Understanding systemic and pulmonary complications after donor stem-cell transplantation
Unraveling the Intricacies of Graft-Versus-Host Disease (GvHD)
Graft-versus-host disease is a potentially serious complication of allogeneic stem-cell transplantation. It develops when donor immune cells recognise the recipient’s tissues as foreign and mount an immune response. GvHD may affect several organs, including the skin, gut, liver, mouth, eyes, lungs, muscles, joints and genital tissues.
- Acute GvHD
- Chronic GvHD
- Organ involvement
- Lung GvHD
- Bronchiolitis obliterans syndrome
- Lung-function monitoring
- Immunosuppressive treatment
- Supportive care
Report new symptoms promptly
People who have undergone an allogeneic stem-cell transplant should contact their transplant team about new rashes, diarrhoea, jaundice, mouth or eye symptoms, breathlessness, cough or reduced exercise tolerance.
Infection can mimic GvHD
Fever, cough, diarrhoea, abnormal liver tests and skin changes can have several causes after transplantation. Infection and other complications must be assessed rather than assuming every symptom is GvHD.
What is graft-versus-host disease?
Graft-versus-host disease occurs after an allogeneic haematopoietic stem-cell transplant when immune cells contained within the donor graft recognise the recipient’s tissues as foreign and cause inflammatory or fibrotic injury.
An allogeneic transplant uses stem cells from another person. These cells rebuild the recipient’s blood-forming and immune systems. Donor immune cells can provide a beneficial graft-versus-tumour effect by attacking residual malignant cells, but they can also damage healthy recipient tissues.
GvHD ranges from mild and localised disease to severe multisystem illness. Symptoms, affected organs, speed of progression and response to treatment vary considerably between individuals.
GvHD differs from rejection of a solid organ. In solid-organ rejection, the recipient’s immune system attacks the transplanted organ. In GvHD, immune cells from the donor graft attack the recipient.
Investigation and treatment should be coordinated by the haematology or transplant team, with respiratory medicine, dermatology, gastroenterology, ophthalmology and other specialists involved according to the organs affected.
Acute, chronic and overlap GvHD
GvHD was historically divided according to whether it developed before or after 100 days following transplantation. Modern classification places greater emphasis on the pattern of clinical features rather than timing alone.
Acute GvHD
Acute GvHD most commonly affects the skin, gastrointestinal tract and liver. It can occur early after transplantation but may also persist, recur or first appear later.
- New widespread or rapidly progressing rash
- Watery or bloody diarrhoea
- Abdominal pain, nausea or vomiting
- Loss of appetite
- Abnormal liver tests or jaundice
Chronic GvHD
Chronic GvHD can affect almost any organ and may cause inflammation, immune dysfunction and progressive scarring or fibrosis.
- Skin thickening or pigment change
- Dry eyes or mouth
- Restricted joint movement
- Oesophageal or swallowing symptoms
- Genital symptoms
- Bronchiolitis obliterans syndrome
What is overlap GvHD?
Overlap GvHD describes chronic GvHD accompanied by one or more features normally associated with acute GvHD. The pattern can change over time, which is why continuing specialist assessment is important.
Which organs can GvHD affect?
GvHD is a systemic condition. A person may have one affected organ or several organs involved simultaneously.
Rash and tissue change
Redness, itching, scaling, pigment change, thickening, tightness, blistering or ulceration may occur.
Gastrointestinal symptoms
Nausea, vomiting, diarrhoea, abdominal pain, bleeding, reduced appetite and weight loss may develop.
Liver inflammation
Liver-test abnormalities may be found before symptoms. Jaundice, itching, dark urine or abdominal discomfort can occur.
Oral symptoms
Dryness, soreness, ulcers, sensitivity to food, white patches, taste change and difficulty opening the mouth may occur.
Ocular surface disease
Dryness, burning, redness, watering, light sensitivity or blurred vision may require ophthalmology assessment.
Small-airway disease
Bronchiolitis obliterans syndrome can cause cough, breathlessness, wheeze and a progressive fall in airflow.
Restricted movement
Fascia, muscles and joints may become painful, weak, stiff or restricted by inflammation and fibrosis.
Pain and scarring
Dryness, pain, inflammation, ulceration, narrowing or scarring can affect sexual function and urinary symptoms.
Infection vulnerability
GvHD and its treatment can impair immune protection, increasing susceptibility to bacterial, viral and fungal infections.
Skin GvHD: symptoms, diagnosis and treatment
Skin involvement is common and may be one of the earliest visible signs of GvHD. The appearance varies according to whether the disease is acute, chronic, inflammatory or fibrotic.
Early inflammatory rash
Red or purple areas may begin on the palms, soles, face, ears or upper body before becoming more widespread.
Itching and tenderness
Skin may feel itchy, hot, sensitive or painful and can resemble sunburn or another inflammatory rash.
Blistering or ulceration
Severe acute skin involvement can produce blistering, detachment or ulceration and requires urgent specialist care.
Thickening and tightness
Chronic GvHD may cause sclerosis, tight skin and restriction of movement around joints.
Pigment and hair change
Areas may become lighter or darker, while hair thinning, hair loss or nail abnormalities can develop.
Similar-looking conditions
Drug reactions, viral infections, fungal disease and other dermatological conditions may resemble GvHD.
How skin GvHD is assessed
Assessment includes the timing and distribution of the rash, associated symptoms, medication exposure and examination of the entire skin surface. Dermatology review and a skin biopsy may be helpful when the diagnosis is uncertain.
Treatment of skin GvHD
Local skin treatment
Topical corticosteroids
Steroid creams or ointments may reduce local inflammation. Strength and duration depend on the site and severity.
Emollients
Regular moisturisers can support the skin barrier and reduce dryness, cracking and discomfort.
Photoprotection
Sun protection may be advised because ultraviolet exposure can aggravate skin disease in some patients.
Systemic and specialist treatment
Systemic corticosteroids
Moderate or severe disease may require oral or intravenous corticosteroid treatment under transplant-team supervision.
Additional immune therapy
Other systemic agents may be added when corticosteroids are ineffective, poorly tolerated or cannot be reduced.
Physiotherapy
Stretching and rehabilitation can help preserve movement where skin or fascial tightening affects joints.
Extracorporeal photopheresis
Extracorporeal photopheresis, commonly abbreviated to ECP, is a specialist treatment in which circulating white blood cells are collected, treated with a photosensitising medicine and exposed to ultraviolet-A light before being returned to the patient.
ECP modifies immune activity rather than simply destroying all white blood cells. It may be used for selected patients with steroid-refractory or steroid-dependent GvHD, particularly where the skin, mouth, liver or other organs are involved.
Repeated sessions
Treatment is generally delivered over repeated appointments, with frequency adjusted according to response and local protocols.
Gradual response
Improvement may take weeks or months, so response is assessed using symptoms, examination and organ-specific measurements.
Vascular access
Treatment requires suitable venous access and may be difficult where veins are limited or blood counts are low.
Specialist monitoring
Blood counts, circulation, medication effects and infection risk remain important throughout treatment.
Gut and liver GvHD
Gastrointestinal symptoms after transplantation require prompt assessment because GvHD, infection, medication toxicity and other complications can produce similar symptoms.
Nausea and vomiting
Persistent nausea, vomiting, early fullness or food intolerance may indicate upper gastrointestinal involvement.
Diarrhoea
Watery, frequent or bloody diarrhoea can lead to dehydration, electrolyte disturbance and malnutrition.
Abdominal pain
Cramping, tenderness or severe abdominal pain requires clinical assessment and may indicate significant intestinal disease.
Weight and nutritional loss
Reduced intake, poor absorption and ongoing inflammation can cause weight loss, muscle loss and weakness.
Liver-test abnormalities
GvHD may be identified through abnormal liver enzymes or bilirubin before obvious symptoms develop.
Jaundice and itching
Yellow skin or eyes, dark urine, pale stools or severe itching require urgent review by the transplant team.
Diagnosis
Investigations may include stool testing for infection, blood tests, medication review, imaging, endoscopy and biopsy. A biopsy can support the diagnosis but must be interpreted with the overall clinical picture.
Treatment and nutritional support
Treatment may involve local or systemic corticosteroids and other immunosuppressive medicines. Fluid, electrolyte and nutritional support are essential. A specialist dietitian may recommend small frequent meals, modified food choices or additional nutritional support.
Contact the transplant team urgently for significant diarrhoea
Persistent diarrhoea, blood in the stool, repeated vomiting, inability to maintain fluids, severe abdominal pain or rapid weight loss should not be managed at home without transplant-team advice.
Lung GvHD and bronchiolitis obliterans syndrome
The best-recognised pulmonary manifestation of chronic GvHD is bronchiolitis obliterans syndrome. BOS affects the small airways, causing progressive airflow obstruction that may initially produce few or no symptoms.
Lung problems after stem-cell transplantation have many possible causes. Infection, medication toxicity, fluid overload, pulmonary embolism, recurrent malignancy, organising pneumonia and other inflammatory or fibrotic complications must be considered.
Dry or persistent cough
Cough may be subtle initially and can be mistaken for a minor infection or upper-airway irritation.
Exertional breathlessness
Difficulty climbing stairs, walking uphill or completing usual activities may be an early sign of deteriorating airflow.
Wheeze or chest tightness
Small-airway narrowing may cause wheeze, chest tightness or prolonged breathing out.
Reduced exercise tolerance
A decline in stamina may precede breathlessness at rest and should be reported rather than attributed automatically to deconditioning.
Hypoxaemia
Low blood-oxygen levels usually indicate more advanced disease or another serious pulmonary complication requiring prompt assessment.
Recurrent infection
Airway damage, impaired mucus clearance and immunosuppression can increase susceptibility to bacterial, viral and fungal infection.
Serial spirometry can identify a decline in forced expiratory volume before severe respiratory limitation develops. Patients should attend the lung-function surveillance arranged by their transplant team even when they feel well.
How pulmonary GvHD is investigated
- Compare symptoms with the post-transplant baseline New cough, breathlessness, wheeze, reduced exercise tolerance, sputum or oxygen changes are reviewed in relation to previous respiratory health.
- Perform lung-function testing Spirometry is central. Lung volumes and gas-transfer measurement may provide additional information about air trapping and gas exchange.
- Review the pattern of FEV1 decline A persistent fall in forced expiratory volume may indicate progressive obstructive small-airway disease.
- Obtain inspiratory and expiratory CT imaging High-resolution CT may demonstrate air trapping, mosaic attenuation, bronchial wall thickening, bronchiectasis or another pulmonary process.
- Investigate infection Viral testing, sputum cultures, blood tests and sometimes bronchoscopy with bronchoalveolar lavage may be required.
- Exclude alternative causes Clinicians consider asthma, COPD, pulmonary embolism, cardiac disease, medication toxicity, relapse and other post-transplant complications.
- Apply specialist diagnostic criteria The diagnosis is based on clinical context, airflow obstruction, evidence of air trapping and exclusion of infection or another explanation.
Read more about spirometry, gas-transfer testing and other lung-function tests .
Lung biopsy is not routinely required to diagnose BOS
Surgical lung biopsy carries significant risk in immunocompromised patients and is generally reserved for selected cases where major diagnostic uncertainty remains and the result is likely to alter treatment.
Management of lung GvHD
Pulmonary GvHD requires coordination between the transplant team and a respiratory physician experienced in post-transplant lung disease. Treatment depends on disease severity, rate of lung- function decline, infection risk and GvHD activity elsewhere.
Control the immune process
Systemic treatment
Corticosteroids or other systemic immune-modifying treatments may be required according to transplant-team assessment.
Steroid-refractory disease
Ruxolitinib, belumosudil, ECP or other specialist treatments may be considered under defined clinical and commissioning criteria.
Response monitoring
Symptoms alone are insufficient. Serial spirometry and other objective measurements help assess whether decline has stabilised.
Inhaled and airway-directed treatment
Inhaled corticosteroid
An inhaled corticosteroid, sometimes combined with a long-acting bronchodilator, may be considered for airway-directed anti-inflammatory treatment.
Bronchodilator therapy
Bronchodilators may help selected patients with reversible narrowing, wheeze or symptomatic airflow obstruction.
Airway clearance
Where bronchiectasis or retained sputum is present, respiratory physiotherapy may support mucus clearance.
Infection prevention and treatment
Microbiology
Sputum or bronchoscopy samples may guide antibacterial, antiviral or antifungal treatment.
Prophylaxis
Preventive antimicrobial treatment may be required while significant immunosuppression continues.
Vaccination
Re-vaccination after transplant follows an individual schedule coordinated by the transplant service.
Rehabilitation and supportive care
Pulmonary rehabilitation
Supervised exercise and education may improve fitness, breathlessness management and confidence.
Oxygen assessment
Supplemental oxygen may be prescribed when testing confirms clinically significant hypoxaemia.
Advanced disease
Selected patients may require advanced respiratory support, palliative symptom care or assessment at a specialist transplant and lung centre.
A note about the FAM regimen
Fluticasone, azithromycin and montelukast have been used together in selected patients with new or established BOS. Evidence is limited, and this approach is not suitable for everyone. Azithromycin has complex benefits and risks in the transplant population and should only be started by, or in agreement with, the responsible transplant team.
Never start long-term azithromycin independently
The transplant team must consider timing after transplantation, relapse risk, microbiology, heart rhythm, hearing, liver function, antimicrobial resistance and possible nontuberculous mycobacterial infection before prescribing long-term macrolide therapy.
General treatment approaches for GvHD
Treatment is personalised according to whether GvHD is acute or chronic, which organs are involved, disease severity, infection risk, previous treatment and the patient’s wider transplant history.
| Treatment approach | Potential role | Important considerations |
|---|---|---|
| Topical treatment | Local therapy for skin, mouth, eye or genital involvement | Product, strength and duration must match the affected organ |
| Systemic corticosteroids | Common first systemic treatment for clinically significant acute or chronic GvHD | Infection, diabetes, osteoporosis, muscle weakness and other adverse effects require monitoring |
| Calcineurin inhibitors | Tacrolimus or ciclosporin may be used as prevention or treatment components | Kidney function, blood pressure, drug levels and interactions require review |
| Extracorporeal photopheresis | Selected steroid-refractory or steroid-dependent chronic GvHD | Requires repeated specialist sessions and appropriate vascular access |
| Ruxolitinib | May be used for steroid-refractory acute GvHD or chronic GvHD after previous systemic treatment | Blood counts, infection risk and drug interactions require close monitoring |
| Belumosudil | May be considered for chronic GvHD after previous systemic therapies under relevant eligibility criteria | Availability and use depend on specialist and commissioning pathways |
| Organ-specific supportive care | Eye lubrication, oral care, nutrition, physiotherapy, inhaled treatment and rehabilitation | Supportive care complements rather than replaces treatment of active systemic disease |
When possible, treatment aims to control GvHD while minimising cumulative corticosteroid toxicity. Additional therapies may be introduced when disease is steroid-refractory, steroid-dependent or associated with unacceptable adverse effects.
Monitoring and self-management
GvHD can evolve gradually or flare when immunosuppressive treatment is reduced. Regular follow-up allows changes to be identified before irreversible organ damage develops.
Take medicines consistently
Missed or altered immunosuppressive doses can lead to unstable drug levels, GvHD flare or treatment toxicity.
Monitor for infection
Fever, chills, cough, urinary symptoms, diarrhoea and new skin lesions should be reported according to the transplant plan.
Attend organ surveillance
Blood tests, lung function, eye review, dental care, skin examination and bone-health monitoring may all be required.
Maintain nutrition
Weight loss, swallowing problems and food intolerance should be addressed early with dietetic and medical support.
Preserve mobility
Physiotherapy, stretching and appropriate exercise can help reduce deconditioning and restriction from skin or fascial disease.
Discuss emotional health
Anxiety, low mood, trauma, isolation and treatment fatigue are common and deserve professional support.
Do not reduce immunosuppression without specialist advice
Immunosuppressive medicines often require gradual, carefully monitored changes. Abrupt reduction can trigger GvHD, while excessive immunosuppression can increase infection and other complications.
When to contact the transplant team
Contact the team promptly for:
- a new or spreading rash;
- skin blistering, peeling, ulceration or increasing tightness;
- new mouth ulcers, severe dryness or difficulty eating;
- eye pain, marked redness, light sensitivity or visual change;
- persistent nausea, vomiting or diarrhoea;
- blood in the stool;
- jaundice, dark urine or pale stools;
- new cough, wheeze or breathlessness;
- declining exercise tolerance;
- fever, chills or another sign of infection;
- painful or restricted joint movement;
- new genital pain, inflammation or ulceration.
Seek urgent or emergency assessment for:
- severe or rapidly worsening breathing difficulty;
- blue or grey lips, collapse or confusion;
- coughing blood or severe chest pain;
- inability to maintain fluids because of vomiting or diarrhoea;
- heavy gastrointestinal bleeding;
- severe abdominal pain;
- rapidly blistering or peeling skin;
- high fever with marked deterioration;
- swelling of the tongue or throat.
Follow the emergency instructions issued by the transplant service. Call 999 for severe breathing difficulty, collapse, heavy bleeding or another immediately life-threatening symptom.
Conclusion
Graft-versus-host disease is a complex immune complication of allogeneic stem-cell transplantation. It develops when donor immune cells attack recipient tissues and can affect one or several organ systems.
Acute and chronic GvHD are distinguished mainly by their clinical features rather than a rigid 100-day cut-off. Acute disease commonly affects the skin, gut and liver, while chronic disease can involve the mouth, eyes, lungs, fascia, joints and genital tissues as well as the classic target organs.
Pulmonary chronic GvHD most commonly presents as bronchiolitis obliterans syndrome. Because early BOS may produce few symptoms, regular spirometry and prompt assessment of any respiratory change are important.
Diagnosis requires careful exclusion of infection, medication toxicity and other transplant complications. Treatment may include topical therapy, corticosteroids, other immunosuppressive agents, extracorporeal photopheresis and newer systemic treatments within specialist pathways.
Successful management relies on close communication between the patient, transplant team and organ specialists. New cough, breathlessness or a decline in exercise tolerance should prompt respiratory assessment rather than waiting for severe symptoms to develop.
Frequently asked questions
What causes graft-versus-host disease?
It occurs when immune cells from an allogeneic donor graft recognise the recipient’s tissues as foreign and trigger an inflammatory immune response.
Can GvHD occur more than 100 days after transplant?
Yes. Acute-type features may persist or appear after day 100, while chronic GvHD can also begin earlier. Classification is based mainly on clinical features.
Which organs are most commonly affected?
The skin, gut and liver are classic targets. Chronic GvHD can additionally affect the mouth, eyes, lungs, muscles, fascia, joints and genital tissues.
What is lung GvHD?
The best-established form is bronchiolitis obliterans syndrome, a chronic small-airway condition that causes progressive airflow obstruction.
What are the early symptoms of bronchiolitis obliterans syndrome?
A dry cough, mild wheeze, exertional breathlessness or reduced exercise tolerance may occur, but early disease can be asymptomatic.
Why are lung-function tests important after transplant?
Spirometry can identify declining airflow before severe symptoms develop, allowing earlier investigation and treatment.
Does every cough after transplantation mean lung GvHD?
No. Infection, reflux, asthma, medication toxicity and several other pulmonary complications can cause cough and must be assessed.
Is a lung biopsy needed to diagnose BOS?
Usually not. Diagnosis generally relies on lung-function decline, CT findings, clinical context and exclusion of infection or another cause.
Can GvHD be cured?
Some patients achieve complete control and can eventually stop immunosuppression. Others have persistent or relapsing disease requiring long-term treatment and monitoring.
What is steroid-refractory GvHD?
It describes disease that progresses or fails to improve adequately despite appropriate corticosteroid treatment. Additional specialist therapy may then be required.
Is extracorporeal photopheresis chemotherapy?
No. It is an immune-modifying procedure in which collected white blood cells are treated with a photosensitising medicine and ultraviolet-A light before being returned.
Should I stop immunosuppressive medicine if I develop an infection?
Do not make this change independently. Contact the transplant team urgently because both the infection and the risk of a GvHD flare need to be considered.
References and further information
- NHS. Complications of a stem-cell or bone-marrow transplant. View NHS information
- NHS England. Treatments for graft-versus-host disease following haematopoietic stem-cell transplantation. Updated July 2025. View the NHS England commissioning policy
- Shanthikumar S, Gower WA, Srinivasan S, et al. Detection of bronchiolitis obliterans syndrome after paediatric haematopoietic stem-cell transplantation: an official American Thoracic Society clinical practice guideline. American Journal of Respiratory and Critical Care Medicine. 2024;210:262–280. View the ATS guideline
- National Institutes of Health Consensus Development Project. Criteria for clinical trials in chronic graft-versus-host disease: diagnosis and staging. View the consensus report
- National Institutes of Health Consensus Development Project. Highly morbid forms of chronic graft-versus-host disease. View the report
- London Chest Specialist. Lung-function tests. Read about spirometry and respiratory testing
- London Chest Specialist. Bronchiectasis diagnosis and treatment. Read about bronchiectasis care
