Isla is an 18-month-old girl who is brought to the emergency department with a history of worsening abdominal pain over the last few days. Her past medical history includes:
– Constipation
– Cow’s milk protein allergy (CMPA)
– Iron-deficiency anaemia, treated with sodium ferri-lactate
– A recent admission with a presumed lower respiratory tract infection, treated with oral antibiotics, followed by a persistent cough
At triage, Isla looks unwell and pale. Her observations show: heart rate 165 bpm, respiratory rate 38 breaths/min, and oxygen saturation 93% on room air. She is apyrexial and has increased work of breathing.
A chest X-ray shows a right-sided consolidation, most marked in the upper lobe.
Initial investigations reveal severe anaemia (haemoglobin 23 g/L, platelets 549 x 10^9/L, white cell count 13.7 x 10^9/L), with no evidence of haemolysis and normal clotting and renal/liver function. Her CRP is 81 mg/L.
She is started on intravenous cefuroxime and receives a red cell transfusion during the first few days of admission.
Despite treatment, Isla has increase oxygen requirement and develops type 1 respiratory failure requiring intubation and ventilation.
Why is she so anaemic and why is she in respiratory failure? Could the two features be connected?
At intubation, fresh blood is noted in the endotracheal tube, with ongoing blood-stained secretions.
She receives tranexamic acid, fresh frozen plasma and further blood transfusions.
Is it really from the lungs?
The first step in assessing a child with ‘haemoptysis’ is to exclude alternative sources of bleeding, such as the upper airways and the gastrointestinal (GI) tract.
The presence of a sore throat/mouth ulcers, and bright red sputum with streaks or clots should raise suspicion for an upper airway bleed, while symptoms such as nausea, vomiting, and epigastric pain, along with the coffee-ground appearance of the expectorate, should point towards the GI tract.
What is pulmonary haemorrhage and when should it be suspected?
Pulmonary haemorrhage (PH) consists of the extravasation of blood into the airways and alveoli and is defined as a triad of:
– A drop in haemoglobin or iron-deficiency anaemia
– Radiographic evidence of pulmonary infiltrates
– Haemoptysis
Haemoptysis is only present in about half (42%) of children with pulmonary haemorrhage (given the frequency with which the sputum is inadvertently swallowed); hence, the association of the first two features warrants careful consideration.
A variable degree of dyspnoea is observed in 35% of cases, and cough in 30%, whilst anaemia is present in up to 87% of cases. Remarkably, 23% of patients can show no respiratory symptoms at all!
Less specific signs and symptoms include chest pain, tachypnoea, hypoxia, digital clubbing, fatigue and failure to thrive.
The misdiagnosis of pneumonia and asthma (based on the finding of crepitations and wheeze, respectively) is common and reported in up to two-thirds of children with pulmonary haemorrhage, leading to a delayed diagnosis.
The physical examination should include an assessment of the skin and joints to identify signs of vasculitis or other autoimmune disorders.
What causes pulmonary haemorrhage?
Pulmonary haemorrhage may arise from:
- High-pressure bronchial circulation
- Low-pressure pulmonary circulation
It can be focal or diffuse.
Table 1. Causes of focal and diffuse pulmonary haemorrhage
| FOCAL | |
| INFECTION | Bronchitis Pneumonia Lung abscess Tuberculosis Aspergilloma Bronchiectasis Cystic fibrosis Primary ciliary dyskinesia Immunodeficiency |
| TRAUMA | Lung contusion Foreign body Suction catheters Inhalation injury |
| VASCULAR DISORDERS | Pulmonary embolism/thrombosis Arterio-venous malformation Pulmonary haemangioma Pulmonary teleangiaectasia |
| BLEEDING DISORDERS | Thrombocytopaenia Von Willebrand disease Anticoagulants |
| CONGENITAL LUNG MALFORMATIONS | Sequestration CPAM Bronchogenic cyst |
| MISCELLANEOUS | Neoplasm Catamenial haemoptysis Factitious haemoptysis |
| CARDIAC | Pulmonary vein atresia/stenosis/occlusion |
| DIFFUSE | |
| CARDIAC | Mitral stenosis Total anomalous pulmonary venous return Pulmonary veno-occlusive disease |
| DIFFUSE ALVEOLAR HAEMORRHAGE | IMMUNE-MEDIATED Wegener’s Granulomatosis Microscopic Polyangiitis Goodpasture Syndrome Henoch-Schönlein Purpura Behçet’s Disease Cryoglobulinaemic Vasculitis JIA Idiopathic Pulmonary Capillaritis DAH associated with autoimmune features (no evidence of vasculitis but raised auto-antibodies) |
| IMMUNO-ALLERGIC Heiner’s Syndrome Lane Hamilton syndrome | |
| NON-IMMUNE MEDIATED IPH (Idiopathic Pulmonary Haemosiderosis) Acute Idiopathic Pulmonary Haemorrhage of Infancy Asphyxiation / Abuse Pulmonary Telangiectasia | |
Children with Trisomy 21 are at higher risk due to immune dysregulation, congenital cardiopulmonary disease, and infection susceptibility, showing therefore a higher incidence of PH.
Idiopathic pulmonary haemosiderosis: not so idiopathic?
Idiopathic pulmonary haemosiderosis (IPH) has historically been described as the commonest cause of diffuse alveolar haemorrhage (DAH) in children, but is increasingly thought to be immune-mediated, based on:
- Its association with CMPA, coeliac disease, and selective IgA deficiency
- Development of auto-antibodies in ~25% of patients over time
- Clinical response to corticosteroids
How does pulmonary haemorrhage damage the lungs?
Following an intra-alveolar bleed, red blood cells are rapidly phagocytosed by the alveolar macrophages, resulting in the production of free heme and iron, which combine to form haemosiderin complexes, a form of iron which the body is unable to use, thus leading to iron-deficiency states.
The association of idiopathic pulmonary haemorrhage with coeliac disease has been explained by some authors, who assume a pivotal role for lymphocytes activated by a delayed-type hypersensitivity reaction to a culprit antigen (e.g., gluten) in a predisposed individual.
The inflammatory reaction resulting from their activation (consisting of a cytokine and chemokine cascade, neutrophil recruitment, and the formation of reactive oxygen species [i]) would be responsible for dysfunction of the alveolar capillaries, leading to extravasation of red blood cells into the alveolar space.
Recurrent episodes can result in pulmonary fibrosis and end-stage lung disease.
Who gets pulmonary haemorrhage and what is the prognosis?
The broad spectrum of conditions that can lead to PH makes it difficult to determine its overall frequency.
Children display a higher incidence of pulmonary haemorrhage compared to adults, accounting for about 80% of reported cases, with an estimated incidence ranging from 0.24 to 1.23 cases per million per year.
Gender distribution is unclear, with some studies suggesting no preference and a recent review of the French paediatric registry showing a female predominance. Onset in children occurs primarily before age 10.
IPH in children has traditionally been associated with poor prognosis, with a mortality of up to 60%. However, more recent retrospective studies have shown 5-year survival rates above 80%, likely due to more aggressive immunosuppressive treatment in the early stage of the illness.
Investigating suspected pulmonary haemorrhage
Once it is established that the bleeding most likely originates from the lungs, the next task is to differentiate between focal and diffuse bleeding.
Imaging: Imaging is paramount in this process, including plain CXR, usually followed by computed tomography (CT), CT pulmonary angiography (CTPA), or MRI angiography.
The typical CT finding is ground-glass lung opacities in diffuse alveolar haemorrhage,
An ECG and an echocardiogram should be obtained whenever a cardiac cause of PH is suspected.
Laboratory: A set of baseline blood tests, consisting of full blood count (FBC), blood film, group and save, clotting (including Von Willebrand factor), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), blood and broncho-alveolar lavage (BAL) cultures can aid the diagnosis of infective causes and coagulopathies. Urinalysis should be performed to rule out haematuria.
An autoimmune panel should be requested to assess for immune-mediated and immuno-allergic causes of DAH. This includes:
- Total immunoglobulins
- Coeliac screen
- Autoantibodies (anti-neutrophil cytoplasmic (p-ANCA, c-ANCA)
- Anti-glomerular basement membrane (GBM)
- Anti-phospholipids (APLA)
- Anti-nuclear (ANA), anti-double strand DNA (dsDNA), anti-smooth muscle (Sm)
Specific genetic panels are available to assess for hereditary conditions predisposing to diffuse alveolar haemorrhage. Remarkably, several patients have been reported to display positive autoantibodies only years (up to 17!) after the onset of clinical symptoms, making it advisable to repeat the immunological workup during follow-up.
Bronchoscopy is central to the diagnosis of DAH, with aspiration of three sequential BAL aliquots to show persistence or increase in blood. The same BAL samples can then be sent for:
(a) cytology to look for haemosiderin-laden macrophages and eosinophil count
(b) bacterial and fungal culture
(c) tuberculosis smear, culture and polymerase chain reaction (PCR)
(d) galactomannan antigen for Aspergillus
(e) PCR for viruses
(f) cow’s milk precipitins in cases where the association with CMPA is either known or suspected.
Lung biopsy is reserved for patients with autoimmune conditions or suspected IPH showing poor response to treatment.
A CTPA is obtained on Isla, and it shows bilateral consolidation and ground-glass opacities, without any specific source of bleeding
Microbiological samples are negative, and haematological and rheumatological investigations exclude a clotting disorder or vasculitis.
The serial collection of three BAL samples confirms the persistence of blood and tests positive for haemosiderin-laden macrophages, supporting a diagnosis of idiopathic pulmonary haemorrhage.
Principles of acute management of pulmonary haemorrhage
Early stabilisation and supportive management
The cornerstone of the acute management of children presenting with PH is supportive, with a focus on securing the airway, prevention of hypoxia and control of haemodynamic instability secondary to the haemorrhage. A systematic (ABCDE) approach is essential.
- Airway: The presence of fresh blood or clots can result in airway obstruction and hypoxia.
In such cases, invasive ventilation should be promptly considered. Intubation should be performed by the most experienced operator with the largest possible endotracheal tube (ETT) to facilitate frequent suctioning.
- Breathing: Blood within the alveoli can significantly impair gas exchange, leading to hypoxia. If the bleed is known to be unilateral, positioning the patient with the healthy side up can aid with ventilation and oxygenation.
An open-lung ventilation strategy based on the delivery of high PEEP not only optimises oxygenation but also provides a tamponade effect at bleeding sites.
The use of high-frequency oscillatory ventilation (HFOV) in patients with a high oxygenation index (OI) follows the same rationale.
Early ECMO referral should be considered and is usually reserved for the most severe cases, given the associated risk of worsening the bleed.
- Circulation: Fluid boluses and transfusions of blood, platelets and FFP can be used for fluid resuscitation, alongside vasoactive agents when needed.
Tranexamic acid, either IV or nebulised, is widely used to aid clotting.
- Disability: Sedation and neuromuscular blockade are usually required to prevent coughing and the resulting increase in intrathoracic pressure, which can dislodge clots and trigger further bleeding.
- Exposure: Hypothermia should be prevented given its negative impact on clotting.
- Infection: Given the potential role of infections in triggering, they should be treated with broad-spectrum antibiotics.
Definitive management
Once the patient is stabilised, more specific management strategies can be initiated, depending on the underlying cause (diffuse or focal), which may have been identified by then.
Rigid bronchoscopy plays a central role in clot removal.
In addition, it allows the topical instillation of cold saline, which could aid bleeding control by causing vasoconstriction.
The role of topical adrenaline is up for debate, due to the reported association with cardiac arrhythmias, which makes it not recommended in patients with congenital heart disease or recent cardiac surgery.
Finally, bronchoscopy can aid in the placement of lung isolation devices, allowing single-lung ventilation, a strategy aimed at protecting the unaffected lung (or lung areas) from blood contamination. The latter is based on the use of dual-lumen ETTs or bronchial blockers and can be technically challenging in the paediatric population due to smaller patient size and subsequent difficulties with siting.
Vasopressin at high doses causes vasoconstriction and increases the concentration of factor VII and von Willebrand factor. Nebulised vasopressin has been used in case reports for a child with haemoptysis.
Bronchial artery embolisation has a limited role in the paediatric population, reserved for cases of severe bleeding in which an active bleeding point is identified.
Surgical resection of bleeding points is the last resort in adults with PH caused by bleeding from the bronchial artery, following failure of embolisation or recurrence of bleeding. It is associated with higher morbidity and mortality when performed in the acute stage of bleeding and is best suited once the bleeding has been brought under control. There is little evidence for its effectiveness in children.
Corticosteroids are the cornerstone of the management of diffuse alveolar haemorrhage, either alone, or in combination with other immunosuppressants.
In patients requiring mechanical ventilation, pulse dose methylprednisolone (30 mg/kg, maximum 1 g) is usually administered for 3-5 days, followed by prednisone 0.5–1 mg/kg/day.
The optimal duration of steroid therapy is unknown; some authors advise a cautious tapering until discontinuation following a period of stability of 12-18 months, others recommending lifelong therapy.
Unfortunately, recurrent bleeding during maintenance therapy is not uncommon and usually requires an escalation of the steroid dose.
Several steroid-sparing immunosuppressive agents have been used with variable results, including hydroxychloroquine, azathioprine, cyclosporine, cyclophosphamide, methotrexate, 6-mercaptopurine, rituximab, intravenous immunoglobulins and inhaled corticosteroids.
Isla has a positive outcome. She requires respiratory support, including high-frequency oscillatory ventilation (HFOV) and nitric oxide, due to oxygenation difficulties.
She receives a 3-day-course of intravenous pulse methylprednisolone, followed by a tapering dose of prednisone.
Following a six-day admission to intensive care, Isla is extubated and makes a full recovery from this acute episode.
At 6-month follow-up, she is on maintenance prednisone, her Hb is stable, and she has not experienced any further episode of PH.
Take home messages
Keep a high index of suspicion for PH in children with respiratory symptoms, new CXR changes and iron-deficiency anaemia, even in the absence of haemoptysis.
Consider CTPA and bronchoscopy as soon as possible, to identify the source of bleeding.
Collect serial BAL samples to assess for the persistence of blood and the presence of haemosiderin-laden macrophages, which supports the diagnosis of DAH.
In cases of DAH, assess the child for signs of associated autoimmune disorders and request appropriate laboratory tests.
Early recognition and treatment with corticosteroids improve outcomes in DAH.
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