Bronchopulmonary Dysplasia

What is chronic lung disease?

Chronic lung disease or prematurity, or bronchopulmonary dysplasia, is a disease that affects pre-term babies who have extremely low birth weights (usually under 1000 g at birth) and is caused by lung damage. It most commonly develops in neonates (babies less than 28 days old) who are being treated with oxygen and ventilation for respiratory failure. In neonates, respiratory failure can be due to a number of causes, such as infant respiratory distress syndrome (also known as hyaline membrane disease), a condition caused by the lungs failing to mature properly; or in pre-term babies where the lungs haven't had time to mature properly. Chronic lung disease was first described in 1967 by Northway, however his definition of the disease has been modified extensively due to changes in medical technology and treatments.

Chronic lung disease is currently usually defined as a need for supplemental oxygen at 36 weeks after conception. Another definition is based upon severity. This definition categorises CLD into mild, moderate, and severe forms, depending on the type of ventilation and the amount of oxygen required. The criteria are different for babies born before 32 weeks' gestational age and babies born at a gestational age of 32 weeks or later.

What are the signs and symptoms of chronic lung disease?

Babies with hyaline membrane disease usually start to improve by their 3rd or 4th day on treatment. However, babies with chronic lung disease will not show any signs of improvement, and their health can worsen.

The signs and symptoms of chronic lung disease include the following:

The infant's oxygen demands do not decrease as they should – they can even increase.
Fast breathing.
A fast heart rate.
Other signs that the baby is having difficulty breathing. You may be able to see the outline or the lower border of their ribs when the baby is breathing, or you might see flared nostrils or grunts when the baby tries to breathe.
Poor weight gain or stunted growth – this is due to the increased demand for energy for breathing. Energy is used to breathe rather than for growth.
Coarse crackles may be heard in the chest with a stethoscope.

In addition, many of these babies have an inadequate amount of oxygen circulating in their blood, and may have difficulty being weaned away from a mechanical ventilator.

Oxygen demands can be measured at the 36th week post menstrual age for babies who were born before the 32nd week of gestation, and are measured between 28 and 56 days' age for babies who were born during or after the 32nd week of gestation. This is used by doctors to classify the disease into mild, moderate, and severe categories.

Who is at risk of chronic lung disease?

Chronic lung disease is most common in infants who were born at 22 – 32 weeks' gestational age. These babies have extremely low birth weights, often less than 1000 grams (normal birth weight for a baby born between 37 and 40 weeks is between 2812 g and 4173 g).

Other risk factors for developing chronic lung disease include:

Hyaline membrane disease – a condition caused by insufficient surfactant in the newborn baby leading to severe breathing difficulties. The importance of surfactant is discussed further down on this page. Chronic lung disease is strongly associated with hyaline membrane disease.
Pulmonary interstitial emphysema – a condition in which air leaks out into the spaces between the air sacs (alveoli). This can again be related to a lack of surfactant.
Patent ductus arteriosus – a problem where a small blood vessel connecting the aorta (a major artery going from the heart to the body) and pulmonary artery (a major artery going from the heart to the lungs) fails to close as it should.
Chronic lung disease is more common in male Caucasian infants.
Chorioamnionitis – a bacterial infection of the mother's womb most often associated with a long labour.
A strong family history of asthma or other allergies.

Why are some children born with extremely low birth weights? There are a variety of factors. The most common factor is if the baby is born prematurely. In addition, 33 % of triplets and 10 % of twins are likely to have a low birth weight. Mothers under the age of 15, and mothers who drink alcohol, smoke, or have poor nutrition are also more likely to have babies with a low birth weight.

What causes chronic lung disease?

Chronic lung disease is frequently seen in infants who have had to use a ventilator to assist their breathing. There are a few ways in which a ventilator or oxygen could cause injury to the lungs.

One factor is the air pressure of mechanical ventilators can cause physical injuries to the underdeveloped lungs. They can increase the lung volume too much, and this can also injure the lungs. Another factor is due to oxygen – it cannot be carried away by the blood quickly enough because the air sacs haven't developed. The oxygen enters the cells of lungs and becomes damaging free oxygen radicals. These free oxygen radicals can destroy cells if they become too much for the body to handle. The antioxidant systems (which remove free oxygen radicals) in extremely low birth weight infants are also immature and cannot remove the free oxygen radicals quickly. In this way, the lungs become damaged. Inflammation also takes place with various types of white blood cell coming to the area and releasing chemicals which can cause further damage.

In addition, if the neonate is not fed well and kept hydrated, or suffers from some infections, it can also develop chronic lung disease. If the blood supply to the baby’s lungs doesn't work properly (pulmonary vascular dysfunction), this can lead to high blood pressure in the blood supply to the lungs (pulmonary hypertension), and this can also be a cause. There may also be a genetic susceptibility to the condition.

How is chronic lung disease diagnosed?

Chronic lung disease is hard to diagnose very early on in the infant's life. Diagnosis can be made if any respiratory problems fail to improve with time. Prolonged difficulty in breathing (respiratory distress) and prolonged dependence on mechanical ventilation are key indicators for the diagnosis.

In addition, there are a number of diagnostic investigations that can be done to confirm or aid a diagnosis.

Chest X-rays are useful for determining the severity of the chronic lung disease, and can also differentiate it from other respiratory problems. An image of the chest will show decreased lung volume, inflammation, leakage of fluid into lungs (pulmonary oedema), and leakage of air into the spaces between the air sacs (pulmonary interstitial emphysema), as well as areas which may have become too inflated or not inflated enough.

Blood tests are also useful, and can show increased blood acidity, more carbon dioxide, and less oxygen present in the blood (these tests are known as arterial blood gases or ABGs). However, this simply shows that the lungs are not functioning properly, rather than being a specific test for chronic lung disease. Blood tests are more often used for monitoring and treatment. Blood gases are best monitored through umbilical artery catheterisation (UAC) – a catheter is placed in the umbilical artery through the belly button or umbilical cord (a tube that used to attach the baby to the mother's womb, allowing it to obtain nutrients and oxygen in the womb), allowing doctors to take blood samples whenever necessary and monitor blood gases continuously.

How is chronic lung disease managed?

Treatment and management for chronic lung disease is centred on making breathing easier and making the exchange of oxygen and carbon dioxide happen normally. A key aim of treatment is to allow the lungs to grow more air sacs and thus become more functional. The doctors at the hospital will make the decisions regarding what treatments to use.

In most cases the infant will require a ventilator to reduce the work of breathing. Positive pressure ventilation (PPV) is one way to help the baby to breathe, and can be life-saving in severely premature babies. PPV involves forcing air into the lungs periodically to match breathing in and out. However, pressurised air from the PPV and damaging free oxygen radicals will cause further injury to the infant's lung. Various tactics of avoiding this have been suggested, such as reducing the power of the PPV or using it intermittently. Continuous positive airway pressure (CPAP) is another way of helping the baby to breathe, and it involves forcing air into the lungs at a calculated pressure to keep the airways open. CPAP seems to cause less damage to the lung compared with PPV. Extra oxygen is also useful.

Weaning the infant off the ventilator can be difficult, and can take several weeks or months. Steroids such as dexamethasone can be useful here.

Nutrition for an infant with chronic lung disease is particularly important. Energy is required for growth, which includes growth of new air sacs in the lungs; as well as for breathing. These infants should be given a high-calorie diet. However, due to difficulties in feeding this is often given through a tube which passes from the nose to the stomach (a nastogastric tube) or a tube which feeds through the skin directly into the stomach (gastrostomy). Sometimes it might be necessary to feed nutrients directly into the bloodstream (total parenteral nutrition). Vitamins A, C, and E are useful defences against free oxygen radicals, and minerals such as copper, zinc, and manganese are required for other antioxidants to work properly. Breast milk is the best source of nutrition for the infant, and can be modified to increase its calorie content whilst keeping fluids low. Diuretics such as furosemide can be given where the infant has too much fluid, and this can prevent high blood pressure in the lungs' blood supply (pulmonary hypertension) and can help remove fluid in the lungs (pulmonary oedema) too.

Bronchodilators are drugs that keep the airways open. β2-adrenergic agonists such as albuterol are a class of bronchodilators commonly used, however they are not useful in all infants suffering from chronic lung disease. These drugs work on the nervous system to make the muscles surrouding the airways relax and open up the airways. Methylxanthines are another type of bronchodilator that also have diuretic effects (making the baby urinate more). Sodium cromoglycate is an antihistamine that can reduce inflammation in the lung.

There is a good chance that the baby will develop an infection in the lungs, such as bacterial or viral pneumonia. Treatments for these should also be given as appropriate. Keeping the baby warm will help with the growth of new air sacs and can also reduce the chances of infection.

These treatments may continue for several weeks or months, even after the baby has gone home. The baby may still remain in poor health and have breathing difficulties, and may continue to get infections. The baby may require oxygen for over 6 months and may be sent home with oxygen. It is also likely that you will need to keep the calorie content of the baby high. Regular medical checkups will help you to take care of the baby at home. Strict hand washing and proper hygiene is essential both in the hospital and at home.

How can chronic lung disease be prevented?

You can prevent chronic lung disease in your baby by staying healthy during your pregnancy. Avoid cigarettes, alcohol, or drugs, eat a balanced diet, do not fall sick from an infection, and see your doctor regularly. You may be given progesterone if you have had a premature baby before. Progesterone is a hormone that can delay the birth. You might also be given corticosteroid injections if your doctor thinks your baby might be born early. This will have the effect of speeding up the foetus' development so the baby’s lungs will be ready to breathe when he or she is born.

If a baby is born with hyaline membrane disease, there are a few things that can be done by doctors in the hospital to reduce the chances that they will go on to develop chronic lung disease. These include giving surfactant treatment early on, and using CPAP rather than PPV (which are two types of ventilator) to help ventilate the infant. However, there are times when PPV must be used and CPAP will not be sufficient.

What complications can the baby develop?

Infants who have suffered or are suffering from chronic lung disease are at high risk of infections in their lungs or airways, particularly during the first 2 years of life. Infections caused by the respiratory syncytial virus (RSV) can be extremely severe and may even be fatal. Monthly injections of RSV antibody can help prevent infection. These infants are at high risk of influenza as well, and the flu vaccine could also be considered.

Other complications include the following:

Nephrolithiasis: kidney stones.
Osteopenia: a condition where the amount of calcium in bones is less than it should be, resulting in weaker bones.
Subglottic stenosis: a narrowing in part of the throat, which may require surgery
Impaired cognitive abilities or even cerebral palsy (a disease which affects the parts of the brain involved with muscles and movement and can cause physical disability). Damage to certain brain cells (periventricular leukomalacia) or bleeding in certain parts of the brain (intraventricular haemorrhage) may also be problems.
Retinopathy of prematurity: a condition affecting the eyes, it is common in infants less than 1000g who have had supplemental oxygen.
Feeding problems, including a drop in blood oxygen saturation during feeds. The baby may also fail to grow or gain weight properly.
During childhood or adolescence, airway obstruction may be a problem. In addition, the airways may have a tendency to suddenly become narrow in response to triggers such as emotions, exercise, or pollen (airway hyperreactivity). The child might also be at an increased risk of emphysema – a condition where the air sacs lose their elasticity and burst.

What are the outcomes of chronic lung disease?

Most neonates with chronic lung disease survive, and prognosis is good if the infant can be weaned off the ventilator successfully. They may require additional oxygen for several months and may suffer respiratory tract infections such as bronchiolitis (inflammation of a type of small airway, caused by the respiratory syncytial virus) for 1 – 2 years. It is generally a bad sign if extra oxygen is still required after one year of age. Lung function usually improves throughout childhood, but signs of damage usually persist. These signs can be seen on tests such as spirometry.

Some infants cannot be weaned off the ventilator. Their lung condition worsens until ventilation becomes difficult, and they die of respiratory failure and cor pulmonale (a disease of the heart caused by pulmonary hypertension).

Because these babies are so small, they can develop other complications such as bleeding in their head or learning difficulties. These complications are not related to chronic lung disease but rather their prematurity, and can present a complex case for doctors. Some of these other complications can lead to problems in later life, such as developmental or mental problems, as well as problems controlling the muscles properly, caused by damage to the baby’s brain.

What is the differential diagnosis of chronic lung disease?

Failure of an infant's hyaline membrane disease to resolve at an appropriate time could simply be due to an unresponsive hyaline membrane disease. However, this is unusual as hyaline membrane disease does not normally last a very long time.

Cystic fibrosis can develop at such an early age in some scenarios, and may present in a similar way to chronic lung disease. However, there will be a family history of cystic fibrosis, and there are additional tests that can be done to differentiate it from chronic lung disease. In addition to a genetic test, there is also a sweat test that looks for abnormally high levels of sodium and chloride in the sweat. Cystic fibrosis is a condition where large amounts of thick, sticky mucus build up in the airways. Signs and symptoms include many repeating chest infections and a cough which may bring up the mucus.

Tracheomalacia is a condition where the cartilage that supports the windpipe is too soft and fails to keep the windpipe open on expiration. The primary symptom of tracheomalacia is stridor, a high pitched croaking sound caused by turbulent air flow in the upper airways. Subglottic stenosis is a narrowing of the airway in part of the throat, and its main feature is also stridor.

Pneumonia is a viral or bacterial illness that is characterised by inflammation in the lungs. In newborns, the organisms causing pneumonia are mainly those found on the mother's genital tract, such as the group B β-haemolytic Streptococcus, as well as organisms such as E.coli. Common signs and symptoms are fever, cough, and lethargy; in addition, the baby might take rapid, shallow breaths. Pneumonia can be diagnosed using a chest X-ray. However, it is important to note that pneumonia may exist alongside chronic lung disease.

A patent ductus arteriosus is the failure of a connecting blood vessel between the aorta (a major artery going from the heart to the body) and pulmonary arteries (another major blood vessel going from the heart to the lungs) to close at birth. It can cause breathing problems, but its main feature is a murmur the doctor will hear when listening to the baby's chest with his stethoscope. It can also be diagnosed with an ultrasound scan (echocardiography) and Doppler studies of the heart or with an ECG (electrocardiography).

How does the foetal lung develop, and how does the lung work after birth?

In order to fully understand how hyaline membrane disease and chronic lung disease develop, you must know something about how the lungs develop before the baby's birth. In the womb, the lungs and the airways aren't used for breathing. Instead, oxygen is obtained from the mother. The airways and the lungs start to develop in the 3rd week of gestation, and go through 5 distinct phases, continuing until several years after birth.

The last stages do not finish in babies with hyaline membrane disease – in pre-term babies, these stages are halted by an extremely early birth. During these phases, the absorptive membrane of the lungs develops and its surface area increases dramatically, and a mix of chemicals known as surfactant is produced. Because this has not taken place in hyaline membrane disease, the surface area stays low and the baby does not have enough surfactant, and this makes breathing more difficult for the baby. Hyaline membrane disease must be treated with oxygen and ventilation, which can cause lung damage, leading to chronic lung disease.

Normally, the baby should take its first breath at birth and begin crying. This first breath should bring about a series of changes in the body, such as closing the ductus arteriosus (a small blood vessel connecting two major blood vessels arising from the heart). There are several muscles surrounding the lungs which work to draw air in and out by changing the volume of the chest and thus changing the pressure of the chest – similar to the way a hand pump or a pair of bellows might work. The air must travel through many different airways of different sizes before it can enter the blood.

Carbon dioxide (a waste product of the body) and oxygen are exchanged in the tiny air sacs (known as alveoli). Some of the cells in the alveoli also have an important task of making a mix of chemicals known as surfactant. These cells do not fully develop until the last few stages of lung development, and babies born prematurely may not have enough surfactant.

What's so important about surfactant?

Pulmonary surfactant is a mixture of fats and proteins. It is made by a certain type of cell in the air sacs in the lungs, and their function is to decrease surface tension. This means that it stops the air sacs from collapsing and sticking together (imagine how two wet sheets of paper stick together and are very hard to separate) when we breathe out. Hence, much less effort is required to breathe in, as the entire lung does not have to be re-inflated. It also stops smaller air sacs deflating and larger air sacs becoming too inflated, and thus maintains the size of the air sacs in the lung. If this didn't happen, larger air sacs would become larger and larger until they would burst. Air would leak into the spaces between them, leading to a condition called pulmonary interstitial emphysema.