Alveolar capillary dysplasia

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Alveolar capillary dysplasia
Other namesAlveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV)
Symptoms Blue lips or skin, rapid breathing [1]
Complications Respiratory failure [1]
Usual onset24–48 hours after birth [1]
Causes FOXF1 mutation (at least 40% of cases) [1]
Diagnostic method Lung biopsy or FOXF1 genetic testing [1] [2]
Differential diagnosis Idiopathic PPHN, sepsis, pneumonia, surfactant deficiencies, hyaline membrane disease, pulmonary hypoplasia, acinar dysplasia, congenital alveolar dysplasia [1]
PreventionNone [1]
TreatmentLung transplant [1]
Medication Pulmonary vasodilators
Prognosis Mortality rate ~100% [1]
FrequencyUnknown [1]

Alveolar capillary dysplasia (ACD) is a rare, congenital diffuse lung disease characterized by abnormal blood vessels in the lungs that cause highly elevated pulmonary blood pressure and an inability to effectively oxygenate and remove carbon dioxide from the blood. ACD typically presents in newborn babies within hours of birth as rapid and labored breathing, blue-colored lips or skin, quickly leading to respiratory failure and death. Atypical forms of ACD have been reported with initially milder symptoms and survival of many months before the onset of respiratory failure or lung transplantation.

Contents

Most cases of ACD are caused by mutations affecting the gene FOXF1 or its nearby enhancer region. [3] Exactly how these mutations lead to abnormal lung development is unknown. Abnormal lung development is characterized by thickened alveolar interstitium, misplacement of pulmonary capillaries away from the alveolar surface, and fewer capillaries overall. This results in poor gas exchange and pulmonary hypertension. [1] There is evidence for connections between pulmonary arteries and systemic vessels, which would additionally contribute to poor blood oxygenation. [4]

ACD is typically diagnosed by examination of lung tissue under a microscope, either from lung biopsy or an autopsy. The characteristic findings of misplaced pulmonary veins adjacent to pulmonary arteries, and abnormal alveolar and capillary development confirm the diagnosis. [1] FOXF1 genetic testing is also available, which can confirm the diagnosis without invasive testing. [2] There are no effective treatments for severe ACD. Standard therapy, which includes mechanical ventilation, pulmonary vasodilators, and possibly ECMO, provide only temporary improvement in symptoms with disease progression returning within hours. For babies with atypical ACD, response to medical therapy is more sustained, lasting for several months. For those that can be stabilized, definitive treatment is bilateral lung transplantation. [1]

ACD is a rare disease. About 100 cases have been reported. [1] The first case was reported in 1981. [5]

Signs and symptoms

ACD is a congenital disease whose symptoms appear within hours to days after birth. Babies with ACD usually have no symptoms at the time of birth, but soon after will begin to breathe rapidly, showing increased work of breathing, and may have blue discoloration around the lips, arms, or legs, especially when feeding or crying. If an echocardiogram is performed, marked thickening of the right ventricle will be seen, resulting from highly elevated pulmonary blood pressure. ACD is generally resistant to treatment. Babies who have persistent symptoms that are poorly relieved by standard therapies for neonatal pulmonary hypertension is commonly observed in ACD. [1]

Atypical forms of ACD have been reported with only mildly rapid breathing shortly after birth. They may present with the above symptoms of ACD at several months of age. Their symptoms may improve with standard pulmonary hypertension therapies for weeks to months before symptoms return. [1]

Babies born with ACD usually have other congenital abnormalities affecting the heart, the intestines, urinary system, or genitals. [1]

Cause

Most cases of ACD are caused by deletions or point mutations involving the gene FOXF1 on chromosome 16 or an area near the FOXF1 gene that regulates its expression. ACD is an autosomal dominant disorder, meaning only one disease-causing mutation affecting FOXF1 or its regulator region is needed to cause ACD. Evidence strongly suggests that the FOXF1 regulatory region is imprinted, which might affect disease severity and may permit some to carry the disease with few or no symptoms. [3]

Mechanism

How mutations affecting FOXF1 or its regulatory region cause ACD is unknown. ACD-causing mutations result in abnormal development of lung vasculature and alveoli. In ACD, the interstitium of alveoli is thickened, with few to no capillaries located at the alveolar surface to perform gas exchange, and with lower capillary density overall. This reduction in capillaries and their misplacement away from the alveolar surface result in poor oxygenation and retention of carbon dioxide in the blood and high pulmonary blood pressure. [1] There is also evidence of direct connections between pulmonary arteries and systemic vessels, which would deliver deoxygenated blood to the body, also contributing to low blood oxygenation. [4]

Another characteristic histologic finding is the presence of a pulmonary vein located next to a pulmonary artery and bronchus in the same bronchovascular bundle. In a normal lung, the pulmonary vein courses with lymphatic vessels in the lung septa.[ citation needed ]

Diagnosis

The gold standard for ACD diagnosis is by examination of lung tissue under a microscope. The diagnosis is made if the pathologist sees the characteristic findings of ACD: misplaced pulmonary veins adjacent to pulmonary arteries, abnormal alveoli with thickened interstitia and abnormal capillary development. Due to the rapidly progressive course of ACD, this diagnosis is frequently made during autopsy. If ACD is suspected early, examination of tissue from lung biopsy results in the quickest diagnosis. [1] Genetic testing for FOXF1 is now available and can allow for slower but non-invasive diagnosis. As not all disease-causing mutations are known, false negatives or results of uncertain significance are possible with genetic testing. [2]

There are no characteristic pattern of routine lab results or imaging findings that allow definitive diagnosis of ACD. [1]

Treatment

Initial treatments attempt to improve low blood oxygenation and high pulmonary blood pressures. Because blood oxygen content is usually very low, babies with ACD are often intubated, sedated, and mechanically ventilated with pure oxygen. Pulmonary vasodilators like sildenafil or inhaled nitric oxide can be used to reduce pulmonary blood pressures. [6] For those with severe ACD, these measures offer only momentary improvement. As symptoms worsen, ECMO can be used, but it also offers only brief improvement. There are no effective treatments for severe ACD. [1]

For infants with atypical ACD who initially had milder symptoms and present at months of life, there can be better response to therapy. There have been reports of infants with ACD surviving to 20 or 36 months without lung transplantation. Bilateral lung transplantation may be the definitive treatment.[ citation needed ]

Epidemiology

ACD is a rare disease. As of 2011, about 100 cases had been reported. It is likely an under-recognized cause of death shortly after birth because diagnosis requires microscopic examination of lung tissue or specialized genetic testing, or death can be attributed to severe heart or intestinal congenital abnormalities which frequently occur in ACD. [1]

History

Congenital alveolar dysplasia was first described by MacMahon in 1948. [7] [8] The seminal case first describing ACD was by Janney and colleagues in 1981. [5] Transmission from a carrier parent to a child was first reported in 1994. [9]

Related Research Articles

Diffusing capacity of the lung (DL) measures the transfer of gas from air in the lung, to the red blood cells in lung blood vessels. It is part of a comprehensive series of pulmonary function tests to determine the overall ability of the lung to transport gas into and out of the blood. DL, especially DLCO, is reduced in certain diseases of the lung and heart. DLCO measurement has been standardized according to a position paper by a task force of the European Respiratory and American Thoracic Societies.

<span class="mw-page-title-main">Pulmonary edema</span> Fluid accumulation in the tissue and air spaces of the lungs

Pulmonary edema, also known as pulmonary congestion, is excessive liquid accumulation in the tissue and air spaces of the lungs. It leads to impaired gas exchange and may cause hypoxemia and respiratory failure. It is due to either failure of the left ventricle of the heart to remove oxygenated blood adequately from the pulmonary circulation, or an injury to the lung tissue directly or blood vessels of the lung.

<span class="mw-page-title-main">Pulmonary artery</span> Artery in pulmonary circulation carrying deoxygenated blood from heart to lungs

A pulmonary artery is an artery in the pulmonary circulation that carries deoxygenated blood from the right side of the heart to the lungs. The largest pulmonary artery is the main pulmonary artery or pulmonary trunk from the heart, and the smallest ones are the arterioles, which lead to the capillaries that surround the pulmonary alveoli.

<span class="mw-page-title-main">Pulmonary hypertension</span> Increased blood pressure in lung arteries

Pulmonary hypertension is a condition of increased blood pressure in the arteries of the lungs. Symptoms include shortness of breath, fainting, tiredness, chest pain, swelling of the legs, and a fast heartbeat. The condition may make it difficult to exercise. Onset is typically gradual. According to the definition at the 6th World Symposium of Pulmonary Hypertension in 2018, a patient is deemed to have pulmonary hypertension if the pulmonary mean arterial pressure is greater than 20mmHg at rest, revised down from a purely arbitrary 25mmHg, and pulmonary vascular resistance (PVR) greater than 3 Wood units.

<span class="mw-page-title-main">Pulmonary alveolar proteinosis</span> Medical condition

Pulmonary alveolar proteinosis (PAP) is a rare lung disorder characterized by an abnormal accumulation of surfactant-derived lipoprotein compounds within the alveoli of the lung. The accumulated substances interfere with the normal gas exchange and expansion of the lungs, ultimately leading to difficulty breathing and a predisposition to developing lung infections. The causes of PAP may be grouped into primary, secondary, and congenital causes, although the most common cause is a primary autoimmune condition in an individual.

<span class="mw-page-title-main">Eisenmenger syndrome</span> Medical condition

Eisenmenger syndrome or Eisenmenger's syndrome is defined as the process in which a long-standing left-to-right cardiac shunt caused by a congenital heart defect causes pulmonary hypertension and eventual reversal of the shunt into a cyanotic right-to-left shunt. Because of the advent of fetal screening with echocardiography early in life, the incidence of heart defects progressing to Eisenmenger syndrome has decreased.

<span class="mw-page-title-main">Atelectasis</span> Collapse or closure of a lung resulting in reduced or absent gas exchange

Atelectasis is the collapse or closure of a lung resulting in reduced or absent gas exchange. It is usually unilateral, affecting part or all of one lung. It is a condition where the alveoli are deflated down to little or no volume, as distinct from pulmonary consolidation, in which they are filled with liquid. It is often called a collapsed lung, although that term may also refer to pneumothorax.

<span class="mw-page-title-main">Interstitial lung disease</span> Group of diseases

Interstitial lung disease (ILD), or diffuse parenchymal lung disease (DPLD), is a group of respiratory diseases affecting the interstitium and space around the alveoli of the lungs. It concerns alveolar epithelium, pulmonary capillary endothelium, basement membrane, and perivascular and perilymphatic tissues. It may occur when an injury to the lungs triggers an abnormal healing response. Ordinarily, the body generates just the right amount of tissue to repair damage, but in interstitial lung disease, the repair process is disrupted, and the tissue around the air sacs (alveoli) becomes scarred and thickened. This makes it more difficult for oxygen to pass into the bloodstream. The disease presents itself with the following symptoms: shortness of breath, nonproductive coughing, fatigue, and weight loss, which tend to develop slowly, over several months. The average rate of survival for someone with this disease is between three and five years. The term ILD is used to distinguish these diseases from obstructive airways diseases.

<span class="mw-page-title-main">Transposition of the great vessels</span> Group of congenital heart defects

Transposition of the great vessels (TGV) is a group of congenital heart defects involving an abnormal spatial arrangement of any of the great vessels: superior and/or inferior venae cavae, pulmonary artery, pulmonary veins, and aorta. Congenital heart diseases involving only the primary arteries belong to a sub-group called transposition of the great arteries (TGA), which is considered the most common congenital heart lesion that presents in neonates.

<span class="mw-page-title-main">Pulmonary hemorrhage</span> Medical condition

Pulmonary hemorrhage is an acute bleeding from the lung, from the upper respiratory tract and the trachea, and the pulmonary alveoli. When evident clinically, the condition is usually massive. The onset of pulmonary hemorrhage is characterized by a cough productive of blood (hemoptysis) and worsening of oxygenation leading to cyanosis. Treatment should be immediate and should include tracheal suction, oxygen, positive pressure ventilation, and correction of underlying abnormalities such as disorders of coagulation. A blood transfusion may be necessary.

<span class="mw-page-title-main">Hypoxemia</span> Abnormally low level of oxygen in the blood

Hypoxemia is an abnormally low level of oxygen in the blood. More specifically, it is oxygen deficiency in arterial blood. Hypoxemia has many causes, and often causes hypoxia as the blood is not supplying enough oxygen to the tissues of the body.

Cardiac asthma is the medical condition of intermittent wheezing, coughing, and shortness of breath that is associated with underlying congestive heart failure (CHF). Symptoms of cardiac asthma are related to the heart's inability to effectively and efficiently pump blood in a CHF patient. This can lead to accumulation of fluid in and around the lungs, disrupting the lung's ability to oxygenate blood.

<span class="mw-page-title-main">Respiratory disease</span> Disease of the respiratory system

Respiratory diseases, or lung diseases, are pathological conditions affecting the organs and tissues that make gas exchange difficult in air-breathing animals. They include conditions of the respiratory tract including the trachea, bronchi, bronchioles, alveoli, pleurae, pleural cavity, the nerves and muscles of respiration. Respiratory diseases range from mild and self-limiting, such as the common cold, influenza, and pharyngitis to life-threatening diseases such as bacterial pneumonia, pulmonary embolism, tuberculosis, acute asthma, lung cancer, and severe acute respiratory syndromes, such as COVID-19. Respiratory diseases can be classified in many different ways, including by the organ or tissue involved, by the type and pattern of associated signs and symptoms, or by the cause of the disease.

A right-to-left shunt is a cardiac shunt which allows blood to flow from the right heart to the left heart. This terminology is used both for the abnormal state in humans and for normal physiological shunts in reptiles.

A pulmonary shunt is the passage of deoxygenated blood from the right side of the heart to the left without participation in gas exchange in the pulmonary capillaries. It is a pathological condition that results when the alveoli of parts of the lungs are perfused with blood as normal, but ventilation fails to supply the perfused region. In other words, the ventilation/perfusion ratio of those areas is zero.

The Alveolar–arterial gradient, is a measure of the difference between the alveolar concentration (A) of oxygen and the arterial (a) concentration of oxygen. It is a useful parameter for narrowing the differential diagnosis of hypoxemia.

Swimming induced pulmonary edema (SIPE), also known as immersion pulmonary edema, is a life threatening condition that occurs when fluids from the blood leak abnormally from the small vessels of the lung (pulmonary capillaries) into the airspaces (alveoli).

<span class="mw-page-title-main">Pulmonary capillary hemangiomatosis</span> Medical condition

Pulmonary capillary hemangiomatosis (PCH) is a disease affecting the blood vessels of the lungs, where abnormal capillary proliferation and venous fibrous intimal thickening result in progressive increase in vascular resistance. It is a rare cause of pulmonary hypertension, and occurs predominantly in young adults. Together with pulmonary veno-occlusive disease, PCH comprises WHO Group I' causes for pulmonary hypertension. Indeed, there is some evidence to suggest that PCH and pulmonary veno-occlusive disease are different forms of a similar disease process.

<span class="mw-page-title-main">Pulmonary venoocclusive disease</span> Medical condition

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension caused by progressive blockage of the small veins in the lungs. The blockage leads to high blood pressures in the arteries of the lungs, which, in turn, leads to heart failure. The disease is progressive and fatal, with median survival of about 2 years from the time of diagnosis to death. The definitive therapy is lung transplantation.

<span class="mw-page-title-main">Ventilation-perfusion coupling</span>

Ventilation-perfusion coupling is the relationship between ventilation and perfusion processes, which take place in the respiratory and cardiovascular systems. Ventilation is the movement of gas during breathing, and perfusion is the process of pulmonary blood circulation, which delivers oxygen to body tissues. Anatomically, the lung structure, alveolar organization, and alveolar capillaries contribute to the physiological mechanism of ventilation and perfusion. Ventilation-perfusion coupling maintains a constant ratio near 0.8 on average, while the regional variation exists within the lungs due to gravity. When the ratio gets above or below 0.8, it is considered abnormal ventilation-perfusion coupling, also known as a ventilation-perfusion mismatch. Lung diseases, cardiac shunts, and smoking can cause a ventilation-perfusion mismatch that results in significant symptoms and diseases, which can be treated through treatments like bronchodilators and oxygen therapy.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Bishop, Naomi B.; Stankiewicz, Pawel; Steinhorn, Robin H. (15 July 2011). "Alveolar Capillary Dysplasia". American Journal of Respiratory and Critical Care Medicine. 184 (2): 172–179. doi:10.1164/rccm.201010-1697CI. PMC   3172887 . PMID   21471096.
  2. 1 2 3 Nogee, Lawrence M. (August 2017). "Interstitial lung disease in newborns". Seminars in Fetal and Neonatal Medicine. 22 (4): 227–233. doi:10.1016/j.siny.2017.03.003. PMC   5537026 . PMID   28363760.
  3. 1 2 Szafranski, Przemyslaw; Gambin, Tomasz; Dharmadhikari, Avinash V.; et al. (12 April 2016). "Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins". Human Genetics. 135 (5): 569–586. doi:10.1007/s00439-016-1655-9. PMC   5518754 . PMID   27071622.
  4. 1 2 Galambos, Csaba; Sims-Lucas, Sunder; Ali, Noorjahan; et al. (January 2015). "Intrapulmonary vascular shunt pathways in alveolar capillary dysplasia with misalignment of pulmonary veins". Thorax. 70 (1): 84–85. doi:10.1136/thoraxjnl-2014-205851. PMC   4405163 . PMID   25052575.
  5. 1 2 Janney, CG; Askin, FB; Kuhn C, 3rd (November 1981). "Congenital alveolar capillary dysplasia--an unusual cause of respiratory distress in the newborn". American Journal of Clinical Pathology. 76 (5): 722–7. doi:10.1093/ajcp/76.5.722. PMID   7293984.
  6. ↑ Kitayama Y, Kamata S, Okuyama H, Usui N, Sawai T, Kobayashi T, Fukui Y, Okada A (January 1997). "Nitric oxide inhalation therapy for an infant with persistent pulmonary hypertension caused by misalignment of pulmonary veins with alveolar capillary dysplasia". Journal of Pediatric Surgery. 32 (1): 99–100. doi:10.1016/s0022-3468(97)90105-6. PMID   9021581.
  7. ↑ MacMahon HE (July 1948). "Congenital alveolar dysplasia of the lungs". The American Journal of Pathology. 24 (4): 919–31. PMC   1942746 . PMID   18874417.
  8. ↑ MacMahon HE (July 1948). "Congenital alveolar dysplasia; a developmental anomaly involving pulmonary alveoli". Pediatrics. 2 (1): 43–57. doi:10.1542/peds.2.1.43. PMID   18874463. S2CID   245161989.
  9. ↑ Boggs S, Harris MC, Hoffman DJ, Goel R, McDonald-McGinn D, Langston C, Zackai E, Ruchelli E (January 1994). "Misalignment of pulmonary veins with alveolar capillary dysplasia: affected siblings and variable phenotypic expression". The Journal of Pediatrics. 124 (1): 125–8. doi:10.1016/S0022-3476(94)70267-5. PMID   8283361.
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