Bronchoalveolar lavage fluid


Bronchoalveolar lavage fluid


Bronchoalveolar lavage fluid


Bronchoalveolar lavage fluid

  48 Bronchoalveolar lavage fluid

Joachim Müller-Quernheim


Bronchoalveolar lavage (BAL) is a technique that allows the recovery of both cellular and noncellular components from the epithelial surface of the lower respiratory tract and differs from bronchial washings, which refer to the aspiration of either secretions or small amounts of instilled saline from large airways /1/.

Technical aspects

BAL is performed as part of routine fiber optic inspection of the bronchial tree and before biopsy or brushing in order to avoid excess blood in the recovered fluid, which would alter the concentration of cellular and noncellular components. In localized disease the involved segment should be lavaged. In diffuse disease, the right middle lobe or lingula is lavaged most commonly because, when the patient is supine, the anatomy favors maximal recovery of fluid and cells from these sites /2/.

48.1 Indication

Diagnostic lavage in non neoplastic lung disease:

  • Rule out of infections, particularly opportunistic infections in immunocompromised hosts by pathogenic organisms not known to colonize the lower respiratory tract
  • Detection of infectious agents, such as bacteria, viral agents fungi and mycobacteria
  • Cellular analysis suggestive of interstitial lung disease /2/.

Therapeutic lavage:

  • Pulmonary alveolar proteinosis
  • Aspiration of contrast media or gastric juice
  • Mucoid impaction associated with bronchial asthma.

48.2 Sampling

BAL is conducted as part of a fiber optic bronchoscopic examination. For details on the procedure of fiber optic bronchoscopy, see Ref. /3/.

The bronchoscope has to be positioned in such a way that maximal recovery of the instilled fluid is assured. This is achieved by using instruments with a diameter of 5.0–6.5 mm upon reaching the bronchoscope wedges in fourth to fifth order bronchi.

Even though the lavage fluid still has to reach to 10th to 12th order bronchi on its way to the alveolus, the bronchial surface represents only approximately 2–4% of the total lavaged surface so that the alveolar surface dominates with a proportion of more than 95%. Artifacts caused by changes of the bronchial epithelia are recognizable in the first fraction of the recovered lavage fluid. If this fluid is discarded, it can be assumed that only alveolar phenomena are detected.

Bronchial artifacts (e.g., due to cough) can be assumed if the differential cytology reveals squamous and ciliary epithelial cells. To avoid contamination, the BAL has to be performed prior to obtaining trans bronchial or brush biopsies. In case of localized disease, the radiologically involved segment has to be lavaged.

To avoid contamination or bronchial artifacts, a catheter can be advanced through the working channel into the segment of interest so that this segment can be selectively lavaged.

In diffuse disease, the BAL is usually performed in the lingula or middle lobe. Provided that the bronchoscope is wedged reaching the fourth to fifth order bronchi, 1.5–3% of the pulmonary surface, corresponding to approximately 106 alveoli, is sampled. The sample should be representative in order to reflect changes caused by diffuse lung disease (e.g., sarcoidosis). In other diffuse lung diseases, a radiographically unequivocally involved segment should be lavaged because changes do not occur evenly throughout the entire lung.

The instilled fluid is usually a buffered or unbuffered, sterile, isotonic, 37 °C saline solution. Fractions of 20–60 mL up to a total volume of 150–300 mL are instilled and immediately aspirated. A pre-set dwelling time does not have to be adhered to. If volumes of less than 100 mL are used, bronchial cells can influence the differential cytology. The first aliquot from each sub segment is generally poorly recovered. Thereafter, the return increases such that 60–70% of the instilled volume is recovered in healthy volunteers. Recovery of fluid is decreased in smokers and in most patients with lung diseases, especially obstructive airway disease /1/.

The lavage fluid is collected in siliconized glass or polyethylene containers and cooled. This prevents the alveolar macrophages from adhering to the walls of the containers because otherwise falsely high proportions of lymphocytes would be found due to the loss of alveolar macrophages. To ensure sufficient reproducibility and diagnostic accuracy, a recovery rate of 30% should be achieved /4/.

Immediate processing for the microbiological investigation is desirable. For routine cytology the BAL can be sent to laboratories outside the hospital. It is, however, better to send out the air dried cytocentrifuge preparations.

48.3 Processing of bronchoalveolar lavage specimens

To determine the total cell yield, the lavage fluid is pooled and mixed thoroughly. To remove mucus flakes, the lavage is filtered through sterile gauze. A small aliquot is used for counting the cells with a hematology analyzer. The BAL fluid is centrifuged at a low speed for 10 to 20 minutes. The supernatant is removed for the determination of non cellular components. The cell pellet is then resuspended in Hank’s balanced salt solution or phosphate-buffered salt solution /12/.

Differential cell counts

Cytocentrifuge preparations are made from cell suspensions containing approximately 4 × 104 cells/mL and are stained with May-Grünwald-Giemsa or Wright-Giemsa. A total of 200 to 500 cells are counted by the random field counting technique, and alveolar macrophages, lymphocytes, neutrophils, eosinophils, and other leukocytes are enumerated. Each cell type is expressed either as a percentage of total cells (excluding red blood cells and epithelial cells) or as the total number per unit volume of fluid recovered /1/.

Lymphocyte sub populations

The determination of lymphocyte sub populations is performed using flow cytometry or immunocytochemical stains /79/.

Noncellular components

Albumin, transferrin, immunoglobulins, complement proteins, enzymes, enzyme inhibitors, tumor markers, and mediators of inflammation can be measured. The minimal changes associated with pathological conditions and inadequately established reference values discourage performing these investigations /7/.

Reference interval

Refer to Tab. 48-1 – Reference intervals for biomarkers bronchoalveolar lavage.

48.4 Clinical significance

Role of bronchoalveolar lavage in diagnosis

BAL cellular and fluid components are widely determined in patients with infectious disease of the lung, in patients with interstitial lung disease, hypersensitivity pneumonitis and idiopathic pulmonary fibrosis. Refer to Tab. 48-2 – Lung diseases in which BAL is a useful adjunct to diagnosis and treatment.

Macroscopic assessment

Macroscopic assessment provides valuable clues. If the fluid shows a milky turbidity, for instance, pulmonary alveolar proteinosis and, with increasing orange-red discoloration of the lavage fractions, pulmonary hemosiderosis is likely to be present.

Differential cytology and lymphocyte immune phenotyping

Differential cytology indicates disorders with increased percentage of specific BAL cell types and alterations in the CD4+/CD8+ ratio (Tab. 48-3 – Disorders associated with increased percentage of specific BAL cell types/2/.

Abnormal BAL differential cell patterns that suggest specific types of interstitial lung disease are /2/:

  • A lymphocyte proportion ≥ 25% suggests granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis, chronic beryllium disease), cellular nonspecific interstitial pneumonia, drug reaction, lymphoid interstitial pneumonia, cryptogenic organizing pneumonia, or lymphoma
  • CD4+/CD8+ > 4 is highly specific for sarcoidosis in the absence of an increased proportion of other inflammatory cell types
  • A lymphocyte proportion > 50% suggests hypersensitivity pneumonitis or cellular nonspecific interstitial pneumonia
  • A neutrophil proportion > 50% supports acute lung injury, aspiration pneumonia, or suppurative infection
  • An eosinophil proportion > 25% is virtually diagnostic of acute or chronic eosinophilic pneumonia
  • A cell proportion > 1% mast cells, > 50% lymphocytes, and > 3% neutrophils is suggestive of acute hypersensitivity pneumonitis.

Alveolar macrophages

During acute processes the morphology of macrophages changes. Less mature, monocyte-like forms occur more frequently. These can also be detected immunocytochemically. Because more than 95% of alveolar macrophages physiologically express HLA-DR genes /10/, no clinically useful differences are to be expected in the case of inflammatory processes. The HLA-DR expression on lymphocytes provides only limited information on their level of activation. Therefore, using this parameter, only sequential observations provide clinically valuable information.

BAL is a safe procedure in patients with pulmonary hemorrhage and provides material in the form of hemosiderin-laden macrophages /1/.

48.4.1 Infectious diseases

Infectious diseases can be diagnosed by direct detection of the pathogen.

Refer to Tab. 48-4 – Pathogen detection in BAL in infectious disease of the lung.

In general, the detection of a pathogen in the lavage is only of clinical importance if saprophytic colonization by the pathogens is unknown /1/. Thus, if Influenza virus and Respiratory syncytial virus, which normally do not colonize the respiratory tract, are detected in the lavage, a viral pneumonia can be presumed. In the case of the Cytomegalovirus, additional cytologically appropriate cytopathic effects have to be observed because the virus can also colonize the respiratory tract of healthy individuals. The selective use of PCR considerably increases the detection limit and is recommended in immunocompromised patients. However, its clinical value has not been clearly established /11/.

Quantitative detection of pathogens

The ability of potentially pathogenic microorganisms to colonize the respiratory tract in the absence of corresponding disease makes the assessment of bacteriologic findings in the lavage difficult. Quantitative measurements are helpful in this situation because if more than 105 colony forming units per mL of lavage fluid are present it is likely that the observed microorganism is the cause of the illness if the other clinical findings coincide /1213/. This is true especially in cases of atypical Mycobacterium sp., Candida sp. and Aspergillus sp. as well as other pathogens as listed in Tab. 48-4 – Pathogen detection in BAL in infectious disease of the lung.

Community acquired pneumonia

In immunosuppressed patients (e.g., HIV infection, patients after transplantation) investigation of BAL is a valuable diagnostic tool /14/. Routine post-procedure examinations in lung or bone marrow of transplanted patients revealed unexpected infections in up to 10% of cases /1516/.

Nosocomial and respiratory pneumonias

BAL with quantitative detection of pathogens provides a comparable or even higher diagnostic sensitivity in contrast to competing procedures like protective specimen brush, biopsy, random aspiration of secretions /17/. It is further improved upon by interrupting antibiotic therapy for 16 h prior to the examination. Clinical significance of the findings can be presumed in the presence of 103–104 colony-forming units per mL of lavage fluid. It must be noted critically that false-negative findings can occur and that, using an integrative approach, respiratory pneumonia can also be diagnosed without the detection of microorganisms /18/.

48.4.2 Non infectious lung injury

In non infectious lung injury BAL investigation focuses on diseases where findings are specific for these disorders. In interstitial lung disease and in assessing some occupational exposures the BAL can provide helpful, additional information. The BAL findings can influence differential diagnostic and therapeutic decisions and be particularly valuable for the monitoring of complicated cases.

Refer to:

48.4.3 Malignant disease

Malignant lung diseases can be diagnosed cytologically by BAL if the tumor grows diffusely, such as in lymphangitic carcinomatosis, malignant lymphomas, leukemias, or alveolar cell carcinoma. Even in poorly accessible peripheral masses BAL can allow a cytologic diagnosis. In suspicious cases a trans bronchial biopsy or brush biopsy should always be performed as well /19/. BAL measurements of tumor markers (e.g. NSE) do not show any value in staging of lung carcinoma /20/.

48.5 Comments and problems

Contra indications

There is no absolute contraindication to the BAL procedure. Relative contra indications are: lack of patient cooperation, forced expiratory volume of less than 1,000 mL, bronchial asthma with moderate airway obstruction, hypercapnia, uncorrectable hypoxemia, pronounced cardiac arrhythmias, myocardial infarction within the last 6 weeks, uncorrected hemorrhagic diathesis, and hemodynamic instability /1/. Fiber-optic BAL is a safe procedure. Lethal complications have not been reported. Occasionally, pyrexia (2.5%), bronchospasm (0.7%), bleeding (0.7%), and pneumonia (0.4%) are observed /21/.

Processing of the lavage specimens

Different procedures for processing, fixation and staining have an impact on the differential cell count, sometimes resulting in a falsely low lymphocyte count. Therefore, the entire process has to be standardized within institutions and the institutions have to establish their own reference intervals.


The cellular analysis should be performed within 1 hour if the BAL fluid is in nutrient poor media (e.g. saline) or within 2 to 3 hours for optimal results if the BAL fluid is in a nutrient supplemented medium /2/.

Differential cytology

The distribution of the individual cell populations is not parametric. A relationship between the differential cytology and age, gender, race, body length, or vital capacity does not exist /5/.

Reference interval

Differential cytology and flow cytometry present identical results for T lymphocytes, CD4+, CD8+ and B cells if each cell type is expressed as a percentage of total cells /22/. Significant differences exist between both methods in the proportion of activated HLA-DR+ lymphocytes. This is because flow cytometry measures the intensity of HLA-DR fluorescence, which is significantly increased in the case of activation, while in the staining methods only the number of positive cells are counted, which are less variable. The flow cytometric measured values are approximately 25% lower than the immunocytochemically determined ones.

Quantitative detection of pathogens

Attention has to be paid to the fact that BAL is considered to be representative of the alveolus and suitable for quantitative diagnosis only if the proportion of epithelial cells in the differential cytology is less than 1% /12141820/.

Pediatric patients

In children, BAL is performed in the same way as in adults. The accepted volume is 3 mL/kg body weight or 10% of the functional residual capacity. The medians of the published reference values are approximately the same as the above-stated medians of adult nonsmokers. However, the ranges are significantly larger and the lymphocyte percentage is twice as high in children under the age of 5 than in adults /23/.


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Table 48-1 Reference intervals for biomarkers of bronchoalveolar lavage

Total cell count

(2–10) × 107/L (Nonsmokers)

(2–50) × 107/L (Smokers)

Differential cytology, data expressed in % /5, 6, 7, 8/





92.5 (75.2–98.4)

96.9 (92.1–99.9


6.5 (1.3–21.6)

2.3 (0.5–6.8)


0.9 (0.0–2.6)

0.5 (0.0–2.2)


0.1 (0.0–0.5)

0.2 (0.0–1.0)

Values are 5th and 95th percentiles

Subpopulations of lymphocytes, data expressed in % /8, 9/





70.3 (15.0–94.9)

69.2 (7.6–95.5)


44.4 (9.0–83.5)

32.2 (6.6–65.0)


20.7 (5.0–49.4)

29.2 (0.5–58.0)


1.4 (0.4–3.5)

1.7 (0.3–3.3)

B cells

3.2 (0.0–17.1)

6.4 (15.0–28.1)

Values are 5th and 95th percentiles

Table 48-2 Lung diseases in which BAL is a useful adjunct to diagnosis and treatment

Non infectious


  • Sarcoidosis
  • Idiopathic pulmonary fibrosis
  • Systemic diseases with pulmonary involvement, inclusive Wegener’s granulomatosis
  • Extrinsic allergic alveolitis
  • Eosinophilic syndrome
  • Idiopathic pulmonary hemosiderosis
  • Asbestosis
  • Alveolitis due to nanoparticles
  • Alveolar proteinosis
  • Histiocytosis X
  • Viral infections
  • Bacterial infections
  • Atypical mycobacteriosis
  • Aspergillosis
  • Candidiasis
  • Crypto­coccosis

Table 48-3 Disorders associated with increased percentage of specific BAL cell types /2/

(> 15%

(> 1%

(> 3%



Collagen vascular


Drug induced



Bone marrow


Drug induced

Asthma, bronchitis

bacterial, fungal

Collagen vascular







Bacterial, fungal,
Pneumocystis sp.

Acute respiratory
distress syndrome


Hodgkin’s disease

Diffuse alveolar

Table 48-4 Pathogen detection in BAL in infectious disease of the lung

Pneumocystis jirovecii

Toxoplasma gondii

Legionella sp.

Histoplasma sp.

Obligate pathogenic atypical mycobacteria

M. pneumoniae

C. pneumoniae


Respiratory syncytial virus

* Diagnosis by detection of the pathogen or its DNA in the BAL fluid

Table 48-5 BAL findings in specific lung disorders

Clinical and laboratory findings

Alveolar proteinosis

Gross appearance of lavage fluid is opaque and/or milky and microscopic evaluation reveals PAS positive inclusions and lamellar bodies in the cytoplasm of the alveolar macrophages as well as large acellular eosinophilic bodies against a background of small eosinophilic granules and amorphous debris /2425/.

Langerhans cell histiocytosis

Langerhans cell histiocytosis is a group of idiopathic disorders characterized by epidermal dendritic cells. More than 4% of total cells are CD1+ cells (MHCII, Birbeck granules) and activated Langerhans cells (CD54+ and CD58+/26/.

Table 48-6 Non-infectious diseases in which bronchoalveolar lavage can provide useful information

Clinical and laboratory findings

Interstitial lung disease (ILD)

According to the American Thoracic Society Clinical Practice Guideline /2/ acute and chronic bilateral parenchymal infiltrative lung diseases with variable degrees of tissue inflammation and fibrosis are collectively referred to as interstitial lung diseases (ILDs) when they occur in immunocompetent hosts without infection or neoplasm. ILDs are generally characterized clinically by exceptional dyspnea, bilateral pulmonary infiltrates on thoracic imaging, abnormal pulmonary physiology, and abnormal gas transfer. ILDs are usually characterized pathologically by an accumulation of inflammatory and immune effector cells that is often accompanied by abnormal extracellular matrix in the distal airways, alveolar walls, and interstitium. The ILDs usually evolve over months to years and include disorders of both known and unknown cause.

The ILDs were subdivided into four categories /35/:

  • ILDs associated with known causes e.g., connective tissue diseases, pneumoconioses, or drugs
  • Idiopathic types, such as idiopathic pulmonary fibrosis and idiopathic nonspecific interstitial pneumonitis
  • Granulomatous ILDs, such as sarcoidosis and hypersensitivity pneumonitis
  • Other, mostly very rare types.

Besides the inflammatory types of ILD the so called fibrosing types involve pulmonary fibrosis and their subtypes. ILD categories and the subtypes which can run as lung fibrosis are diopathic interstitial pneumonias (ILD), granulomatous ILD (sarcoidosis, hypersensitivity pneumonitis and berylliosis), known causes (drugs, pneumoconioses, systemic diseases), and other types (pulmonary alveolar proteinosis, eosinophilic pneumonitis, lymphangioleiomyomatosis and pulmonary Langerhans-cell histiocytosis).

Laboratory testing: Testing includes serologic screening for systemic disease e.g., antinuclear antibodies, rheumatoid factor, collagenosis- and vasculitis associated antibodies, and, when indicated, a myositis panel /35/.

Conclusions of the American Thoracic Society Clinical Practice Guideline about the clinical utility of BAL cellular analysis in interstitial lung disease /2/:

  • Following the initial clinical and radiographic evaluation of patients presenting with suspected ILD, BAL cellular analysis may be a useful adjunct in the diagnostic evaluation in patients who lack a confident usual interstitial pneumonia pattern on high-resolution computed tomography imaging of the thorax
  • Recognition of predominantly inflammatory cellular pattern in the BAL differential cell profile frequently helps the clinician narrow the differential diagnosis of ILD
  • A normal BAL differential cell profile does not exclude microscopic abnormalities in the lung tissue
  • BAL cellular analysis is insufficient to diagnose the specific type of ILD, except in malignancies and some rare ILDs. However, abnormal findings may support a specific diagnosis when considered in the context of the clinical and radiographic presentations.
  • BAL cellular analysis has no firmly established prognostic value and cannot predict the response to therapy.


Sarcoidosis is characterized by a cell-rich alveolitis with an absolute and relative lymphocytosis > 15%, an elevated CD4+/CD8+ T-cell ratio, a marked absolute but not relative increase in alveolar macrophages, and discrete neutrophilia /26/. According to a review and meta-analysis the cut-off CD4+/CD8+ ratio of sarcoidosis is in the range higher than 3-4. Estimates for the diagnostic performance were diagnostic sensitivity 70% specificity 83%, positive likelihood ratio 4.04, negative likelihood ratio 0.36, and Odds ratio 11.2 /27/.

The acute form, which generally has a good prognosis, shows marked changes while the chronic form, which has a doubtful prognosis, presents with only minor abnormalities or a normal finding. The threshold values are for guidance only, since even healthy individuals may exceed them due to the non-parametric distribution of the reference values. Approximately 4% of sarcoid patients have a BAL CD4+/CD8+ ratio < 1.0. Chronic progressive forms and forms necessitating treatment present with neutrophilia (> 3%) in nonsmokers and smokers /29/.

In a clinical multicenter trial /28/ significantly more granulomas were detected at endosonography vs. bronchoscopy (74% vs 48%). Diagnostic sensitivity of the BAL for sarcoidosis based on CD4+/CD8+T cell ratio was 54% (95% CI 46%–62%) for flow cytometry and 24% (95% CI 16%–34%) for differential cell count (cytospin analysis).

Idiopathic pulmonary fibrosis (IPF)

IPF is a specific form of chronic, progressive fibrosing interstitial lung disease (ILD) of unknown cause. In ILD the pulmonary alveolar walls are infiltrated by various combinations of inflammatory cells, fibrosis, and proliferation of certain cells that make up the normal alveolar wall. Categorie of ILDS are the IPF, SSc-ILD, rheumatoid arthritis ILD, sarcoidosis, chronic fibrotic hypersesnsitivity pneumonitis , and the unclassified fibrotic ILD. BAL contributes to the diagnosis of hypersesnsitivity pneumonitis and sarcoidosis.

IPF primarily occurs in older adults and is limited to lungs. IPF is characterized by an imaging and pathological pattern of usual interstitial pneumonia without an identifiable cause or association with a disease known to be associated with pulmonary fibrosis. The clinical symptoms are nonspecific and can be shared with many pulmonary and cardiac diseases. Results from routine laboratory studies are nonspecific. The fibrotic response of the disease is driven by abnormally activated alveolar epithelial cells. The fibroblast and myofibroblast foci secrete amounts of extracellular matrix, mainly collagens, resulting in scarring and destruction of the lung architecture /29/.

Extrinsic allergic alveolitis (EAA)

EAA is caused by a variety of antigens. Well known substances causing hypersensitivity pneumonitis exist in microorganisms (e.g. Thermoactinomycetes sp., Aspergillus sp.). The disease is characterized by a biphasic course. Immediately post exposition, during the acute stage, a neutrophilic alveolitis is found. In the subacute and chronic phases, an extensive lymphocytic alveolitis (up to 80% lymphocytes) occurs with a decline in the CD4+/CD8+T cell ratio, increased HLA-DR expression, and an increase in cytotoxic cells. The typical change of the CD4+/CD8+T cell ratio is not always found /30/.

Idiopathic chronic eosinophilic pneumonia (ICEP)

ICEP is characterized by subacute or chronic respiratory and general symptoms. The patients have peripheral pulmonary infiltrates on chest imaging and alveolar or blood eosinophilia /31/. ICEP is twice as rare in childhood and twice as frequent in women as in men. One half of the patients have a history of asthma. The detection of an eosinophilic BAL (mean 60% eosinophils in differential cell count), as well as a discrete increase in neutrophils are diagnostic clues. Blood eosinophilia ≥ 109/L.

Wegener’s granulomatosis can be differentiated by its neutrophilic alveolitis (up to 50% neutrophils). The possibility of a tropical disease must be considered.

Idiopathic pulmonary hemosiderosis

Idiopathic pulmonary hemosiderosis (Ceelen’s disease) can be detected by the typical iron load of the alveolar macrophages. If the hemorrhage is still acute at the time of the examination, the lavage fluid will take on a characteristically red discoloration.


In asbestosis, the number of asbestos fibers in the lavage correlates with that present in the lung parenchyma. If more than one asbestos fiber is found per mL, this corresponds to an asbestos load of more than 1,000 fibers/g dry lung tissue. The lavage can, however, not distinguish between asbestos exposure and asbestosis. Furthermore, asbestosis is associated with a neutrophilic and lymphocytic alveolitis /32/.


Positive beryllium lymphocyte transformation test of the BAL cells. In smokers, false-negative results occur. Differential cytology same as seen in sarcoidosis /33/.

Systemic diseases with pulmonary involvement

They present with heterogenous patterns of alveolitis. Those with a lymphocytic alveolitis seem to have a better prognosis than those with a neutrophilic or eosinophilic alveolitis. The eosinophilic alveolitis has a favorable treatment prognosis. Transitions to idiopathic pulmonary fibrosis are frequently found /34/.

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