• An estimated 60 lung transplant procedures are carried out in children worldwide per year.
• Lung donors are currently found for only around 50% of children who require a lung transplant. This means that half of all children listed for lung transplant will die, before a suitable organ is found.
• The general paucity of donated organs is compounded for paediatric lung transplant candidates for two reasons. First, only an estimated 25% of multiorgan cadaveric donors provide suitable lungs for transplantation. Second, the donor organ needs to be of a suitable size. Matching is based on major blood groups and organ size only.
• The most common indication for lung transplantation (Box 55.1) is respiratory failure secondary to CF, accounting for one-third of all transplants and two-thirds of lung transplants in adolescents.
Timing of referral
• Discussion with the child and family regarding referral for transplantation (Box 55.2) should be initiated before the child has end-stage disease, so that there can be a period of reflection and decision.
• Consideration of a referral for transplantation involves frank discussion within the family unit and an open acceptance of life limitation for the patient.
• This may be the first time the family has broached this subject, and it will be difficult for many families.
• A substantial proportion of children and families will decline a referral for transplantation.
Disease-specific guidelines for the timing of referral
• FEV1 <30% predicted or FEV1 > 30% with a rapid fall in FEV1 or clinical deterioration.
• Hypoxia (PaO2 <7.7 kPa); hypercapnia (PaCO2 > 6.7 kPa).
• Severe haemoptysis, despite embolization.
• Female patients with rapid deterioration should be considered for early referral.
Primary pulmonary hypertension
• Symptomatic progressive disease.
• Right atrial pressure >15 mmHg.
• Cardiac index >2.1 L/min/m2.
• Mean pulmonary artery pressure >55 mmHg.
• Pulmonary artery saturation <63%.
• 6-min walk test <400 m.
• Consider referral at the time of starting epoprostenol, as some will be unresponsive to this therapy.
Consult the transplant centre for details of required investigations, prior to referral. Some investigations may otherwise be repeated at transplant assessment.
• Full spirometry and lung volumes.
• Exercise performance (e.g. 6-min walk).
• Liver function, viral serology (hepatitis B, hepatitis C, CMV, HIV, measles, rubella, varicella-zoster).
• Renal function with 24 h creatinine clearance.
• Sputum microbiology, including Pseudomonas resistance patterns; Burkholderia cepacia, MRSA, or NTM infection/colonization; history of ABPA.
• Echocardiography and, in some children, cardiac catheter.
• Investigation for GOR (pH and/or impedance study)
• Recent dental review to exclude any dental caries
Important information for the transplant service
• Detailed past medical and surgical history.
• Rate of decline in the respiratory function.
• Detailed microbiology.
• Possible contraindications (Box 55.3).
• Compliance history.
• Psychosocial assessment of the patient and family.
Ongoing medical care at the referring hospital
• Monitor disease.
• Optimize nutrition.
• Maintain mobility and exercise.
• Treat chest exacerbations aggressively.
• Consider early non-invasive ventilatory support.
• Avoid intubation, if possible—transfer to the transplant centre and establishing ECMO are preferable.
• Avoid high-dose steroid treatment, if possible.
Evaluation of donor lungs
• Potential donor lungs are assessed using arterial blood gases, CXR, airway cultures, and laryngobronchoscopy.
• The donor is screened for hepatitis A, B, and C, HIV, VZV, CMV, EBV, and herpesviruses.
• Ischaemic time is limited to 4 h.
Surgical approaches for lung transplant
• Heart–lung transplant. Historically, lung transplantation involved total heart–lung transplantation or domino surgery where the recipient received a donor heart–lung transplant and donated his/her healthy heart to a patient awaiting heart transplant. This avoided the need for tracheal anastomosis and the consequent complications associated with tracheal stenosis.
• Bilateral sequential lung transplantation is now performed in the majority of cases in children. The procedure is performed through a ‘clamshell’ incision and utilizes mainstem bronchial anastomoses, therefore eliminating the complications of tracheal anastomosis. This approach avoids unnecessary post-transplant cardiac complications and is performed in some centres without the need for bypass surgery, as the patient may be managed using selective lung ventilation. Children and small adults have a lower chance of getting size-matched donor lungs, because of the scarcity of small donors. Where there is an urgent clinical need, lobar lung transplantations can be performed.
• Single lung transplant is performed much more rarely in children than in adults and is never performed in CF.
• Living donor lower lobe (or complete lung) transplantation is available in a few centres worldwide, principally for transplant candidates who are unlikely to survive to receive an organ from a deceased donor. These organs are in good condition and are HLA-matched.
• Induction immunotherapy. Anti-lymphocyte or anti-thymocyte globulin, or a monoclonal IL-2 receptor antagonist (basiliximab or daclizumab) may be given at the time of transplantation.
• Post-transplant triple-drug immunosuppression:
• calcineurin inhibitor (tacrolimus, ciclosporin);
• azathioprine or mycophenolate mofetil;
• Antimicrobial treatment.
• IV antibiotics pre- and post-transplant. Donor and recipient sputum cultures are used to determine the specific regimen.
• TMP-SMZ, three times weekly as prophylaxis for Pneumocystis jiroveci for 1 year (oral dapsone is an alternative).
• CF patients who have isolated Aspergillus species in the past receive IV amphotericin or voriconazole perioperatively, with a transition to oral itraconazole or voriconazole thereafter.
• Oral nystatin for the prevention of candidal disease.
• CMV prophylaxis if either the donor or recipient is seropositive. Ganciclovir or valganciclovir are generally given for 1–3 months post-transplant.
• Post-operative bleeding from cardiopulmonary bypass.
• Diaphragmatic dysfunction from damage to the phrenic nerve.
• Vocal cord palsy from damage to the recurrent laryngeal nerve.
Early graft dysfunction
• Presents in the first week post-transplant.
• Related to organ harvest and ischaemia–reperfusion injury.
• Characterized by marked hypoxaemia, diffuse pulmonary infiltrates, and diffuse alveolar damage on biopsy.
• Clinical spectrum from mild acute lung injury to ARDS.
• Treatment is supportive, with careful fluid balance, ventilation, and expectant treatment of infection.
• Complete dehiscence of bronchial anastomosis is rare and requires urgent surgery.
• Partial dehiscence is managed conservatively, with drainage of pneumothorax and reduction in the steroid dose.
• Bronchial anastomotic stenosis typically occurs weeks to months after the transplant. May be managed with balloon dilatation or bronchoscopic stent insertion.
• Excess granulation may be removed at surveillance bronchoscopy.
• Airway collapse may occur at the site of anastomosis.
• Early infection may come from the donor (from seeding to the blood or mediastinum during explantation of chronically infected lungs), through spread to the lungs from chronic sinus disease in CF patients, or extrinsic ICU-acquired pneumonia.
• Most commonly caused by coagulase-negative Staphylococcus and Gram-negative organisms, especially Pseudomonas aeruginosa (in both CF and non-CF patients).
• CMV is the second commonest infection after bacterial pathogens, with a peak incidence 1–6 months post-transplant.
• CMV disease may vary from a mild disease, presenting as a febrile illness with leucopenia, to an invasive disease usually of the lung or GI tract. CMV pneumonitis presents with fevers and chills, cough, respiratory distress, crackles on auscultation, and diffuse interstitial changes on imaging.
• CMV-negative recipients who have received lungs from a seropositive donor are at highest risk of CMV disease, with up to 75% affected in the first 6 months, despite post-operative prophylaxis.
• Treatment is with IV ganciclovir for 2–4 weeks.
• CMV may be linked to the development of subsequent BO.
Respiratory syncitial virus, parainfluenza, influenza, and adenovirus
• There is a risk of severe disease with any of the common respiratory viruses.
• Prevention with active immunization for influenza and passive immunization for RSV (palivizumab) should be considered.
• Adenovirus may cause an overwhelming illness and death.
• Viral infection may be linked to a rapid development of BO.
• Prophylactic TMP-SMZ has dramatically reduced the burden of pneumocystis disease in post-transplant patients.
• Invasive disease presents with fever, profound hypoxia, crackles, and interstitial infiltrates.
• IV TMP-SMZ is usually effective.
• Chronic infection with Aspergillus post-transplantation is common, although clinical disease is unusual. Fifty per cent of previously infected CF patients and 40% of non-infected CF patients will have chronic infection post-transplant, despite prophylaxis. Thirty per cent of non-CF patients will have chronic infection post-transplant.
• Infection with Aspergillus usually occurs in the first 3 months post-transplant.
• Infection may be detected with surveillance bronchoscopy.
• The spectrum of disease associated with Aspergillus infection includes tracheobronchial lesions with ulceration and necrosis, infection at the anastomosis with potential dehiscence, pneumonitis, and disseminated aspergillosis.
• Invasive disease has a high mortality and has been associated with chronic graft rejection.
• Treatment is with IV voriconazole or amphotericin B.
Medication side effects
Treatment with immunosuppressive therapy aims to strike a balance between the risks of graft rejection and the risks of opportunistic infection. Therapy will need to continue lifelong post-transplantation.
• Headache and sleep disturbance.
• Hirsutism and gingival hypertrophy.
• Hypertension and nephropathy (75% at 5 years post-transplant).
• Rare complication due to circulating recipient antibodies, occurring a few hours post-transplantation.
• Can lead to graft loss.
• Very common. Usually occurs between 2 and 12 weeks post-transplant. May rarely occur up to 3 years post-transplant.
• Difficult to distinguish from infection. Non-specific signs include malaise, cough, fever, dyspnoea, and hypoxia, with crackles on auscultation. CXR may show non-specific infiltrates. Lung function studies show an obstructive pattern.
• Bronchoscopy with BAL and transbronchial biopsy is indicated. Histology shows perivascular lymphocytic infiltrates, with or without airway inflammation.
• Some patients may be asymptomatic.
• Acute rejection is a major risk factor for BO syndrome (BOS) and therefore needs to be detected and treated quickly and aggressively. Surveillance bronchoscopy is therefore performed in many centres at 2, 4, 8, and 12 weeks post-transplant.
• Treatment is with pulsed IV methylprednisolone (10 mg/kg) daily for 3 days. The majority of patients respond quickly to treatment. Persistent acute rejection may be managed with anti-thymocyte Ig or modulation of immunosuppression.
• Transplant recipients under 3 years of age appear to have fewer episodes of acute rejection.
Chronic rejection and bronchiolitis obliterans syndrome
• Chronic lung allograft dysfunction (CLAD) is the term used to describe the insidious onset of breathlessness, cough, and worsening airflow obstruction seen in transplant recipients from 6 months post-transplantation.
• The underlying causes of CLAD are poorly understood—there are likely to be contributions from immune-mediated damage as well as post-infectious damage, especially from viral infections.
• Subgroups of CLAD can show a predominantly restrictive disease (sometimes called restrictive allograft syndrome) and more commonly predominantly an obstructive pattern, called BOS.
• The major criterion for the diagnosis of BOS is an unexplained drop in FEV1 of >20% predicted.
• Histology shows BO with progressive and irreversible bronchiolar stenosis, fibrosis, and airway occlusion. The distribution of disease is patchy, and transbronchial biopsy therefore has a low sensitivity.
• The two major risk factors for BOS are acute rejection and non-compliance with immunosuppressive therapy. Other postulated risk factors include infection with CMV and other respiratory viruses, anastomotic complications, and graft ischaemic time. GOR may also contribute, and early fundoplication is used in some centres.
• Treatment is with increased immunosuppression and aggressive treatment of infection.
• BOS is a heterogeneous condition, and some forms may be reversible. A drop in FEV1 should therefore be assessed aggressively for treatable causes of BOS, e.g. endobronchial Pseudomonas infection in CF patients acquired from chronically infected sinuses.
• Sixty per cent of paediatric lung transplant recipients have evidence of BO 6 years post-transplant. BO is responsible for >40% of all deaths after 1 year post-transplantation.
• The aims of treatment are to halt further deterioration in lung function, ameliorate symptoms, and treat infection aggressively. Retransplantation is the only definitive treatment.
• The incidence is around 5% at 1 year, and 9% at 5 years post-transplant.
• Post-transplant lymphoproliferative disease (PTLD) accounts for the majority of malignancies.
• PTLD is an EBV-associated lymphoma in an immunocompromised host.
• PTLD is more common in CF patients, in children, compared to adults, and in the lung, compared to other solid organ transplants. This is thought to be due to the increased requirement for immunosuppression in these groups and to the fact that many children are EBV-seronegative at the time of transplant.
• The most common site for post-transplant malignancy is the lung allograft.
• A high index of suspicion is needed, since symptoms are non-specific, including cough, fever, and dyspnoea.
• The disease may present with pulmonary nodules on CXR.
• Other sites of disease include the lymph nodes, tonsils, skin, and bowel.
• In 80% of cases where the disease is detected early, a reduction in immunosuppressant treatment is successful (this approach, however, increases the risk of BOS). Late-stage disease is treated with the chemotherapy protocol for NHL.
• Children are generally discharged from hospital 4–6 weeks after transplantation. During this period, they will commence an intensive course of exercise rehabilitation.
• Surveillance bronchoscopy with BAL and transbronchial biopsy may have been performed pre-discharge, depending on local protocols.
• At home, patients will document daily spirometry, temperature, and weight.
• They will be followed closely by the transplant centre but may also visit the referring centre for assessment, spirometry, ECG, radiology, blood tests, and immunosuppressant blood drug levels.
• Advice should be sought from the transplant team, if there is any suspicion of complications.
• International registry survival rates for children following lung transplantation, published in 2008, report survival of around: 75% at 1 year; approximately 50% at 5 years; and approximately 40% at 10 years. Survivors at 1 year had a median survival of around 7 years.
• Graft failure and infection are the major causes of death in the first year of life.
• After the first year, the major cause of death is BO, but infection remains an important cause.
• Lung transplantation in children conveys a clear survival benefit, when compared with patients on the waiting list.
• For patients with primary pulmonary hypertension, the 5-year survival is greater for double lung (65%), compared to single lung, transplantation (25%).
• Eighty per cent of recipients report no exercise limitation at 1 and 5 years post-transplantation.
• Lung function can return to the normal range in infants and children.
• At 5 years post-transplantation, 75% of recipients will have systemic hypertension, 25% will have renal dysfunction, and 30% will have CF-related diabetes.
• Quality of life assessments are difficult to perform but suggest a score lower than that in the normal population, but equivalent to that in children with other chronic diseases such as asthma or JIA.
• The growth of children after lung transplantation remains a problem, because of chronic poor nutritional status pre-transplant and chronic steroid treatment thereafter.
• Increased GOR disease or gastroparesis post-transplant may compromise enteral nutrition.
• Studies in young children have shown that, in the absence of BO, lung allograft growth can occur post-transplant (as measured by the FVC and TLCO).
Aurora P (2004). When should children be referred for lung or heart–lung transplantation? Pediatr Pulmonol Suppl. 26, 116–18.Find this resource:
Aurora P, Edwards LB, Christie J, et al. (2008). Registry of the International Society for Heart and Lung Transplantation: eleventh official pediatric lung and heart/lung transplantation report – 2008. J Heart Lung Transplant 27, 978–83.Find this resource:
Burch M, Aurora P (2004). Current status of paediatric heart, lung, and heart–lung transplantation. Arch Dis Child 89, 386–9.Find this resource:
Radley-Smith R, Aurora P (2006). Transplantation as a treatment for end-stage pulmonary hypertension in childhood. Paediatr Respir Rev 7, 117–22.Find this resource: