial infections, particularly in patients with haematological cancers and diseases undergoing HCT. The cleaning staff must be well prepared and need to be informed and trained, with particular attention to the problems of immunosuppressed patients. It is preferable to assign stable staff to the division, in order to ensure a continuity of service. The hospital room must be cleaned more than once a day, with special dust control, which must be removed by damp.

The light fxtures and outdoor ventilation grills, vents and all horizontal surfaces should be cleaned with pre-moistened disposable cloths with a disinfectant FDA and Environmental Protection Agency approved. The design and selection of the furniture of a transplant program should be focused in creating and maintaining an environment: free of dust and the foors and fnishes should be brushable, waterproof, easy to disinfect and antistatic (Tomblyn et al. 2009).

To verify that hospital rooms are at effective reduced environmental load, periodic monitoring of the environments must be guaranteed.

#### **<IP_ADDRESS> Management of Linen**

All linen should be changed daily and pillows and mattresses should have protective coatings. During the hospital stay for the patient undergoing HCT, it is enough to wash clothes and linens at high temperatures in a washing machine (Tomblyn et al. 2009).

# **<IP_ADDRESS> Access to Low Environmental Loading Department**

Each centre has its own policy on the number of visitors allowed and the frequency of visits. However, all centres are in agreement in pointing out that they cannot come into contact with the patient when suffering from infections, rashes, nausea and/or vomiting or recent exposure to exanthematous diseases such as chickenpox or measles (Tomblyn et al. 2009).

#### **<IP_ADDRESS> Personal Hygiene**

Personal hygiene is a key aspect for the patient undergoing HCT. It represents the most effective way to reduce infections caused by endogenous organisms. It is important to explain the importance of personal hygiene and its role in preventing infections as seen in Table 8.6.

# **<IP_ADDRESS> Oral and Gastrointestinal Mucositis**

Oral and gastrointestinal mucositis caused by high-dose chemotherapy and/or radiation continues to be an important clinical problem.

Oral care is an important aspect in the control of infections in transplant patients (Quinn et al. 2008) (see Chap. 10).

#### **<IP_ADDRESS> Central Venous Devices**

The use of central venous catheters (CVC) is linked to the need to infuse complex therapies for a long time, having available a valid and secure access. The goals of care, for the CVC management, must aim to ensure prevention of infections and maintenance of the patency (see Chap. 4).

#### **<IP_ADDRESS> Low Bacterial Diet**

The low bacterial diet (LBD), also known as neutropenic diet or low microbial diet, is a diet aimed at reducing the ingestion of bacterial and fungal contaminants excluding it from foods such as **Table 8.6** Recommendations for personal hygiene (Centers for Disease Control and Prevention 2020)

fresh fruits and vegetables, raw eggs, raw meat and fsh, unpasteurized dairy products, ice and yogurt that will be excluded from any type of diet

**Table 8.7** Handling of food items during allogeneic haematopoietic cell transplantation

or raw food containing probiotics. The consumption of fruits with thick skin, if peeled and washed, in accordance with good hygienic practices has low probability to be contaminated (Todd et al. 1999).

For decades, a LBD implied a strict limitation of foods allowed for consumption. The rationale was to limit the introduction of potentially harmful bacteria into the gastrointestinal tract by the restriction of certain foods that might harbour those organisms (Fox and Freifeld 2012).

However, there is no clear evidence that this actually decreases the number of infections. Many studies have limitations and conclude that there are no differences in terms of infectious episodes and survival when comparing a normal to a neutropenic diet (Van Tiel et al. 2007; Gardner et al. 2008; Triflio et al. 2012).

A more liberal diet could bring benefts in terms of palatability, cholesterol reducing, use of parenteral nutrition and an improvement in quality of life. Increasingly, centers are replacing the strict LBD with safe food handling guidelines (https:// www.fda.gov/food/buy-store-serve-safe-food/ safe-food-handling). Four essential steps "clean, separate, cook and chill" are highlighted, and detailed recommendations regarding washing hands and surfaces "clean", how to prevent crosscontamination from one food product to another "separate", how to cook different food items to safe temperatures "cook" and how to refrigerate properly "chill" are given. A recent paper published by the Pediatric Diseases Working Party of the EBMT concluded that replacing the strict neutropenic diet in HCT recipients with a more palatable diet should not result in an increased risk of infection and would improve the quality of life and further result in an increase in oral intake of calories and protein, helping to prevent undesirable weight loss (Ifversen et al. 2021). An example of handling foods items in HCT are in Table 8.7.

# **8.13 Psychological Support**

Protective isolation can have signifcant psychological effects on the patient. Patients are encouraged to personalize their rooms with family pictures. Some may have computer access and are able to maintain communication with family members and friends in this way. However, the length of time spent in isolation does lead to many patients having feelings of anxiety, fear for the future, concerns about the family and worry about whether engraftment will occur (Brown 2010). Nurses should be aware of the potential effect that both the transplant and the isolation can have on patients. For further information see Chap. 11

Increasing implementation of ambulatory treatment has the potential to decrease patient exposure to MDRO in the hospital and to provide patients with the possibility to spend the neutropenic phase at home and to facilitate more admissions to the haematology ward (Mank et al. 2015).

# **8.14 Health Education at Discharge**

Going home is the "most diffcult time" in the course of treatment. The patient and family will have to face everyday life far from a safe hospital environment. In fact, in the hospital, the continued support of the multidisciplinary team makes them feel protected; in hospital, doctors, nurses and other professionals are always present to clarify doubts, give advice and also try to reduce anxiety and fears. Being aware of the risks of infection means that going home can be stressful (Brown 2010).

Nurses should spend time with the patient, identify and explore any concerns before discharge. In some cases, the patient may become overdependent on nursing staff, and this may need to be addressed. Allogeneic transplant patients have a high risk of readmission as a result of infection, and it is critical that discharge planning provides patients with the understanding and information on how best to minimize the risk of infection (Grant et al. 2005).

The patient will require a great deal of information before and at discharge, and this would include information on follow-up treatment. See also Chap. 11.

# **8.15 Nursing Implications**

All patients undergoing HCT are at risk for pulmonary complications. Bedside nurses are the most likely to observe subtle changes in the patient's condition, and for this reason it is critical that nursing staff working with the HCT population be highly trained in oncology and critical care interventions. Prompt reporting of symptoms can ensure proper and timely medical intervention and facilitate improved patient outcomes. This has been found particularly true in identifying GvHD, with clinical nurses at the forefront of identifying and reporting suspicious symptoms to the healthcare team (Mattson 2007). Nurses take a central role in patient and family education regarding the course of treatment, complications and other key pieces of the HCT process, including caring for a central line (Stephens 2013). By educating patients on what to expect after transplant with regard to troubling symptoms, nurses ensure patient participation in identifying developing complications early and improving HCT outcomes. A thorough assessment can assist the nursing staff in detecting changes indicative of developing complications. Vital signs, including the rate and quality of respirations, and oximetry should be performed per program protocols, usually every 4 h and more frequently for patients at risk for pulmonary insuffciency. Taking the patient's temperature every 4 h or as necessary is another critical respiratory intervention, as most post-HCT complications are infectious in nature (Stephens 2013). Nurses are crucial in assessing patients for symptoms of bacterial infection and should perform routine laboratory tests as necessary.

Regarding pulmonary infections, nurses should closely monitor patients for symptoms of progressing respiratory disease, such as decreased auscultation of air sounds in the lungs, increasing fevers and appearance of a productive cough with coloured sputum. Antibiotics should be started as soon as possible in these patients. A nursing study of neutropenic patients in the early HCT phase showed that commencement of antibiotics within 1 h of the onset of infectious symptoms can signifcantly reduce infectious complications, including sepsis (Hyman 2005).

It is important that patients in the posttransplant period are encouraged to pace their activity with their level of ability. Coughing and deep breathing exercises accompanying the regular use of an incentive spirometer constitute critical ways to open deep alveolar tissue and encourage pulmonary toileting on patients prone to fatigue and malaise and whose blood counts are very low (Stephens 2013).

# **8.16 BMT Settings, Infections and Infection Control for Paediatric Patients Be Aware**

# **8.16.1 Inborn Errors of Immunity Patients**

Immunization with live viral or bacterial vaccines is a known hazard to patients with serious immunodefciencies (Shearer et al. 2014). They have no protective immune response and therefore are at risk of developing the disease itself (Marciano et al. 2014).

*Avoid* immunization with live Bacillus Calmette-Guerin (BCG), rotavirus vaccine or live poliovirus since they can cause persistent and disseminated infection (Shearer et al. 2014; Rivers and Gaspar 2015; Lankester et al. 2021). Patients with SCID that received BCG vaccine prior to diagnosis will need to start prophylactic treatment with two antimycobacterial drugs in the absence of symptoms (Rivers and Gaspar 2015; Lankester et al. 2021).

Breast-feeding from a CMV positive mother should be avoided (Lankester et al. 2021).

# **8.16.2 BCGitis**

If BCG vaccine is given to infants with severe primary immune defciencies, they will develop BCGitis. It is characterized by local erythema and purulent regional lymph node enlargement,

BCG-osis. The more severe form is disseminated infection, which could be fatal. It involves distant lymph nodes, bone, liver and spleen (Shrot et al. 2016). In case of BCGitis administration of four antimycobacterial drugs has been recommended (Lankester et al. 2021).

# **References**

patient ratings, and quality of care. BMJ Qual Saf. 2017;26:559–68.

Tanaka Y, Fujita S, Watanabe T, Kobayashi Y, Tobinai K, Takaue Y. Long-term low-dose acyclovir against varicella-zoster virus reactivation after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2001;28:689–92.

haemopoietic stem cell transplantation. Bone Marrow Transplant. 2005;35:1065–9.

cell transplantation. Haematologica. 2019;104(11): 2155–63.

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# **Transplantation Through the Generations 9**

Alberto Castagna, Hilda Mekelenkamp, Lisa Mcmonagle, Michelle Kenyon, Corien Eeltink, and Sarah Jayne Liptrott

#### **Abstract**

Whilst the basic principles of HSCT remain the same, regardless of the age of the patient, there are a number of important additional considerations relating to transplantation of our younger and older patients and those of adolescent age. The principles outlined in this chapter serve as a valuable reminder supporting age-appropriate patient-centred care delivery. This chapter initially focuses on transplanting the child and its physiological and psycho-social aspects. Subsequently, the nursing challenges in the AYA population will be addressed. This chapter ends with considerations for treatment and care for the older adult.

#### A. Castagna

H. Mekelenkamp (\*) Willem-Alexander Children's Hospital, Department of Pediatrics, Leiden University Medical Centre, Leiden, The Netherlands e-mail<EMAIL_ADDRESS>
L. Mcmonagle

#### **Keywords**

HSCT · Paediatric · AYA · TYA · Older patients · Fragile · Geriatric problems · Geriatric assessment · Patient information · Decision making

# **9.1 Transplanting the Child**

HSCT offers the ability to cure pediatric patients with blood cell diseases. In Europe, around 5000 children are transplanted on an annual basis. Different stages of growth and development can be identifed during childhood. Undergoing HSCT has a major impact on children, their parents and siblings, especially when they have a double role

Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, UK e-mail<EMAIL_ADDRESS>
C. Eeltink Centrum voor Oncologie, Dijklander Ziekenhuis, Hoorn, The Netherlands e-mail<EMAIL_ADDRESS>
S. J. Liptrott Ospedale Regionale Bellinzona e Valli and Istituto Oncologico della Svizzera Italiana. Ente Ospedaliere Cantonale, Bellinzona, Switzerland e-mail<EMAIL_ADDRESS>