Infection after haematopoietic stem-cell transplantation

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

HSCT deliberately dismantles and rebuilds immunity. Conditioning injures skin and mucosa, central catheters create direct access and pre-engraftment neutropenia removes phagocyte defence. Neutrophils recover before functional lymphocyte populations; allogeneic recipients then face prolonged T-cell, B-cell and humoral dysfunction, especially with graft-versus-host disease and its treatment. Infection patterns therefore follow immune recovery more closely than fixed dates.

Pre-engraftment disease is often bacterial or Candida bloodstream infection, HSV mucositis, enterocolitis or invasive mould disease during prolonged neutropenia. During early post-engraftment, CMV and other DNA viruses, Pneumocystis, moulds and respiratory viruses emerge. Late aftercare is heterogeneous: an autologous recipient off therapy may regain useful immunity, while an allogeneic recipient with chronic graft-versus-host disease can remain vulnerable for years.

Several non-infectious complications mimic infection and sometimes coexist. Engraftment syndrome, graft-versus-host disease, drug pneumonitis, diffuse alveolar haemorrhage, transplant-associated thrombotic microangiopathy and sinusoidal obstruction can produce fever and organ failure. Giving corticosteroids for a presumed immune complication before adequate microbiology may amplify an occult pathogen; delaying immunosuppression in severe graft-versus-host disease can also harm. Early multidisciplinary sampling resolves this tension.

Key points

Before engraftment, neutropenia, mucositis and central access favour Gram-negative and Gram-positive bloodstream infection, enteric translocation, Candida, HSV and mould disease when neutropenia is prolonged.
From engraftment to about day 100, impaired cellular immunity and acute graft-versus-host disease favour CMV, HHV-6, adenovirus, respiratory viruses, Pneumocystis and Aspergillus.
After day 100, chronic graft-versus-host disease, corticosteroids, hypogammaglobulinaemia and delayed B- and T-cell recovery sustain VZV, Pneumocystis, mould and encapsulated-bacterial risk.
Autologous HSCT usually has shorter neutropenia and no allogeneic graft-versus-host disease, so its prolonged opportunistic risk is lower unless treatment or disease creates another immune defect.
First-line assessment always defines transplant type, day, engraftment, donor-recipient viral serology, graft-versus-host disease, current prophylaxis and the exact immunosuppressive regimen.
Blood cultures and syndrome-led molecular tests come before antimicrobials when safe; CT, bronchoalveolar lavage, endoscopy or tissue may be needed because blood assays cannot prove every organ infection.
Letermovir prevents CMV reactivation in eligible CMV-seropositive allogeneic recipients but has no HSV or VZV activity and does not replace quantitative CMV surveillance.
The infection framework centres on immune phase and pathogen-directed sampling; conditioning toxicity, graft-versus-host disease treatment and donor-cell decisions remain owned by the transplant service.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Endogenous flora and devices

Conditioning-damaged mucosa, central access and neutropenia allow oral, enteric and skin bacteria or Candida to enter blood before engraftment.

Latent viral reactivation

CMV, EBV, HSV, VZV, HHV-6, adenovirus and polyomaviruses emerge as cellular immune surveillance falls and may target specific organs.

Environmental opportunists

Airborne mould, Pneumocystis, nocardia, toxoplasma, mycobacteria and community respiratory viruses exploit prolonged phagocyte, T-cell or corticosteroid-mediated defects.

Donor and epidemiological exposure

Donor serostatus, household contacts, hospital transmission, food, water, construction dust and travel alter pathogen exposure alongside the recipient's immune state.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Conditioning barrier injury
Chemotherapy and irradiation damage oral and intestinal epithelium, enabling microbial translocation and releasing inflammatory signals that blur infection with transplant toxicity.
2
Pre-engraftment phagocyte deficit
Profound neutropenia prevents containment of extracellular bacteria and invasive mould hyphae, while signs such as pus and radiographic consolidation remain attenuated.
3
Delayed adaptive reconstitution
Functional T-cell, B-cell and antibody recovery lags behind neutrophils, permitting viral reactivation, Pneumocystis and encapsulated-bacterial disease after apparent marrow recovery.
4
Alloreactivity and GVHD
Donor immune attack injures epithelial organs, and corticosteroid or other graft-versus-host disease treatment further weakens cellular and innate pathogen control.
5
Prophylactic selection pressure
Sustained antimicrobials delay susceptible infections but select breakthrough organisms, resistant strains and drug toxicity, changing rather than abolishing the expected timeline.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Pre-engraftment feverRed flag

Fever, rigors, mucositis, abdominal symptoms or line discomfort during profound neutropenia represents bacterial sepsis until treated, even when examination shows little inflammation.

Viral reactivation syndromeRed flag

Cytopenia, hepatitis, diarrhoea, pneumonitis, encephalopathy or haemorrhagic cystitis after engraftment should prompt targeted CMV, HHV-6, adenovirus, BK and other viral assessment.

Pulmonary opportunistic diseaseRed flag

Subacute cough, exertional desaturation, pleuritic pain, haemoptysis or CT nodules and ground glass require early bronchoscopy planning rather than empirical diagnosis from imaging alone.

Late humoral failure

Recurrent sinus, chest or bloodstream infection with encapsulated bacteria may reflect chronic graft-versus-host disease, functional asplenia or hypogammaglobulinaemia.

Red flags requiring action

Fever, hypothermia, rigors or any sepsis physiology before neutrophil recovery requires immediate neutropenic-sepsis treatment.
New hypoxaemia, dry cough or diffuse ground-glass change may be Pneumocystis, CMV, respiratory virus, mould, bacterial infection, diffuse alveolar haemorrhage or idiopathic pneumonia syndrome.
Severe watery or bloody diarrhoea, abdominal pain, ileus or dehydration requires urgent investigation for infection and gastrointestinal graft-versus-host disease.
Confusion, seizure, personality change, focal neurology or severe headache raises concern for HHV-6 encephalitis, fungal or bacterial CNS infection, toxoplasma, drug toxicity or posterior reversible encephalopathy.
Vesicular or disseminated rash, eye symptoms, mucosal ulceration or dermatomal pain may signal severe HSV or VZV and needs immediate antiviral and infection-control assessment.
Acute or chronic graft-versus-host disease requiring high-dose corticosteroids prolongs mould, CMV, Pneumocystis and encapsulated-bacterial risk beyond ordinary time boundaries.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Transplant and immune-phase assessmentFirst step
Why
Set the pre-test probability for bacterial, viral, fungal and non-infectious disease before selecting specialised tests.
Interpretation and limitations
Record autologous versus allogeneic graft, source, conditioning, transplant day, neutrophil and lymphocyte recovery, graft-versus-host disease, corticosteroid exposure, prophylaxis, serostatus and previous organisms.
02
First-line cultures and severity testsFirst line
Why
Recover bacteria or yeast and detect marrow, kidney, liver, coagulation and perfusion abnormalities that change urgent therapy.
Interpretation and limitations
Take paired peripheral and catheter blood cultures, FBC, renal and liver profiles, CRP and lactate before antibiotics when this is immediate. Sample urine, stool, skin or respiratory tract only as the syndrome indicates.
03
Quantitative viral nucleic-acid testing
Why
Detect and trend CMV, EBV, adenovirus and other protocol-defined reactivation and guide pre-emptive intervention.
Interpretation and limitations
Use transplant-centre assays, specimen type and thresholds consistently. A rising trend may matter more than one low value, while tissue-limited disease can require biopsy despite modest blood DNA.
04
High-resolution CT chest
Why
Identify ground glass, nodules, halo change, cavitation or focal consolidation when radiography and examination understate pulmonary disease.
Interpretation and limitations
CT patterns prioritise tests but are not pathogen specific. Diffuse ground glass spans infection, haemorrhage and inflammatory lung injury; nodules span mould, nocardia, bacteria and malignancy.
05
Bronchoalveolar lavage
Why
Obtain lower-respiratory material for bacterial, fungal, mycobacterial and viral tests before prolonged empirical treatment obscures diagnosis.
Interpretation and limitations
Send microscopy and culture, Aspergillus galactomannan or molecular testing, Pneumocystis PCR, respiratory viral PCR and cytology according to risk. Interpret a highly sensitive PCR with organism burden and clinical phenotype.
06
Endoscopy or tissue biopsy
Why
Separate graft-versus-host disease, CMV or other infection, drug injury and malignant disease in organ-specific syndromes.
Interpretation and limitations
Histology with targeted immunostaining, culture and molecular tests is the reference approach for proven tissue-invasive infection; coordinate platelet support and specimen allocation before sampling.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Graft-versus-host disease

Rash, diarrhoea, hepatitis and lung dysfunction overlap with infection; endoscopic, skin, liver or lung tissue may be needed before escalating immune suppression.

Engraftment syndrome

Fever, rash, weight gain, pulmonary infiltrates and organ dysfunction around neutrophil recovery can be inflammatory but require cultures and infection exclusion.

Drug toxicity

Calcineurin neurotoxicity, antiviral marrow suppression, azole hepatic injury and medication diarrhoea can reproduce infectious syndromes and alter antimicrobial exposure.

Non-infectious lung injury

Diffuse alveolar haemorrhage, idiopathic pneumonia, fluid overload and drug pneumonitis can cause ground glass and hypoxaemia, sometimes alongside a respiratory pathogen.

Relapse or lymphoproliferation

Recurrent malignancy and EBV-associated post-transplant lymphoproliferative disease may cause fever, cytopenias, nodes, organ lesions and marrow abnormalities requiring tissue diagnosis.

Additional chapter-specific clues

Infectious diarrhoea versus GVHD

Watery diarrhoea, cramps, nausea and weight loss overlap extensively; stool microbiology, medication review and frequently endoscopic biopsy are required before attributing symptoms.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01PRE-ENGRAFTMENTTreat neutropenic infection nowFirst stepFever, rigors or clinical deterioration occurs before neutrophil recovery or during renewed profound neutropenia.

1Use the emergency neutropenic-sepsis pathway, take paired cultures rapidly and give locally approved antipseudomonal therapy without waiting for imaging or cell counts.
2Examine mouth, line, skin and abdomen, avoid rectal instrumentation and arrange urgent CT for abdominal danger signs or pulmonary features.
3Use previous colonisation and prophylaxis to identify resistant bacterial and breakthrough fungal gaps and involve microbiology at the first dose when standard cover may fail.
4EscalationEscalate persistent fever through CT, biomarkers and targeted sampling, then select mould-active treatment from prior prophylaxis, likely species, organ function and interactions.

02POST-ENGRAFTMENTInvestigate cellular-immune failureFever or organ dysfunction develops after engraftment, particularly before day 100 or during graft-versus-host disease treatment.

1Continue ordinary bacterial cultures while adding protocol CMV, EBV, adenovirus and syndrome-specific viral tests rather than treating the episode as purely viral.
2Obtain CT chest early for respiratory symptoms and arrange bronchoalveolar lavage when safe before multiple empirical agents reduce diagnostic value.
3For diarrhoea, isolate appropriately, send enteric bacterial, viral and Clostridioides difficile tests, review medicines and plan endoscopic biopsy if the diagnosis remains uncertain.
4Treat the defined pathogen and ask the HSCT team to adjust immunosuppression, graft-versus-host disease therapy and immune replacement together.

03CMV PREVENTIONCombine prophylaxis and surveillanceA CMV-seropositive adult receives an allogeneic HSCT and meets the commissioned and licensed criteria.

1Start letermovir on transplant day or within the licensed early window and no later than day 28, using the transplant protocol and current product information.
2Give 480 mg once daily, reduced to 240 mg once daily with ciclosporin, and continue through day 100; selected high-risk patients may continue through day 200 under the current licence and centre pathway.
3Continue HSV and VZV prophylaxis because letermovir has no activity against those viruses, and maintain scheduled CMV quantitative surveillance.
4When DNAemia reaches the centre threshold or CMV disease develops, move to renal-adjusted pre-emptive or treatment antiviral therapy; letermovir is not treatment for established CMV disease.

04LATE PHASEReassess immune recoveryInfection occurs after day 100 or recurs during chronic graft-versus-host disease and prolonged immunosuppression.

1Recalculate risk from current corticosteroids, lymphocyte recovery, immunoglobulins, functional asplenia, graft-versus-host disease and ongoing antiviral, antifungal and Pneumocystis prophylaxis.
2Investigate community respiratory and urinary disease promptly while retaining a differential of VZV, Pneumocystis, mould, nocardia, mycobacteria and encapsulated bacteria.
3Check whether revaccination has begun and follow the transplant schedule; treat the recipient as having lost previous vaccine memory rather than assuming childhood vaccines remain protective.
4Continue or restart prophylaxis according to immune suppression and graft-versus-host disease, not an arbitrary anniversary, and give written fever and exposure advice.

Key medicines and prescribing safety5 treatments · regimens, roles and cautions

Covers time-critical bacterial infection before engraftment and during any later episode of profound treatment-related neutropenia.

Immediate empirical antibacterial therapy

Use the centre's HSCT febrile-neutropenia regimen at emergency loading doses after rapid cultures, with renal adjustment and resistant-organism modification directed by microbiology.

Prior prophylaxis and colonisation may invalidate the usual regimen; review every added aminoglycoside or glycopeptide and do not let transfer to the transplant centre delay treatment.

NICE-recommended prevention of CMV reactivation and disease in eligible CMV-seropositive adult allogeneic HSCT recipients.

Letermovir

Give 480 mg orally or intravenously once daily, reduced to 240 mg once daily with ciclosporin; start from day 0 to day 28 and continue through day 100, or to day 200 when the licensed high-risk extension is selected.

It does not treat established CMV or prevent HSV and VZV. Check ciclosporin, tacrolimus, sirolimus, azole and statin interactions and follow the latest product and transplant protocol.

Prevents HSV reactivation and contributes to VZV prevention when letermovir provides no activity against either virus.

Aciclovir prophylaxis

A common adult HSCT regimen is aciclovir 400 mg orally twice daily, adjusted for renal function; the centre specifies route, dose and duration for HSV and VZV serostatus and absorption.

Ensure hydration, adjust in kidney impairment and review neurotoxicity or crystal nephropathy; disseminated HSV or VZV requires treatment-dose intravenous therapy rather than prophylactic dosing.

Preferred Pneumocystis prophylaxis with activity against toxoplasma and some nocardia after engraftment.

Co-trimoxazole prophylaxis

A common adult regimen after count recovery is 960 mg orally three times weekly; the HSCT protocol determines start, alternative schedule and continuation during graft-versus-host disease treatment.

Monitor marrow, potassium and renal function and distinguish toxicity from graft or infection effects; use a specialist alternative when cytopenia, allergy or interaction prevents safe delivery.

Mould-active prevention during selected prolonged neutropenia or significant graft-versus-host disease, not universal prophylaxis for every recipient.

Posaconazole prophylaxis

For gastro-resistant tablets, give 300 mg orally twice on day 1 then 300 mg once daily from day 2 when the HSCT mould-prophylaxis pathway identifies high risk.

Do not interchange formulations milligram for milligram; check hepatic tests, QT effects, absorption and concentrations where indicated, and manage major calcineurin, mTOR and other CYP3A4 interactions.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Multiorgan sepsis

Attenuated early inflammation permits bloodstream or pulmonary infection to progress rapidly to shock, respiratory failure, coagulopathy and kidney or hepatic injury.

Disseminated viral disease

Uncontrolled CMV, adenovirus, HSV or VZV can spread across lung, gut, liver, brain, marrow, skin and eye with high treatment toxicity.

Invasive mould dissemination

Angioinvasive fungi thrombose and invade pulmonary vessels and may spread to sinuses, brain, skin and other organs, causing infarction and haemorrhage.

Chronic immune dysfunction

Graft-versus-host disease and delayed reconstitution produce recurrent respiratory infection, hypogammaglobulinaemia, functional asplenia and prolonged dependence on prophylaxis and vaccination.

Treatment-limiting toxicity

Marrow suppression, renal injury, hepatic toxicity and drug interactions can interrupt both anti-infective therapy and graft-versus-host disease control, worsening competing risks.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Track temperature, haemodynamics, oxygenation, stool volume, neurological status, weight and fluid balance against transplant day, engraftment and graft-versus-host disease activity.
Review FBC, renal and liver profiles and every culture daily during acute illness; marrow suppression may come from infection, antivirals, graft failure, drugs or disease relapse.
Follow CMV and other viral loads using the centre's specimen, assay and schedule, recording prophylaxis exposure and treatment dose so trends remain interpretable.
Measure calcineurin or mTOR inhibitor concentrations promptly after azole, macrolide, rifamycin, letermovir, diarrhoea or organ-function changes and act with transplant pharmacy.
Reassess the continuing need for antibacterial, antiviral, antifungal and Pneumocystis prophylaxis whenever graft-versus-host disease treatment or immune recovery changes.
Audit revaccination and infection plans at long-term review, including influenza, COVID-19, pneumococcal and the staged transplant schedule; defer live vaccines until specialist criteria are satisfied.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Engraftment is partial recovery

A rising neutrophil count reduces some bacterial and mould risk but does not restore T-cell, B-cell or antibody function and cannot end opportunistic surveillance.

Autologous and allogeneic risk differs

Absence of donor alloreactivity and chronic graft-versus-host disease shortens immune dysfunction after autologous transplantation, although the underlying disease and later therapy still matter.

GVHD and infection overlap

Skin, gut, liver and lung graft-versus-host disease can resemble or coexist with infection; tissue should be divided deliberately for histology and microbiology.

Letermovir leaves herpes gaps

CMV terminase inhibition is narrow: HSV and VZV prophylaxis remains necessary and breakthrough CMV DNAemia still follows the transplant surveillance pathway.

Revaccination rebuilds memory

HSCT recipients are approached as if previously unvaccinated because conditioning and immune replacement erase dependable vaccine memory; schedules restart under specialist supervision.

11Common pitfallsFrequent interpretation and management errors.

01
Using day 100 as proof of immune recovery despite active graft-versus-host disease, corticosteroids or persistent lymphopenia.
02
Starting high-dose corticosteroids for presumed graft-versus-host disease or pneumonitis before obtaining feasible stool, respiratory or tissue microbiology.
03
Interpreting a positive respiratory or Pneumocystis PCR without organism burden, imaging and host probability, or dismissing disease solely because one assay is negative.
04
Assuming letermovir covers HSV and VZV or using it as treatment for established CMV replication.
05
Failing to adjust calcineurin-inhibitor exposure when starting posaconazole, letermovir or another interacting anti-infective.
06
Treating childhood vaccination records as adequate after HSCT instead of rebuilding protection through the transplant revaccination schedule.