Keywords

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 refine and direct investigations and potential treatments appropriately.

Fig. 8.1
A chart of infection phases. They are 1. pre-engraftment, 2. post-engraftment, and 3. late phase, over a period of 365 days and beyond. There are more and less common bacterial, viral, and fungal infection types.

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

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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

8.2.1.1 Introduction

Cytomegalovirus (CMV) disease is a serious potential complication of HCT leading to life-threatening 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:

 

Recipient

Donor

High risk

Positive

Negative

Medium risk

Negative

Positive

Medium risk

Positive

Positive

No risk

Negative

Negative

Risk factors for CMV reactivation

  • CMV serostatus of recipient/donor (+/− or +/− > > −/+)

  • Previous CMV reactivation

  • Time post-transplant—increased in early post-transplant period (to day 100)

  • T-cell-depleted transplant conditioning protocols (e.g. Campath 1-H)

  • Systemic immunosuppression (particularly corticosteroids, antibodies directed against T-cells, e.g. ATG/Campath 1-H)

  • Recipient age—increased in older patients

  • Graft versus host disease

Risk factors for primary CMV infection

  • Person-to-person transmission

  • Low risk in use of blood not screened negative for CMV (Meijer et al. 2003)

8.2.1.2 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.

8.2.1.3 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.

8.2.1.4 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 first 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).

8.2.1.4.1 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 significantly reduced the incidence of clinically significant 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).

8.2.1.5 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-specific disease are identified. 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, first-line therapy is with intravenous ganciclovir. An outpatient oral alternative is valganciclovir, but can lead to significant 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 (Maffini et al. 2016).

Second- and third-line treatments are with foscarnet and cidofovir. Foscarnet may be adopted as a first-line treatment if the patient reactivates within the first 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 (Maffini 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

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 significant 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 sulpha-containing 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

8.2.2.1 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-specific cytotoxic T-cell response) that occurs in the immunocompromised host (Deeg and Socie 1998; Heslop 2009). PTLD are classified as either early-onset lesions which develop within 1 year or late onset occurring greater than a year post transplant (Ibrahim and Naresh 2012).

8.2.2.2 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 nonspecific 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 specific 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).

8.2.2.3 Diagnosis

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

Early lesions

Show features when biopsied of infectious mononucleosis and plasmacytic hyperplasia. These are the first signs in the spectrum of PTLD diagnosis

Polymorphic PTLD

Comprises small- and medium-sized lymphocytes and Reed-Sternberg like cells. Underlying cell structure is destroyed and may show malignant features

Monomorphic PTLD

Comprises large lymphocytes and plasma cells that are uniform in appearance with most being B cells with a clonal abnormality

Classic Hodgkin Lymphoma

This is a rare form of PTLD usually found in renal transplant patients

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

EBV DNA-aemia

Detection of EBV DNA in the blood

Primary EBV infection

EBV detected in a previously EBV seronegative patient

Probable EBV disease

Significant lymphadenopathy (or other end organ disease) with high EBV blood load, in the absence of other aetiologic factors or established diseases

Proven EBV disease

PTLD or other end organ disease: EBV detected from an organ by biopsy or other invasive procedures with a test with appropriate sensitivity and specificity together with symptoms and/or signs from the affected organ

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).

8.2.2.4 Treatment

Withdrawal of immunosuppression in the first 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-cell-specific 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

8.2.3.1 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).

8.2.3.2 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.

8.2.3.3 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 fluid (CSF), HHV6 DNA is observed (Ward et al. 2019).

8.2.3.4 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

8.2.4.1 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).

8.2.4.2 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 difficult 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 significant 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.

8.2.4.3 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 difficult to treat.

8.2.4.4 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 specific and sensitive.

8.2.4.5 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.

8.2.4.6 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

8.2.5.1 Background

The hepatitis B virus (HBV) is a DNA virus classified 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 HBV-negative 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).

8.2.5.2 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).

8.2.5.3 Treatment

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

8.2.5.4 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

8.2.6.1 Background

The hepatitis C virus (HCV) is a double-stranded RNA virus classified within the Flaviviridae. Six major genotypes have been identified, 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 significantly increased by immunosuppression and may cause a direct cytopathic effect in infected cells. The identification of pre-transplant 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).

8.2.6.2 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. Pre-transplant HCV infection is associated with a lower rate of platelet recovery.(Nakasone et al. 2013).

8.2.6.3 Treatment

All HCT recipients with HCV infection should be evaluated for HCV therapy before the start of conditioning therapy. Whenever possible, HCV-infected 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 fibrosing 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.

8.2.6.4 Prevention

A vaccination against HCV does not exist. However, to prevent the complication of co-infection, 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

8.2.7.1 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.

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).

8.2.7.2 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).

Table 8.1 Extrahepatic manifestations of acute and chronic hepatitis E
Full size table

8.2.7.3 Treatment

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

8.2.7.4 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 life-threatening clinical manifestations, multi-organ failure leading to death (Lion 2019).

8.3.4 Diagnosis

Samples taken from nasopharyngeal, rectal and corneal secretions, urine and unfixed 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 significant mortality of 20–80% (Robin et al. 2007).

8.3.5 Treatment

If possible immunosuppressive therapy should be tapered as the first step (Lion 2019). Cidofovir is first-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

8.4.1.1 Introduction

A new coronavirus SARS-CoV-2 was first 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).

8.4.1.2 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).

8.4.1.3 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 first place was the most effective strategy. Time from exposure to symptoms ranged from 2–14 days (Ljungman et al. 2020).

8.4.1.4 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.

8.4.1.5 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 (Pfizer 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 re-vaccinated 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 first 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 non-hospitalised 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 confirmed 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 specifically for the management of COVID-19 symptoms. Children under 12 years and less than 40 kg are also excluded (NHS England Green Book 2021).

8.4.1.6 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 beneficence 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 staffing is also a critical concern during a pandemic. While there is a need to be context specific and fluid 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 staffing 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 staffing 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 reflect 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).

Table 8.2 PPE recommendations from Paterson et al. (2020)
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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 significant 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 justified 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 significant 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 classified as either infectious or noninfectious. The rate of complications is significantly 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).

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 (non-myeloablative and myeloablative) and immunosuppressive prophylaxis to prevent and treat GvHD. A study by Escuissato et al. (2005) reviewed CT findings 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)

Day 0 to day 30

 

Infections and complications related to conditioning regimen and neutropenia

Pulmonary oedema

Pleural effusion

Transfusion-related acute lung injury

Idiopathic pneumonia syndrome

Engraftment syndrome

Diffuse alveolar haemorrhage

Aspergillosis

Candidaemia (Candida sepsis) and candidiasis (general Candida infections)

Respiratory viruses—respiratory syncytial virus, parainfluenza, influenza

Bacteraemias of gastrointestinal origin

Infections of central venous catheter origin

Acute respiratory distress syndrome (ARDS)

Chemotherapy-associated pulmonary toxicity

Day 31 to day 100

Classic opportunistic infections and complications

Pulmonary veno-occlusive disease (due to hepatic sinusoidal obstructive syndrome)

Diffuse alveolar haemorrhage

Cytomegalovirus

Aspergillosis

Pneumocystis carinii pneumonia

Respiratory viruses—Respiratory syncytial virus, parainfluenza, influenza

Toxoplasmosis

ARDS

Idiopathic pneumonia syndrome

Chemotherapy-associated pulmonary toxicity

Greater than day 100

Infections from encapsulated organisms

Aspergillosis

Respiratory viruses—Respiratory syncytial virus, parainfluenza, influenza

Varicella zoster virus

Cytomegalovirus

Pneumocystis carinii pneumonia

Post-transplant lymphoproliferative disorder

Pneumonia

ARDS

Bronchiolitis obliterans

Bronchiolitis obliterans organizing pneumonia

Chemotherapy-associated 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 two-dimensional 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 flushing of fluid (usually a sterile normal saline solution) into a localized area of the lower respiratory tract and then immediately suctioning the fluid 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 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, fine-needle aspiration biopsy is considered the first-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 significant 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.

Table 8.3 Other virus that cause infections in allo-HCT patients
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8.6 Bacterial Infections

8.6.1 Gram-Positive and Gram-Negative Bacteria

In the first phase post allo-HCT there are two main sources of bacterial infections: endogenous gastrointestinal flora (prevalently Gram−) and vascular catheters (prevalently Gram+).

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 identification, adherence to contact precautions and strict hand hygiene. More expensive approaches include dedicated equipment and staff.

Bacterial infections most commonly occur in the first month but can occur at any time. Both gram-negative and gram-positive organisms can cause pneumonia and have significant morbidity and mortality in HCT recipients (Tripathi and Sapra 2021). The most common being Escherichia coli, Klebsiella, Pseudomonas, Enterobacter, Acinetobacter, Staphylococcus aureus, coagulase-negative Staphylococcus, Streptococcus pneumoniae, Streptococcus viridans and Enterococcus. One also needs to recognize the risk of Mycoplasma and Chlamydia infections, although the common use of fluoroquinolones 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, Methicillin-resistant 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 flora 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
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8.7 Infection Control Management

Adapted from Weston (2013).

8.7.1 Isolation

  • In the event of confirmation of a Clostridium difficile (CD) toxin-positive and MDRO result in a patient with diarrhoea, who is not already isolated, the patient must be moved to a single room with en suite bathroom or dedicated night commode.

  • An isolation notice must be displayed on the door.

  • The nurse looking after the patient should inform the infection prevention control team.

  • Isolation can be discontinued once the patient has been asymptomatic for 48 h and is passing “normal” stools.

8.7.2 Equipment and Cleaning

  • Dedicated patient equipment must be used, including disposable blood pressure cuffs and tourniquet.

  • Floors, night commodes, toilets and bedframes are subject to the heaviest faecal contamination; it is important that the ward environment should not be cluttered in order to facilitate thorough and effective ward cleaning.

  • On discharge or transfer of the patient, it is important that an accurate cleaning of the room is undertaken using 1000 ppm available chlorine and/or a sporicidal agent.

8.7.3 Hand Hygiene

  • The patient should be assisted with hand hygiene after using the toilet or night commode and before eating if unable to wash his or her hands independently.

  • Healthcare workers must wash their hands with soap and water after contact with the patient or his/her environment. Alcohol hand rubs or gels are not effective against Clostridium difficile spores and MDRO.

8.7.4 Personal Protective Equipment (PPE)

  • Wear gloves and apron before entering the patient’s room.

  • Remove apron and gloves before leaving the patient’s room.

  • Hands must be decontaminated before putting on and after removing gloves.

  • Ensure that all healthcare workers and visitors wear and dispose of PPE appropriately.

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

  • Patients with CD and MDRO should not be transferred to other wards in the hospital, except for isolation purposes or if they require specialist care on another ward.

  • When patients need to attend departments for essential investigations, the nurse looking after the patient is responsible for informing the receiving area in advance of the patient’s CD positive status; if possible, symptomatic patients should be seen at the end of the working session and should be sent for only when the department is ready to see them; it should be avoided to leave them in a waiting area with other patients.

  • CD spores are known to contaminate the environment, are resistant to standard disinfectants and are capable of surviving for long periods on dry surfaces. 10% bleach solutions are sporicidal and should be used for environmental decontamination during outbreaks.

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

Further treatments of recurrent CDI are fidaxomicin, 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 difficile 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

  • Imaging shows nodules or cavitating infiltrates.

  • The classic “halo sign” may be seen on chest CT, but imaging may not be helpful.

  • BAL may be useful.

  • Galactomannan and beta glucan testing may be helpful but are not always informative.

8.10 Mycobacteria

Testing with purified 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 reclassified 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 trimethoprim-sulfamethoxazole (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 non-productive 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 infiltrates 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 difficulties of culturing samples, the diagnosis of PJP is made through microscopic examination of sputum or bronchoalveolar fluid 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 inflammatory 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 inflammatory 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).

8.12.2.1 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 benefit (Pizzo 1981).

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

For autologous HCT, there is no specific 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 confirmed infection of patients (Tomblyn et al. 2009). The effectiveness of specific precautions in preventing infections in patients undergoing autologous HCT has not been evaluated but must follow the standard precautions for every patient contact.

Table 8.5 Standard precautions of infection control (https://www.dhs.wisconsin.gov/ic/precautions.htm)
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Some centres use additional protection in an effort to reduce the risk of infection, but there are insufficient 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 filters 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 flowers 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 flowers do not enter the room during hospitalization (conditioning phase included) because of the Aspergillus sp., isolated from soil of ornamental plants and flowers. In addition it was found a high proportion of gram-negative bacteria is in the water of cut flower 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 filter mask (N95) to prevent inhalation of spores. There are no recommendations regarding use of the mask with filter in the absence of the construction work (Tomblyn et al. 2009).

8.12.2.2 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 five moments of hand hygiene as defined by the World Health Organisation (2020) are:

  1. 1.

    before touching the patient

  2. 2.

    before a clean/aseptic procedure

  3. 3.

    after body fluid exposure risk (blood, body fluids or excretions, mucous membranes, non-intact skin or dressing)

  4. 4.

    after touching a patient

  5. 5.

    after touching patient’s surrounding

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.

8.12.2.3 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 fixtures 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 floors and finishes 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.

8.12.2.4 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).

8.12.2.5 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).

8.12.2.6 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.

Table 8.6 Recommendations for personal hygiene (Centers for Disease Control and Prevention 2020)
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8.12.2.7 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).

8.12.2.8 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).

8.12.2.9 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 fresh fruits and vegetables, raw eggs, raw meat and fish, unpasteurized dairy products, ice and yogurt that will be excluded from any type of diet 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; Trifilio et al. 2012).

A more liberal diet could bring benefits 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 cross-contamination 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.

Table 8.7 Handling of food items during allogeneic haematopoietic cell transplantation
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8.13 Psychological Support

Protective isolation can have significant 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 difficult 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 insufficiency. 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 significantly reduce infectious complications, including sepsis (Hyman 2005).

It is important that patients in the post-transplant 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 immunodeficiencies (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 deficiencies, 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).