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Abstract
The case of an 11-year-old child presenting with acute haemoptysis and breathlessness is described. The girl was Malaysian and had recently arrived in the UK. She subsequently deteriorated, developing respiratory failure. The course of the illness is described, with reference to the diagnostic process at each stage. The case demonstrates the importance of having a broad investigatory approach in acute haemoptysis.
- Paediatric Practice
- Intensive Care
- Respiratory
- Nephrology
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Presentation
Mira (not her real name), an 11-year-old Malaysian girl, presented to the emergency department (ED) with a 1-day history of cough, haemoptysis, lethargy and breathlessness. Her family had arrived in the UK from Kuala Lumpur that morning. Mira had previously been fit and well, apart from a minor febrile illness with cough for 3–4 days before travel.
Mira's siblings and parents were well. They lived in an urban area in Malaysia, though Mira had attended a camp in a rural area 4 weeks before the onset of her illness. Her mother had negative HIV tests during each pregnancy. A 60-year-old uncle of Mira had been suffering from a chronic cough with haemoptysis, and was being treated for tuberculosis (TB) though the family was unsure how this had been diagnosed. There was no other family history.
During the 13-hour flight Mira became breathless, with a worsening cough. On arrival the family went sightseeing but in the evening she coughed up approximately 5 mL of fresh blood.
On arrival in the paediatric ED, Mira appeared unwell. She had a temperature of 36.3°C, heart rate of 144 bpm, respiratory rate of 44/min and transcutaneous oxygen saturation of 98%. Examination of her chest revealed evidence of mild subcostal recession, and reduced air entry to both bases and scanty bibasal crackles. Mira was in the early stages of puberty, with stage 2 breast development; she had not yet gone through menarche. Her height was 137.5 cm (9th centile) and weight 33 kg (25th centile). Mira had an episode of frank haemoptysis in the ED.
Comment: issues for foreign nationals receiving treatment in the NHS
Many doctors in the National Health Service (NHS) feel uncomfortable with the topic of payment for care. Although we would not allow the patient's financial situation to affect the care we provide, it is useful to briefly consider the issue and be aware of this additional strain on overseas families in an already stressful situation. As overseas visitors, Mira's family will be invoiced for treatment provided after she is accepted as an inpatient. It is not required of clinicians to assess their patient's liability to charges; this is the responsibility of the Trust's Overseas Visitors Manager. Here follows a brief summary of the law concerning the NHS in England.
Accident and emergency services are free of charge, but emergency treatment required in hospital including provision of intensive care is chargeable.1
All treatment for infectious diseases of public health concern such as measles, pertussis and invasive meningococcal disease is free of charge.1
Urgently required treatment must be provided without delay, in accordance with the Human Rights Act.1 However, non-urgent treatment should not be provided until payment has been made.
If parents decline treatment that is in the best interests of a child, this can be challenged in court. Court-enforced treatment is not chargeable.1
Travel insurance cover may include caveats regarding existing conditions and cases where preventative measures should have been taken.2 Many families travel without insurance.
Comment: differential diagnosis at presentation
It is often difficult to distinguish between haemoptysis and haematemesis in children. Important clues include:
Colour: bright in haemoptysis and darker in haematemesis
Appearance: vomited blood may contain food particles; coughed blood is often frothy in appearance
History: nausea and vomiting would increase the suspicion of haematemesis
pH: testing the expectorated blood with pH strips may be helpful, acidity suggests haematemesis
Mira was coughing up bright, frothy blood, and this was associated with respiratory symptoms, making it highly suggestive of haemoptysis. The key working differential diagnoses are discussed in table 1.
Differentials and features for and against each diagnosis
Investigations were ordered to aid in refining the differential diagnosis including full blood count, erythrocyte sedimentation rate and C reactive protein for evidence of infection or inflammation, and urea and electrolytes for renal function. See table 2 for initial blood test results. Mira was anaemic and had a raised creatine and urea for her age. Blood gas sampling was not performed as Mira was not hypoxic on transcutaneous saturation monitoring.
A chest radiograph of Mira was performed in the ED.
Comment: the use of chest radiography in haemoptysis
Chest radiographs are a useful initial imaging investigation in a child presenting with haemoptysis (see table 1). Two major patterns of changes may be seen on X-ray, which help to narrow the initial differential diagnosis.
Diffuse reticulonodular changes may be due to cardiac disease, toxin-mediated injury, immune-mediated multisystem disease or infection.
Focal changes may occur in infective disease, infarction (pulmonary embolus), foreign body aspiration, neoplasm or vascular malformation.
Mira's chest radiograph revealed diffuse shadowing and small bilateral pleural effusions (figure 1). Miliary TB or other atypical respiratory infection was considered the most likely diagnosis. Broad-spectrum antibiotics were started in the ED. Ceftriaxone and clarithromycin were chosen as per local policy for lower respiratory infections, providing cover against Gram-negative, Gram-positive and atypical organisms. Unfortunately a sputum sample was not obtained for culture before initiation of antibiotic treatment. Sputum samples are challenging to obtain in children, and usually require physiotherapy input. Mira was transferred to a paediatric infectious diseases unit.
Plain X-ray of the chest on presentation to the emergency department, showing diffuse reticulonodular shadowing and small bilateral pleural effusions with loss of the costophrenic angles and fluid in the horizontal fissure.
Comment: infectious diseases
In addition to common causes of respiratory infection and TB, several tropical organisms found in Malaysia were of particular concern. Avian influenza can cause fever, respiratory distress and sputum which may be bloody.5 Hantavirus causes haemorrhagic fever with renal syndrome, which presents with fever and bleeding, though usually in the subconjunctivae or skin. This virus is contracted from contact with rodent waste.6 Further investigation revealed that a virulent strain of adenovirus had caused several deaths in Mira's home city of Kuala Lumpur in the days before she left.7
After arrival on the infectious diseases ward, Mira was stable overnight, though she was tachypnoeic and hypertensive, with a blood pressure of 136/104 mm Hg. This is above the 99th centile blood pressure for her age, sex and height, which is 126/86 mm Hg.8 She was nursed with respiratory precautions: in a negative pressure side room, with filtering facepiece masks in addition to gloves and aprons.
Comment: hypertension in children
Hypertension in children is defined as a systolic blood pressure greater than the 95th centile for their age, height and gender. Stage 1 hypertension describes systolic blood pressure above the 95th centile but no more than 5 mm Hg above the 99th centile, with stage 2 describing levels higher than this.8
A practical approach to hypertension in children:
Confirm that the reading is valid
Correct cuff size and equipment validated for use in children
Appropriate positioning
Consider physiological causes
Pain
Anxiety
Distress
Consider pathological causes only when the hypertension has been confirmed (three separate measurements for stage 1, not required in stage 2).
Essential hypertension (primary): Very rare in childhood
Secondary causes
Anatomical: Coarctation of the aorta
Hormonal: Phaeochromocytoma, Cushing’s syndrome
Volume overload: Renal disease (renin-mediated water and sodium retention or reduced glomerular filtration rate) including inflammatory disease, structural diseases and renal scarring.
Obesity
Otherwise well children with stage 1 hypertension should be referred for investigation within 1 month. Initial treatment may include lifestyle modifications such as dietary modification and increased activity levels. Pharmacological treatment will be required if this fails, or earlier in the presence of symptoms, end-organ damage, diabetes mellitus, or an identified secondary cause of hypertension.8 Most confirmed hypertension in young children is secondary, and the choice of treatment is influenced by the underlying cause. If stage 2 hypertension is present, an urgent referral must be made, for assessment within 1 week. If the child has any symptoms of hypertension, immediate referral is necessary, for prompt initiation of treatment.8
Hypertensive emergencies occur with a systolic blood pressure well above the 99th centile, which may present with severe headaches, vomiting and seizures. This indicates the presence of hypertensive encephalopathy, also termed posterior reversible encephalopathy syndrome, in which posterior cerebral oedema can be detected on MRI. The condition is particularly associated with hypertension in renal disease.9 Correction of blood pressure should not be attempted too rapidly, aiming for no more than a 25% reduction in the first 8 hours. There are numerous options for emergency intravenous therapy, including labetalol and nicardipine.8
Progression
The morning after admission Mira’s condition deteriorated rapidly. Her respiratory distress escalated and there was further haemoptysis of several teaspoons of bright blood. She was transferred to the paediatric intensive care unit (PICU) and during the transfer her transcutaneous oxygen saturation fell to 54% in 15 L/min of oxygen delivered by face mask. Tracheal intubation was performed and mechanical ventilation was started. Though high ventilation pressures were needed initially, these were rapidly weaned. During the 1st day on intensive care norepinephrine and milrinone were required for hypotension, and Mira received a blood transfusion. Pertinent blood results are shown in table 3. Her renal function showed further deterioration and Mira was noted to be oedematous and oliguric. A significantly raised urine albumin-creatine ratio confirmed proteinuria. Respiratory function was now stable, with transcutaneous oxygen saturation of 99% on FiO2 0.3. Furosemide was given to maintain adequate urine output, and intravenous fluids limited to 80% of maintenance.
It was now apparent that there was renal as well as respiratory involvement in Mira's illness. She had an acute kidney injury with oliguria, haematuria and proteinuria. It was not known whether this was due to:
Renal injury secondary to critical illness, with increased glomerular permeability (secondary to cardiac failure or infection)
Renal involvement in an immunological response to infection
A systemic illness, either infective (eg, viral illness) or inflammatory
The first two options were thought to be most likely. Antibiotic cover was extended on PICU to include gentamicin (to improve cover against Gram-negative organisms) in addition to ceftriaxone and azithromycin. Gentamicin can be safely used in renal impairment as long as doses are appropriately adjusted and blood levels regularly monitored to ensure that toxicity does not occur.
A CT scan of the chest was carried out on day 3 of admission, as the cause of respiratory deterioration remained unclear. This showed consolidation with air bronchograms, and partial collapse of both lower lobes (figure 2, solid arrows). Pleural effusions were also present bilaterally (dashed arrows) and patchy ground-glass shadowing is seen across the rest of the lung field.
CT scan of the chest performed during paediatric intensive care unit admission. Solid arrows indicate consolidation; dashed arrows indicate pleural effusions.
In order to exclude cardiac failure, Mira had a cardiology review. Echocardiography showed normal anatomy, moderately impaired left ventricular function, with mild mitral and tricuspid regurgitation. Myocarditis (most likely viral) was considered as a possible cause of her myocardial dysfunction.
Comment: myocarditis
Key features of myocarditis are outlined in table 4. Although her ECG was normal, this does not rule out a diagnosis of myocarditis.10
Features of myocarditis.10
Microbiological and virological investigations for Mira can be categorised into tests for potential respiratory pathogens, causes of viral myocarditis and causes of systemic infections (table 5).
Further investigations for infectious diseases
Although one nasopharyngeal aspirate for adenovirus was positive by PCR, amplification for typing of the virus failed, making it impossible to link this infection with the strain in Malaysia.
Comment: which TB test?
There are numerous investigations for the detection of mycobacterium TB infection. Table 6 describes their methods and the context in which they should each be used.
Comparison of tuberculosis (TB) investigations
Whereas sputum microscopy is useful in adult patients to determine infectivity, this is not true in children. Sputum cultures take up to 8 weeks, making interferon-γ tests extremely useful in assessing likelihood of disease. A UK paediatric TB network study found that neither of the interferon-γ release assays was more effective for the diagnosis of culture-confirmed active TB infection than the Mantoux test.16 A Mantoux result of over 15 mm had a sensitivity of 82%, compared with 78% for QuantiFERON and 66% for T-SPOT.16 However, combining the investigations significantly improved the sensitivity to a maximum of 96% which was achieved by combining Mantoux with T-SPOT.16 Testing for TB with several different investigations, as was carried out with Mira, is important because agreement between results is often poor.
Refining the differential diagnosis
No evidence had emerged of an acute infective cause underlying Mira's respiratory and renal dysfunctions, and an inflammatory/autoimmune condition now seemed most likely. The differential diagnosis now included a number of diseases which are responsive to steroid therapy (see table 7). The paediatric nephrology consultant became involved in addition to infectious diseases and intensive care specialists. Autoimmune investigations were sent, and on day 4 once daily intravenous methylprednisolone was started.
Autoimmune diseases and use of steroids
In total Mira received 5 days of mechanical ventilation. After gradual improvement on PICU, she was extubated and transferred to the ward with no oxygen requirement.
Comment: immune-mediated renal disease
Urine dipstick on returning to the ward showed protein (+++) and blood (++++). During the course of the illness, Mira had developed all of the features of an acute glomerulonephritis (GN): hypertension, haematuria, proteinuria, oedema and acute kidney injury.26 Several causes of acute GN can be revealed by immunology tests: Goodpasture's syndrome by antiglomerular basement membrane antibody, and Wegener's granulomatosis by antineutrophil cytoplasmic antibody.26 Goodpasture's syndrome classically causes haemoptysis by autoimmune damage to the alveolar membrane, though a similar pathological process may be seen with other autoantibodies.
Other immune-mediated renal diseases include systemic lupus erythematosus (SLE) and postinfectious glomerulonephritis (PIGN). SLE can be expected to cause low levels of C3 and C4, and a positive double stranded DNA antibody. PIGN is associated with a low C3 and a normal C4, and the diagnosis is supported by the presence of antibodies to streptococcus: antistreptolysin O titre (ASOT) and anti-DNAse B. PIGN has been reported as a complication of numerous different viral and bacterial infections, but is most commonly secondary to group A streptococci (GAS), and is termed poststreptococcal glomerulonephritis (PSGN). Although ASOT and DNAse B are not raised in acute infection, positive titres indicate previous GAS exposure with an immune response.27 Combination of ASOT with anti-DNAse B gives the optimal sensitivity and specificity for detecting a poststreptococcal disease at 95.5% and 88.6%, respectively.27 ASOT can be non-specifically raised, for example, in other types of GN.28 ASOT and anti-DNAse B are extremely useful tests, and should be included in the initial investigations for children with possible GN.
If a vasculitic or purpuric rash had been present in Mira's case, Henoch-Schonlein purpura would also have been considered as a cause of her acute GN, and can also rarely cause pulmonary haemorrhage.
The results of immunological tests for Mira are shown in table 8.
Mira's inflammatory markers and serology results
There were clear indications for renal biopsy: abnormal renal function, significant proteinuria and hypoalbuminaemia (lowest albumin 25 g/L). Histopathological diagnosis is important in severe cases of GN to determine the aetiology, aid treatment decisions and delineate the prognosis. Crescentic GN is usually treated with immunosuppression to attempt to reduce the risk of progression to renal failure. The evidence base for this varies depending on the underlying cause (see table 7). Renal biopsy should be taken prior to starting immunosuppression. This did not occur with Mira, who had already received methylprednisolone.
Mira's biopsy showed a segmental proliferative GN with no crescent formation (figure 3). Immunofluorescence staining showed deposition of complement C3 (figure 4). This was reflected in the electron microscopy finding of a thickened and irregular basement membrane with subepithelial deposits in a characteristic ‘hump’ shape (figure 5).
Light microscopy showing a glomerulus with endocapillary proliferation and a mild increase in mesangial matrix and cellularity.
Immunoflourescence showing granular capillary wall and mesangial ‘starry-sky’ staining for C3 deposition.
Electron microscopy showing segmental foot process effacement of epithelial cells; slight thickening and irregularity of the glomerular basement membrane with some discrete intramembranous electron-dense deposits and occasional subepithelial hump-like deposits (arrowed); and an increase in mesangial cells and matrix with sparse mesangial electron-dense deposits.
These biopsy findings, along with the low serum C3 and presence of antibodies to GAS, support a diagnosis of PSGN.
Comment: managing PIGN
PIGN is the most common cause of acute GN in children. Basic investigations should be carried out in all cases (see box 1) with additional tests guided by the clinical picture.
Initial investigations in suspected PIGN
Urine culture, microscopy and protein:creatine ratio.
A ‘renal profile’ of blood tests: urea and electrolytes, calcium, phosphate, chloride, bicarbonate and albumin, plus full blood count, complement C3 and C4 levels, antinuclear antibody and ASOT.
A throat swab to detect group A streptococci infection.
ASOT, antistreptolysin O titre; PIGN, postinfectious glomerulonephritis.
Most cases are mild and do not require specialist renal services. Referral is only necessary when renal function is effected (raised creatine, electrolyte imbalance, hypertension), proteinuria is in nephrotic range (urine protein:creatine ratio over 50 mg/mmol Cr) or an alternative diagnosis is suspected.29 PIGN is usually a self-limiting disease and treatment is therefore supportive. However, in some severe cases, if crescentic GN is seen on biopsy, steroid treatment may be given (as described above). The key areas of supportive management are:8 ,30
Fluid restriction: Guided by fluid balance (including estimation of insensible losses).
Salt restriction.
Management of hypertension: diuretics, hydralazine or calcium channel blockers. Reduction in fluid overload with diuretics is often sufficient.
Haemodialysis/haemofiltration: rarely required. Indications include fluid overload despite furosemide and progressive renal failure (uraemia, hyperkalaemia, acidosis).
Penicillin: may be given even in the absence of symptomatic throat infection. This is an attempt to eradicate the nephritogenic strain of streptococci and therefore protect contacts of the patient from infection. Guidelines recommend that a course of penicillin is only given when there is evidence of current streptococcal infection.
Children with PIGN should be followed up for a minimum of 6 months. This can be with a general paediatrician in uncomplicated disease. Referral to renal clinic is indicated in the presence of hypertension, proteinuria, hypoalbuminaemia or persistence of low C3 level beyond 3 months.29 This finding would suggest an alternative diagnosis of C3 nephritis with poorer prognosis.
An impressive recovery
Over the following days Mira’s condition improved dramatically. Urea and creatine fell to below the level at initial presentation (urea 5.6 mmol/L; creatine 54 μmol/L) by day 7.
Weight loss during this time indicated the loss of significant excess interstitial fluid. A total of 4.4 kg was lost in 4 days (34.2 to 29.8 kg). On reflection, the initial weight in the ED (33.0 kg) shows that Mira was already salt and water overloaded at presentation. A repeat chest X-ray before discharge (day 10) was normal. Blood pressure also improved, and was normal at follow-up 14 days after admission (systolic 106 mm Hg).
Learning points
Haemoptysis is rare in children. There are a large number of potential causes and it is important to follow a logical and multisystem investigatory approach. The presence of marked tachycardia and hypertension, with or without clinically obvious oedema, are significant clues to the possibility of fluid overload. This indicates likely renal disease. In addition to standard blood tests and chest X-ray, urinalysis is an important point-of-care test, which would have provided an earlier indication of the diagnosis in this case. Given there was not a clear preceding history of streptococcal infection, an ASOT at presentation would also have been particularly useful.
PSGN is a relatively common condition, but it is unusual for it to present with frank haemoptysis. Only four papers were identified which describe pulmonary haemorrhage as a presenting feature of PSGN.31–34 Similar presentations to Mira's, with frank haemoptysis and oliguria followed by rapid severe respiratory deterioration requiring intensive care admission, are described in one adult and one child.31 ,32 In a paper describing PSGN in New Zealand children, two patients are reported to have had haemoptysis in a case series of 27, one at presentation and the other developing later in the illness.33 Although this suggests a reasonably high rate of this complication, PSGN is particularly common among New Zealand Maori and Pacific Island peoples and is more likely to follow an aggressive course.33
It is possible that cases such as Mira's are also seen more frequently in other populations, particularly in low income, middle income countries. GAS is widespread, and can occur in outbreaks in any community. However, it spreads more easily in poorer living conditions, and the greatest burden of disease is therefore seen in low- and middle-income countries. WHO has estimated that 97% of PSGN cases occur in less developed countries.35
Of the total of five patients described in the literature, only one had crescents on renal biopsy.34 The use of pulsed methylprednisolone is described in four cases, with several authors reporting an apparent beneficial effect.31–33 Several patients underwent bronchoscopy, with findings consistent with pulmonary capillaritis.31 ,33 It is therefore possible that Mira's pulmonary haemorrhage was immune-mediated, though the combination of pulmonary oedema and hypertension may also have contributed. Certainly, significant fluid overload was a major contributor to the severity of Mira’s clinical deterioration.
We have described a case of severe PIGN with haemoptysis and acute respiratory compromise. The case posed a diagnostic challenge due to the unusual presentation, which gave an initially broad differential diagnosis. Seen in retrospect, there were indications of a renal cause from the start, and early recognition of these features is the principle learning point to be gained from Mira's case.
Key messages
Fluid overload may not present with obvious peripheral oedema. Be alert to other signs such as hypertension. Take a detailed history of fluid intake and output and weight change (if baseline known).
Always perform urinalysis in children with an unusual presentation or possible systemic illness.
Discuss early with a paediatric nephrologist in cases of suspected glomerulonephritis with evidence of renal dysfunction, significant fluid overload or electrolyte imbalance.
Fluid overload in glomerulonephritis may require diuretics and fluid restriction, and in severe cases can cause respiratory compromise requiring intensive care.
References
Footnotes
Contributors All of the authors were involved in the clinical care of the patient described. The manuscript was initially written by EW, and subsequently edited by all other authors who contributed changes and additions of sentences or paragraphs particularly in the sections corresponding to their respective specialties.
Competing interests None declared.
Patient consent Parental/guardian consent obtained.
Provenance and peer review Not commissioned; externally peer reviewed.