Clinical Interpretation of Transfer Factor (TLCO) Measurements

JMB Hughes

Imperial College School of Medicine, Hammersmith Hospital Campus

 

The measurement of the transfer factor for carbon monoxide (TLCO) [called the pulmonary diffusing capacity (DLCO) in North America] and the KCO is one of the most useful measurements to be made in the Pulmonary Function Laboratory. The TLCO and KCO assess the integrity of the gas–exchanging part of the lung. Alveolar and/ or microvascular destruction reduce the surface area for gas exchange and lower the TLCO and KCO, the commonest causes being emphysema, diffuse parenchymal lung disease (diffuse alveolar damage), and selective microvascular pathology.

Alveolar–capillary gas exchange

During breath-holding, the disappearance of oxygen from alveolar gas depends upon:

A) passive diffusion (down a concentration gradient) across the alveolar-capillary membranes, plasma and red cell membrane —called the membrane conductance (DM).

B) chemical combination with haemoglobin (Hb) — the reactive conductance

C) capillary blood flow

Why use carbon monoxide (CO) to measure alveolar oxygen transfer? First, it is easier technically to use a foreign gas; over a short time period (10 s breath-holding), there will be no "back pressure" in blood coming into the alveoli, so only alveolar concentrations need to be monitored. Second, for CO, the rate of combination with Hb is so rapid (200 times faster than for oxygen) that step B (see above) becomes rate limiting (an infinite sink), and downstream events, i.e. blood flow (C), have no influence on the disappearance rate of CO. So, the rate of alveolar uptake of CO is blood flow-independent, reflecting only the membrane conductance (A) which is proportional to alveolar-capillary surface area, and the reactive conductance (B) which is determined by the product q.Qc where qCO is the reaction rate of carbon monoxide with Hb, and Qc is the pulmonary capillary volume. Qc is a function of the haematocrit, i.e. the number of Hb molecules per ml blood; hence anaemia can reduce the TLCO and KCO. TLCO and KCO are influenced by changes in blood flow but only because an increase in blood flow, e.g. on exercise, increases Qc, the capillary blood volume.

TLCO and KCO and ventilation–perfusion (VA/Q) ratios.

In the steady state, during normal breathing, the efficiency of transfer of oxygen from alveolar gas to arterial blood (the alveolar–arterial PO2 gradient) and the PaO2 itself is determined in the main by the spread of VA/Q ratios, particularly the deviation in different parts of the lung from the ideal value, c. 0.86. The clinical measurement of TLCO and KCO, with breath-holding at full inflation, is designed to minimize the influence of VA/Q. Since the level of PaO2 is VA/Q determined and TLCO and KCO are alveolar- and capillary surface area-determined, the two measurements may be discordant. For example, TLCO and KCO are normal (or even high) in straightforward asthma, but PaO2 may be lower than expected. PaO2 may be relatively well-preserved in emphysema or CFA at a time when TLCO and KCO are severely reduced.

 

Measurement of TLCO and KCO

The subject, in the seated position, and breathing through a mouthpiece with a noseclip, exhales completely to residual volume, is switched to a reservoir bag containing 0.3% CO, 14% helium (He), 18% O2 (balance N2) and inhales rapidly to total lung capacity (i.e. a vital capacity inspiration). The breath is held (automatically against a closed shutter) for approximately 10 s at maximal inspiration, before a rapid and complete expiration is made. The first 750ml are discarded as contaminated with the anatomic dead space gas, and the next 500 ml are collected in a bag as an alveolar sample for analysis of CO and He.

 

Calculation of TLCO and KCO

This is a source of some confusion, but it is actually quite simple!

1. The rate of disappearance of CO from alveolar gas during breath-holding = kCO (units: min-1) kCO is calculated as loge [CO0/COt]/BHT where CO0 and COt are the alveolar CO concentrations at the beginning and end of the breath-holding time (BHT).

2. The lung volume "seen" by the marker gas (CO) during breath-holding = VA (ml STPD), calculated from the dilution of Helium (a reference gas in the inhaled mixture which does not cross the blood–gas barrier). In normal subjects, VA should be 90-95% of TLC.

3. TLCO = kCO x VA per unit pressure

= [kCO x VA] / Pb* [mmol. min-1 kPa-1 in SI units]

where Pb* is barometric pressure minus water vapour pressure at 37 degrees.

4.TL/ VA BTPS = KCO [mmol. min-1 kPa-1 L-1]

KCO is the same as kCO except for the Pb* term, an STPD–BTPS conversion, and (in SI units) a ml to mmol conversion.

 

Analysis of TLCO and KCO

1. A frequent and fundamental misconception is that the KCO (also called TL/ VA or DL/ VA) is the "volume–corrected" value of TLCO.

2. In fact, KCO and VA are the primary measurements (see equation 3, previous section) from which TLCO is derived.

3. KCO is an index of gas exchange efficiency, related to the alveolar–capillary surface to volume ratio for CO uptake.

4. TLCO is the gas exchange potential of the lung under specific conditions, a) at rest, b) at full inflation.

5. A low value of TLCO must be caused by a low value of KCO or VA or both. The primary measurements must be inspected first. A TLCO of 60% predicted can arise from a variety of combinations of KCO and VA (see later, Tables 3-4 ), each combination having a different clinical connotation.

 

Physiological influences on TLCO and KCO

1. Alveolar expansion. In normal lungs, if CO uptake is measured at lung volumes less than TLC, KCO rises (by about 10% per 10% fall in VA from VA at TLC), and TLCO falls (c. 5% per 10% VA fall). Thus, in acute diaphragm weakness, with VA = 60% of VA at TLC, a TLCO of 80% and a KCO of 140% predicted would be expected.

2. Cardiac output. On exercise, pulmonary microvascular pressure rises and blood volume increases, raising Qc and DM. For each 100% rise in cardiac output above the resting value (5 L min-1), TLCO and KCO rise by about 20%. The same arguments apply to regional blood flow in terms of blood flow per unit lung volume. For example, a pneumonectomy (given about equal partitioning of blood flow pre-operatively) would be associated with a doubling of blood flow per unit volume in the remaining lung post-operatively, and a rise in KCO of 1.2 times, e.g. from 100% to 120%; the expected change in TLCO would be 0.5 TLCO x 1.2, e.g. a fall from 100% to 60%.

3. Anaemia. A low haematocrit reduces TLCO and KCO by lowering the "effective" Qc. A correction for the current Hb level is usually applied.

4. Smoking (acutely). With very heavy cigarette consumption (CarboxyHb ~ 10%), TLCO and KCO will be reduced by about 10%. Smoking 2-3 cigarettes in the 2-3 hours before a TLCO measurement will reduce the value by 5% approximately.

Clinical interpretation

A low alveolar volume (VA)

It is very common to find a low VA. Predictions for VA are based on predictions for TLC (a value of 94% of predicted TLC, or predicted TLC - 500 ml can be substituted). In absolute terms, the VA / TLC ratio should be > 85%, lower values being found in the presence of airflow obstruction, or if the subject has made a sub-optimal inspiration. In clinical practice, there are basically four mechanisms leading to a low VA.

Table 1: Different mechanisms reducing single breath VA in respiratory disease

(taken from Hughes and Pride, 2000, to be published)

Restrictive Disease with a small TLC and normal VA/TLC ratio

Obstructive Disease

with normal or

increased TLC

A

KCO high

B

KCO high

C

KCO low

D

KCO variable

Lack of lung expansion:

lung structure normal

Loss of units:

remaining lung

structure normal

Diffuse alveolar damage

Sampled VA < TLC due

to incomplete mixing

during breath-holding

‘Prototype’

Acute inspiratory

muscle weakness

Pneumonectomy

Fibrosing alveolitis

Emphysema

Other examples

Chest wall disease and

pleural disease, but lack

of expansion is usually

non-uniform

Local alveolar infiltrate

or collapse, consolidation

or local destruction

Pulmonary oedema,

congestive heart failure,

mitral stenosis,

bleomycin lung,

Wegener’s granulomatosis.

In all these conditions,

severity of alveolar

involvement varies and

some normal alveoli survive

and contribute to CO uptake

Incomplete mixing

may be associated with

alveolar destruction,

space-occupying lesions

(bullae) or normal

alveolar structure (asthma)

The high KCO in categories A and B has been discussed in the previous section (Physiological influences on TLCO and KCO.) . Both the Loss of units (or pneumonectomy) and Lack of alveolar expansion models assume that the remaining lung is structurally normal, but this does not often happen in practice and the compensatory rise in KCOmay be somewhat less than that expected. In D (Airflow obstruction), TLC is normal and VA is reduced because the inhaled CO only reaches the better ventilated parts of the lung; therefore, the KCO is probably an "optimistic" or upper-bound value.

 

Clinical abnormalities of KCO

Some of the commoner causes of a KCO which is lower or higher than the reference value are listed below.

Table 2: Causes of a abnormal KCO value

(taken from Hughes and Pride, 2000, to be published)

 

Low KCO

High KCO

Diffuse alveolar damage:

Pulmonary fibrosis

Connective tissue/ autoimmune diseases

Sarcoidosis, asbestosis, bleomycin

 

Loss of units (discrete):

Pneumonectomy

Local destruction / infiltrates

Pulmonary hypertension associated:

Vasculitis

Thromboembolic

Congestive heart failure / mitral stenosis

Pulmonary oedema

Incomplete alveolar expansion

Pleural disease

Neuromuscular

Chest wall deformity

Poor technique

 

Intrapulmonary shunting:

Pulmonary arteriovenous malformations

Hepatopulmonary syndrome

Alveolar haemorrhage † :

Anti-GBM disease

Pulmonary vasculitis

Wegener’s granulomatosis

SLE

Idiopathic haemosiderosis

 

Airflow obstruction:

Emphysema

Churg-Strauss syndrome

Bronchiolitis

Increased pulmonary blood flow †:

ASD

Asthma

† TLCO (as % predicted) may be high as well

Note that a low KCO is a feature of pulmonary vascular disease [alveolar structure (VA and vital capacity) may be normal]. Alveolar haemorrhage causes a transient rise in KCO, but measurements need to be made at frequent intervals (daily) to observe the rises and falls (a Hb correction must be made for each measurement). In asthma, the increase in pulmonary blood flow is in the apical (cranial) regions.

 

Is the TLCO itself helpful?

In diffuse alveolar damage which reduces both the KCO and the VA, changes in the product (TLCO) will be greater than changes in either KCO or VA individually (Chinet et al, 1990). In CFA, for example, TLCO may be the most sensitive monitor of the pathological process. Again, in situations where VA is low and KCO is high in compensation, TLCO will be the better reflection of the gas exchange potential of the lungs as a whole. But, from a diagnostic point of view, there is more information in the components (VA and KCO) than in the product (TLCO). This is shown in Tables 3-4, where the same value of TLCO is associated with different combinations of KCO and VA, leading to quite different clinical interpretations.

Table 3. Different combinations of KCO and VA (as % predicted) associated with a TLCO value of 60% predicted.

Question - suggest a clinical interpretation

[Click here to view the answers in Table 4] (taken from Hughes and Pride, 2000, to be published)

 KCO (TL/VA) (%)

VA (%)

Interpretation / suggested diagnoses

 

Without airflow obstruction

172

35

I.

120

50

II.

100

60

III.

84

70

IV.

71

85

V.

 

With airflow obstruction

71

85

VI.

84

71

VII.

120

50

VIII.

 

 

Comments: suggestions for further reading.

The idea of basing the clinical interpretation of the TLCO on its components (KCO and VA) rather than the TLCO itself has been developed in weekly Pulmonary Function teaching sessions at Hammersmith Hospital over the past two decades! The notion that TL/ VA (DL/ VA) is only the primary measurement (the kCO or rate of alveolar uptake) under a different name (and is not a "volume correction") has yet to catch on generally. The analysis in this article is outlined in greater detail in Chapters 6 and 17 of "Lung Function Tests ....." and the arguments are developed more rigorously in an article "In defence of the carbon monoxide transfer coefficient, KCO ....." to be published in the European Respiratory Journal later this year (2000). See Further Reading for the full references which also list the ATS, ERS and BTS recommendations for standardizing the technique of measuring TLCO and KCO.

 

Further reading

Hughes JMB and Pride NB (eds). Lung Function Tests: Physiological Principles and Clinical Applications. WB Saunders, London, 1999. [Chapters 6 and 17].

Hughes JMB, Pride NB. In defence of the carbon monoxide transfer coefficient, KCO (TL/ VA). Eur Respir J 2000;16: (In Press).

Kinnear WJM. Lung Function Tests: a guide to their interpretation. Nottingham University Press, 1997.

Cotes JE. Lung Function: Assessment and Application in Medicine, 5th edn. Blackwell Scientific Publications, 1993.

BTS and ARTP recommendations. Guidelines for the measurement of respiratory function. Respir Med 1994; 88: 165-94.

Cotes JE, Chinn DJ, Quanjet Ph, Roca J, Yernault J-C. Standardization of the measurement of transfer factor (diffusing capacity). Eur Respir J 1993, 6 (suppl 16), 41-52.

American Thoracic Society. Single breath carbon monoxide diffusing capacity (transfer factor), recommendations for a standard technique – 1995 update. Am Rev Respir Dis 1995; 52: 2185-98.

Chinet T, Jaubert F, Dusser D, Danel C, Chrétien J, Huchon GJ. Effects of inflammation and fibrosis on pulmonary function in diffuse fibrosis. Thorax 1990; 45: 675-78.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 4. Different combinations of KCO and VA (as % predicted) associated with a TLCO value of 60% predicted, with an appropriate clinical interpretation

(taken from Hughes and Pride, 2000, to be published)

 KCO(TL/VA)(%)

VA (%)

Interpretation / suggested diagnoses

 

Without airflow obstruction

172

35

I. Acute neuromuscular (lack of alveolar expansion)

or (if transient) alveolar haemorrhage (loss of units)

120

50

II. Lung resection,collapse, infiltrates,

(loss of units)

100

60

III.Inadequate KCO compensation for the low VA

suggests mild diffuse alveolar damage

84

70

IV. Diffuse alveolar damage

(more severe than in III)

71

85

V. Pulmonary vascular pathology

With airflow obstruction

71

85

VI. Emphysema orChurg-Strauss vasculitis

84

71

VII. Bronchiolitis

120

50

VIII. Bronchiectasis or Lung resection

Back to article text (suggestions for further reading)

 

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