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Pulmonary disease in the immunocompromised (non-HIV) 

Pulmonary disease in the immunocompromised (non-HIV)
Pulmonary disease in the immunocompromised (non-HIV)

Stephen Chapman

, Grace Robinson

, John Stradling

, Sophie West

, and John Wrightson

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date: 16 May 2022

Clinical assessment

Pulmonary disease is a significant cause of morbidity and mortality in the immunocompromised, and its diagnosis and management are challenging. In the UK, this is encountered most commonly in the setting of immunocompromise 2° to cytotoxic chemotherapy, haematological malignancy, immunosuppression post-transplant (particularly renal and haematopoietic stem cell transplant (HSCT, including bone marrow, foetal cord blood, and growth factor-stimulated peripheral blood transplantation)), prolonged corticosteroid use, and AIDS (see Pulmonary disease in the immunocompromised (non-HIV) p. [link]).

Most pulmonary diseases present in a similar manner in the setting of immunocompromise, with fever, dyspnoea, dry cough, chest pain, and often hypoxia. This non-specific clinical presentation, combined with the large number of possible causes, makes reaching a precise diagnosis difficult; the diagnosis remains unclear in up to 10% of cases, even at autopsy. There is limited evidence to demonstrate that obtaining a definitive diagnosis leads to an overall improvement in mortality, although, in subgroups such as patients with respiratory infection, early identification and treatment of pathogens have been shown to improve outcome.

Causes of pulmonary infiltrates in the non-HIV-infected immunocompromised are presented on Pulmonary disease in the immunocompromised (non-HIV) pp. [link][link], and treatment on Pulmonary disease in the immunocompromised (non-HIV) p. [link]. Specific conditions are described separately (e.g. invasive aspergillosis, see Pulmonary disease in the immunocompromised (non-HIV) pp. [link][link]; PCP, see Pulmonary disease in the immunocompromised (non-HIV) pp. [link][link]).

Key steps in the management of these patients are as follows.

Clinical assessment

In the history, the underlying cause of immunocompromise and the timing and location of respiratory disease onset may provide clues to the diagnosis. The rate of disease onset may also suggest possible causes:

  • Acute onset (<24h) Bacterial pneumonia, viral pneumonitis (e.g. CMV), pulmonary oedema or haemorrhage, PE, ARDS

  • Subacute onset (days) Fungi (e.g. Pneumocystis, Aspergillus), bacteria (e.g. Nocardia, Legionella), viral (e.g. CMV), drug-induced pneumonitis

  • Chronic onset (weeks) Malignancy, mycobacteria, fungi.

Chest examination may suggest the extent of pulmonary involvement, although this can be misleading and there are often no abnormal signs (e.g. in PCP, or bacterial pneumonia in the setting of neutropenia). Assess fluid status; pulmonary oedema is common following transplantation. Extrapulmonary involvement may be helpful in suggesting a pathogen, e.g. cutaneous lesions (herpes simplex and varicella-zoster; necrotic lesions from Pseudomonas and other Gram-negative bacteria, mycobacteria, and fungi; subcutaneous abscesses in Staphylococcus aureus and Nocardia), CNS involvement (Pseudomonas, Aspergillus, Cryptococcus, Nocardia, mycobacteria, Streptococcus pneumoniae, Haemophilus influenzae, varicella-zoster).

Initial investigations

  • CXR appearance is very variable; may be normal or show consolidation, nodular infiltrate, or diffuse shadowing. CXR is of limited diagnostic value, as appearances are non-specific and atypical presentations are common; the ‘first-choice’ diagnosis based on CXR is correct in only a third of cases. CXR may, however, be helpful in monitoring disease progression and response to treatment

  • Blood and pleural fluid (if available) sampling for microscopy andculture. Consider viral serology (e.g. CMV following transplantation), urinary Legionella antigen

  • Sputum examination is often of little diagnostic value in immunocompromised patients, with the possible exceptions of invasive aspergillosis and TB. Send sputum for acid-fast stain and mycobacterial culture, fungal stain, and culture. Induced sputum has a low yield for PCP in non-HIV patients

  • The degree of hypoxia is often not appreciated; measure O2 saturations, and consider ABGs. Severe hypoxia tends to be more commonly associated with infection due to bacteria, viruses, or Pneumocystis than with mycobacteria or fungi.

Is immediate antibiotic treatment required?

Immediate empirical treatment with broad-spectrum antibiotics prior to further investigation should be considered, depending on the nature of immunological defect and local hospital policy. In general, neutropenic patients with fever are at significant risk of developing overwhelming sepsis and should receive prompt antibiotic cover, irrespective of the CXR appearance and presence or absence of respiratory symptoms/signs. More invasive diagnostic procedures can then be reserved for patients who deteriorate or fail to improve within a period of observation (e.g. 2–3 days). In non-neutropenic patients, depending on the clinical circumstances, it is often possible to withhold treatment until definitive investigations have taken place.

Further investigations

More invasive diagnostic techniques are usually required for a definitive diagnosis.

CT chest

  • Specific indications not yet defined. May not be needed in typical cases of bacterial pneumonia or PCP

  • Useful in identifying the location and extent of pulmonary disease, and aiding invasive sampling procedures

  • Often detects pulmonary disease in the presence of a normal CXR—consider if respiratory symptoms or unexplained fever, but normal CXR

  • May be diagnostic, e.g. PE (CTPA), lymphangitis carcinomatosis, invasive aspergillosis (‘halo’ and ‘air crescent’ signs).

Bronchoscopy with BAL

  • First-line investigation; consider early in management. Diagnostic inabout 60% of patients overall; up to 70% of patients with infection. Results in change to treatment in ~50% of cases overall. Complications are rare

  • Useful in the diagnosis of bacterial pneumonia, PCP (sensitivity 80–90%), CMV (sensitivity 85–90%), aspergillosis (sensitivity 50%), TB, malignant disease, diffuse alveolar haemorrhage, and alveolar proteinosis

  • BAL fluid analysis: routine microscopy and culture for bacteria; additional stains and culture for fungi, mycobacteria, Nocardia; silver or immunofluorescence stain for Pneumocystis; cytology, including flow cytometry, for malignant cells; viral serology; haemosiderin-laden macrophages if alveolar haemorrhage suspected

  • Consider additional tests on BAL fluid such as Cryptococcus antigen detection or CMV PCR. Aspergillus antigen detection or PCR and Toxoplasma gondii PCR are less well validated

  • TBB has a slightly higher sensitivity than BAL for the diagnosis of infection but carries a risk of bleeding and pneumothorax, which can be serious complications in this patient group; it is not usually performed at initial bronchoscopy although may be considered, e.g. if lymphangitis is suspected.

Lung biopsy

Consider as a second-line investigation if BAL is non-diagnostic. Options include:

  • Repeat bronchoscopy with transbronchial lung biopsy is useful in the diagnosis of malignancy, mycobacteria, fungi, OP, and drug-induced lung disease

  • VATS or open lung biopsy has a greater diagnostic yield than TBB, although it is unclear if this can be directly translated into an improved survival. Results in change to treatment in <50% of patients, and complications may be serious

  • Percutaneous image-guided fine-needle aspiration (FNA) or biopsy for investigation of peripheral nodules.


Causes of pulmonary disease in the immunocompromised can be broadly divided into infectious and non-infectious; multiple disease processes are common. The nature of immunosuppression may provide clues to the cause(s) of pulmonary disease—solid organ (kidney and liver) transplants are further discussed on Pulmonary disease in the immunocompromised (non-HIV) p. [link], lung transplantation on Pulmonary disease in the immunocompromised (non-HIV) p. [link], HSCT on Pulmonary disease in the immunocompromised (non-HIV) pp. [link][link], and HIV on Pulmonary disease in the immunocompromised (non-HIV) p. [link].

Infectious causes

(>75% of cases) Infection is the commonest cause of respiratory disease in the immunocompromised. The nature of immunological defect may provide clues to the likely infectious agent:

  • Neutropenia or impaired neutrophil function ( leukaemia or cytotoxic treatment) Bacteria (P. aeruginosa, S. aureus, S. pneumoniae, E. coli, Klebsiella, H. influenzae, Nocardia), fungi (Aspergillus, Candida, mucormycosis)

  • Impaired T-lymphocyte function ( transplantation, cytotoxic treatment, high-dose steroids, lymphoma, AIDS) Fungi (PCP, Cryptococcus neoformans, Candida, endemic mycoses), viruses (CMV, herpes simplex, varicella-zoster), bacteria (mycobacteria, Listeria, Legionella, Nocardia), parasites (Toxoplasma gondii)

  • Hypogammaglobulinaemia or impaired B-lymphocyte function ( myeloma, acute and chronic lymphocytic leukaemia, lymphoma) Encapsulated bacteria (S. pneumoniae, H. influenzae).

It should be noted, however, that considerable overlap exists between immune deficiencies, and the pattern of infection will be further modified by prophylactic treatment, e.g. CMV and PCP prophylaxis.

Non-infectious causes

(<25% of cases) Often present with similar, if not identical, clinical and radiological features to infection, and signs, such as fever, do not reliably differentiate between them. Causes include:

  • Pulmonary oedema Particularly following renal transplant or HSCT

  • ARDS, e.g. 2° to sepsis, drugs (e.g. cytarabine, gemcitabine, OKT3 antilymphocyte antibodies, interleukin-2), massive blood trans-fusion, transfusion-related acute lung injury, aspiration, ‘engraftment syndrome’ (coinciding with neutrophil engraftment) following HSCT

  • Drug-induced disease Causes include all-trans retinoic acid (ATRA), antithymocyte globulin, azathioprine, bleomycin, busulfan, carmustine, chlorambucil, cyclophosphamide, cytosine arabinoside, hydroxycarbamide, liposomal amphotericin B, melphalan, mitomycin, methotrexate, sirolimus

  • Respiratory involvement from the underlying disease, e.g. lymphoma, leukaemic infiltration, lymphangitis carcinomatosis, connective tissue disease, leucostasis with very high leucocyte counts in leukaemia

  • PE Often complicated by 2° infection; clinical/radiological features may be confused with invasive aspergillosis; may be more common after kidney transplant

  • Radiation-induced pulmonary disease Pneumonitis (dyspnoea; clear margins on CT; typically follows lung radiotherapy; may be delayed and triggered by subsequent chemotherapy treatment, so-called ‘radiation recall pneumonitis’) or OP (cough; extends beyond radiation field on CT; typically follows breast radiotherapy).

  • Diffuse alveolar haemorrhage is not an uncommon complication of leukaemia and allogeneic or autologous HSCT; similar clinical presentation to that of pneumonia; haemoptysis is rare; multilobar CXR/CT infiltrates; proposed diagnostic criteria include exclusion of infection, progressively bloodier returns from BAL of three different subsegmental bronchi (although limited sensitivity and specificity), and ≥20% of alveolar macrophages haemosiderin-filled (although may require several days to appear); reported mortality ranges 30–100%

  • ‘Idiopathic pneumonia syndrome’ following allogeneic or autologous HSCT; breathlessness with hypoxia and multilobar CXR/CT infiltrates; infection excluded with BAL and ideally a second later investigation (e.g. repeat BAL or lung biopsy); diffuse alveolar damage or interstitial pneumonitis on biopsy; mortality >70%

  • Engraftment syndrome comprises fever, ARDS, and erythematous rash during marrow recovery post-HSCT

  • Bronchiolitis obliterans syndrome (BOS) following allogeneic HSCT (from non-identical sibling or unrelated individual; occurs only extremely rarely following autologous procedure); typically associated with other forms of chronic graft-versus-host disease (GVHD), e.g. cutaneous; gradual onset of dry cough, dyspnoea; CXR often normal; fixed obstructive spirometry with FEV1 <75% predicted, FEV1/FVC ratio <0.7, and RV >120% predicted; air trapping and bronchial dilatation on HRCT (request expiratory images); superimposed airways infection is common

  • Post-transplant lymphoproliferative disease may complicate allogeneic HSCT or solid organ transplant, most commonly lung (see Pulmonary disease in the immunocompromised (non-HIV) p. [link])

  • Pulmonary alveolar proteinosis (see Pulmonary disease in the immunocompromised (non-HIV) pp. [link][link])

  • Pulmonary veno-occlusive disease

  • Pulmonary metastatic calcification may complicate chronic renal failure and rarely progress after transplantation; usually asymptomatic, rarely causes restrictive ventilatory defect; CXR shows single or multiple nodules or patches of consolidation, may not appear calcified; CT typically diagnostic, although biopsy occasionally needed

  • Right hemidiaphragm dysfunction is common after liver transplant and usually not relevant clinically.

Multiple disease processes

About 30% of patients have two or more disease processes accounting for their respiratory involvement. 2° infection with a different infectious agent (commonly Aspergillus or Gram-negative bacteria such as P. aeruginosa) may complicate either a 1° respiratory infection or a non-infectious process such as PE. 2° infection is associated with a poor prognosis; consider particularly in patients who deteriorate after an initial response to treatment and in patients who are neutropenic.

Pleural effusion

Causes in non-HIV immunocompromised patients include cardiac failure and fluid overload, PE, drug-related, parapneumonic (bacterial, including Nocardia; fungal, e.g. PCP), or related to underlying disease (e.g. leukaemic infiltrates, lymphoma, chylothorax, myeloma). Pleural effusions are common after liver transplant: usually right-sided or bilateral transudates and resolve by third week; may require drainage if symptomatic.

Differential diagnosis of pulmonary complications based on time course after transplantation

Solid organ transplantation

First month post-transplant (recent surgery ± ICU)

  • Nosocomial bacterial infection (Gram-negative, S. aureus—including MRSA, Legionella)

  • ARDS

  • Pulmonary oedema

  • Drug-induced

  • PE

  • Pleural effusion (especially after liver transplant)

  • Right hemidiaphragm dysfunction (after liver transplant).

Months 1–6 (maximal immunosuppression)

  • Opportunistic infection (CMV, PCP, Nocardia, Aspergillus, Scedosporium apiospermum)

  • Drug-induced

  • Post-transplant lymphoproliferative disease.

Months >6 (reduction in immunosuppression, unless rejection)

  • Common community-acquired pathogens (H. influenzae, S. pneumoniae, Legionella, TB, non-tuberculous mycobacteria (NTM), PCP, endemic mycoses, e.g. Histoplasma, viruses, e.g. influenza, parainfluenza, adenovirus, RSV)

  • Opportunistic infection (see under Months 1–6)

  • Post-transplant lymphoproliferative disease

  • Pulmonary metastatic calcification.


First month post-transplant (prolonged neutropenia pre-engraftment)

  • Infection (bacteria, e.g. P. aeruginosa, E. coli, Klebsiella pneumoniae, H. influenzae, S. aureus, Legionella species; fungi, e.g. Aspergillus; viruses, e.g. herpes simplex, adenovirus)

  • Pulmonary oedema

  • ARDS

  • Transfusion-related acute lung injury

  • Drug-induced

  • Diffuse alveolar haemorrhage

  • Idiopathic pneumonia syndrome.

Months 1–3 (impaired cellular immunity post-engraftment, related in part to immunosuppressive drugs and GVHD)

  • Opportunistic infection (Gram-negative bacteria, Nocardia, CMV, herpes simplex, PCP)

  • Drug-induced

  • Diffuse alveolar haemorrhage

  • Idiopathic pneumonia syndrome

  • Engraftment syndrome

  • Post-transplant lymphoproliferative disease

  • Pulmonary veno-occlusive disease.

Months >3 (poor lymphocyte function, particularly following allogeneic HSCT)

  • Infection (Gram-positive bacteria, CMV, herpes, varicella-zoster, TB, NTM, PCP, Aspergillus, endemic mycoses, e.g. Histoplasma)

  • BOS (pulmonary GVHD; may occur up to 5y post-allogeneic HSCT, typically within 2y)

  • Post-transplant lymphoproliferative disease

  • Pulmonary veno-occlusive disease.



Depending on the clinical circumstances, antimicrobials may need to be started prior to definitive investigations (see Pulmonary disease in the immunocompromised (non-HIV) p. [link]), although blood cultures should always precede antibiotic treatment. Choice of antimicrobial depends on the underlying condition and local hospital policy.

  • In general, most neutropenic patients are treated with broad-spectrum antibiotics providing both Gram-positive and Gram-negative cover, e.g. piperacillin (4.5g IV qds); antifungals are considered if slow response to treatment or subsequent deterioration. Consider vancomycin if MRSA is a possibility

  • Treatment for CMV and PCP is associated with significant side effects and ideally should be based on a definitive diagnosis. In unwell patients who are strongly suspected to have PCP, treatment (see Pulmonary disease in the immunocompromised (non-HIV) pp. [link][link]) can be started immediately, as BAL Pneumocystis jirovecii stains remain positive for up to 2 weeks

  • Antituberculous treatment should only rarely be administered in the absence of a microbiological diagnosis.


Fluid overload and pulmonary oedema are common following renal transplantation and HSCT, and typical clinical and radiological signs may be disguised; consider a trial of diuretics.


Despite a lack of RCTs, prednisolone (1mg/kg/day PO or methylprednisolone 1g IV daily for 3 days) is often considered in the treatment of drug- or radiation-induced lung disease, engraftment syndrome, diffuse alveolar haemorrhage, and idiopathic pneumonia syndrome following HSCT. Ideally, exclude underlying infection prior to starting steroids. Prednisolone (40–80mg daily PO) is recommended for the treatment of PCP in patients with respiratory failure. BOS, following allogeneic HSCT, is usually treated with increased immunosuppression (after exclusion/treatment of airways infection), typically oral prednisolone 1mg/kg/day, and there may also be roles for inhaled steroids, azithromycin, and anti-reflux therapy in this condition.

Supportive treatment

Administer O2 to maintain saturations 94–98%. Respiratory failure in immunocompromised patients is associated with a poor outcome; mortality following intubation and mechanical ventilation ranges 60–100%. Early intermittent use of NIV in immunocompromised patients with pulmonary infiltrates and hypoxia has been shown to reduce the need for intubation and improve mortality. Before NIV is commenced, a decision regarding suitability for intubation and mechanical ventilation should be made.


Surgical wedge resection or lobectomy may be considered in the treatment of invasive aspergillosis, either acutely for lesions adjacent to pulmonary vessels that are judged to have a significant risk of massive haemoptysis, or at a later date for residual lesions at risk of reactivation with further chemotherapy.