de intensivist

Abstract

Diffuse alveolar haemorrhage (DAH) is a life-threatening condition characterized by acute onset of dyspnoea, haemoptysis and respiratory failure. A known cause, amongst others, is anti-glomerular basement membrane (anti-GBM) disease, which can be caused by inhalation of substances. In this case report we describe an adolescent male with severe DAH due to anti-GBM disease without renal failure, related to smoking and water pipe inhalation, possibly aggravated by inhalation of nitrous oxide (N₂O). He recovered completely after treatment with mechanical ventilation in prone position, veno-venous extracorporeal membrane oxygenation, methylprednisolone, plasmapheresis and cyclophosphamide.

 Introduction

Diffuse alveolar haemorrhage (DAH) is a life-threatening condition with a high mortality rate.[1] Clinical characteristics include dyspnoea, acute respiratory failure, anaemia, new pulmonary infiltrates on chest radiograph, and in two thirds of cases haemoptysis. DAH is caused by bleeding in the alveoli of the lungs due to disruption of the alveolar-capillary basement membrane, secondary to pulmonary capillaritis, most commonly due to auto-immune vasculitis. Other causes include pulmonary infections, left ventricular failure, malignancy, coagulation disorders and illicit drugs such as cocaine, heroin, (met)amphetamines and marijuana.[2–7] In case reports, DAH has also been described secondary to e-cigarette smoking, vaping and water pipe smoking.[8–10] When DAH is suspected, bronchoalveolar lavage (BAL) should be conducted for confirmation of alveolar origin of blood and to exclude infection. Since erythrocytes are phagocytosed by alveolar macrophages, cytological examination demonstrates the presence of hemosiderin-laden macrophages with percentages of >20% considered diagnostic for DAH.[11] Lung biopsy is the gold standard in diagnosing DAH, however it is only considered when all other diagnostics to establish underlying aetiology are inconclusive, such as extensive autoimmune diagnostics.[2]

A cause of immune DAH is anti-glomerular basement membrane (anti-GBM) disease, also Goodpasture disease, which is a rare condition with an incidence of 0.5 to 1 per million persons per year.[2] In this autoantibody-mediated disease, deposition of anti-GBM autoantibodies at the renal glomeruli and alveolar capillary basement membranes leads to small vessel vasculitis. Its diagnosis relies on anti-GBM antibody detection in serum together with the presence of alveolar or glomerular disease.[12] Anti-GBM disease presenting with only DAH and absence of clinical renal involvement has been described.[13] An association with anti-GBM disease in conjunction with exposure to (inhaled) drugs, inhaled vapor or fumes, and tobacco smoking has been described in case series and case reports.[13–16] Nitrous oxide (N2O) inhalation has never been related to anti-GBM. Therapy consists of immunosuppressive therapy with cyclophosphamide or rituximab to limit de novo production of antibodies, and corticosteroids.[17,18] In addition, removal of circulating anti-GBM antibodies through therapeutic plasma exchange for 14 days or until anti-GBM is no longer detectable is recommended, as it is associated with better renal recovery.[19–22]

Immune DAH has a mortality of 77% when mechanical ventilation is necessary.[23] Although veno-venous extracorporeal membrane oxygenation (VV-ECMO) is frequently complicated by bleeding due to the need for therapeutic anticoagulation therapy, VV-ECMO may be considered for severe respiratory failure due to DAH. Seeliger et al have shown a mortality of 47% amongst patients with immune DAH receiving ECMO, without aggravating pulmonary bleeding.[24]

Here we report a case of anti-GBM disease related to inhalation of tobacco, water pipe smoking and excessive use of N₂O, resulting in DAH with severe acute respiratory failure treated with VV-ECMO whom recovered without sequelae after extensive treatment.

Case presentation

A 21-year-old male was presented to the emergency department of a local hospital with acute respiratory failure. A few weeks prior to admission he had been coughing, with progression of dyspnoea with development of haemoptysis over the course of two weeks. He had a history of obesity (body mass index 34 kg/m²), diabetes mellitus type II. There were no known allergies and no recent history of infectious diseases. He was an excessive user of N₂O inhalation (multiple balloons per day) in combination with tobacco and water pipe smoking. Conventional chest X-ray showed severe bilateral consolidations (figure 1). Empirical antibiotic treatment for community acquired pneumonia was commenced and he was admitted to the intensive care with hypoxemic respiratory failure. High-flow nasal oxygen therapy was swiftly followed by mechanical ventilation in prone position with high pressures (PEEP 20cmH₂O, ΔP 22cmH₂O), fraction of inspired oxygen (FiO2) of 1.0, tidal volumes of 250 ml (3.3 ml/kg ideal body weight) and permissive hypercapnia (pH 7.19, PaCO2 9.2 kPa). The patient was referred to our hospital for VV-ECMO as a bridge-to-diagnosis and bridge-to-recovery strategy. VV-ECMO was commenced within a few hours after admission.

Figure 1
Conventional X-ray of chest with bilateral infiltrates

BAL was conducted repeatedly which showed sanguinolent secretions, without bronchial obstruction, confirming DAH. Cytological analysis of the BAL specimen revealed the presence of many red blood cells, haemosiderophages and alveolar macrophages. No malignant cells were observed. Extensive viral, bacterial and fungal diagnostics remained negative. Galactomannan was low (0.3). HIV-test was negative. Drugs of abuse screening in urine, including (met)amphetamines, barbiturates, benzodiazepines, tricyclic antidepressants, cannabis (THC) and cocaine, were negative.

Blood results showed anaemia (initial haemoglobin 6.6 mmol), leucocytosis (33.9x10⁹ units/L), CRP of 74 mg/L, normal platelet count, prolonged prothrombin time test (14.4 seconds) and activated partial thromboplastin time (35 seconds) and normal liver and kidney function tests. Analysis of urine contained 1g/L proteins and 20-40% dysmorphic red blood cells. Extensive immunologic and rheumatologic serology showed a weak positive lupus anticoagulant and anti-GBM, and a negative ANCA. Quantitative measurement of anti-GBM was 11 U/ml (upper normal margin of 10 U/ml), confirming anti-GBM disease. Transthoracic echocardiography showed normal function of both ventricles, without signs of congenital or acquired cardiomyopathy or valvular dysfunction. Chest computed tomography (CT) angiography showed diffuse bilateral consolidations with sparse aerated pulmonary tissue, multiple enlarged lymph nodes cervical, supraclavicular and mediastinal, no pleural effusions and no pulmonary embolism (figure 2A).

With a diagnosis of DAH due to anti-GBM disease the patient was treated with a combination of methylprednisolone 1 g daily for three days continued by prednisolone intravenously, plasmapheresis (initially daily), and cyclophosphamide, while continuing lung protective mechanical ventilation in prone position and VV-ECMO. The patient received anticoagulation therapy with unfractionated heparin in a slightly lower dose than normally aimed for in VV-ECMO (heparine ratio of 1.5 to 1.8), without aggravating DAH or problems with clots in the circuit. Effect of treatment was monitored through measurement of serum anti-GBM antibodies, which had increased to a maximum of 25 U/ml on the day therapy was commenced and decreased after the start of the treatment with plasmapheresis over the course of ten days (figure 3). High resolution CT of the chest showed decreasing bilateral infiltrates (figure 2B). Pulmonary compliance improved slowly and on the 13th day of mechanical ventilation the patient could be ventilated in supine position. VV-ECMO was continued until the 23rd day. Plasmapheresis was continued three times per week and cyclophosphamide intravenously was repeated one month after the first dose. After 29 days mechanical ventilation was stopped, and oxygen therapy was tapered. At 34 days after presentation he was discharged to the ward. He recovered further and within 15 days he was discharged without oxygen suppletion. Intravenous cyclophosphamide was continued for a total of six doses. Azathioprine was prescribed as consolidation therapy. The patient was urged to quit N₂O, cigarettes and water pipe smoking.

Figure 2
2A CT scan of the chest showing bilateral infiltrates and atelectasis
2B CT scan of the chest showing decreased abnormalities during treatment

Figure 3 Values of anti-GBM antibodies over time and arrow indicating start triple therapy consisting of methylprednisolone, plasmapheresis and cyclophosphamide.

Discussion

We present a case of severe DAH from anti-GBM disease with predominant pulmonary involvement and spared kidney function. We hypothesize inhalation of tobacco and water pipe was causative in formation of anti-GBM antibody production. Excessive N₂O inhalation possibly generated aggravation of DAH. Patient’s history and extensive negative diagnostic tests led to no other likely cause.

The pathophysiology of development of anti-GBM disease after exposure to various inhalants is not completely clear yet. Interesting is that naturally occurring anti-GBM antibodies with low titres have been found in healthy individuals.[25] When inhalation induces damage to the capillary endothelium, this might lead to circulating anti-GBM antibodies reaching the alveolar basement membrane (ABM), which is normally protected by the non-fenestrated pulmonary endothelium. A finding supporting the hypothesis that local damage secondary to inhalation may lead to anti-GBM is that patients in a case series described by Lazor et al whom had been exposed to inhaled substances had significantly lower initial serum creatinine, suggesting revealing anti-GBM disease at an early stage before renal failure has developed.[13] Furthermore, cigarette smoke damages the ABM directly leading to formation of anti-ABM antibodies and it alters antigenic determinants in the ABM enabling it to cross-react with anti-GBM antibodies. Lastly, smoking could enhance the local inflammatory response triggered by binding of antibody to the ABM. Resumption of smoking can also lead to redevelopment of lung haemorrhage in anti-GBM disease.[14]

Mechanisms through which deep inhalation of substances may lead to DAH in general include enhanced endothelial permeability of the pulmonary capillaries, pulmonary infarction following pulmonary arterial vasoconstriction (in cocaine inhalation), and an increase in negative alveolar pressure and barotrauma leading to damage of the alveolar-capillary membrane.[4,5,7,10] Inhalation of tobacco through water pipe leads to oxidative stress and inflammation through inhalation of similar harmful substances found in cigarettes, such as nicotine, particulate matter, carbon monoxide, volatile organic chemicals, acrolein, arsenic and heavy metals, but at greater amounts.[9,26] Furthermore, it is suggested that the use of home-made bongs from plastic bottles, of which the heating could lead to concomitant inhalation of acid anhydrides, is a cause of DAH.[8] In the described case it was not exactly clear which type of water pipe the patient used and which substances he had exactly inhaled. We recommend extensive history taking, intoxication history and (hetero)anamnesis in patients with unclear aetiology of DAH as it could reveal important information.

Remarkable was the excessive use of N₂O in our case, which raised questions whether this could have triggered or exaggerated autoantibody formation. N₂O has not been associated to anti-GBM disease or DAH before. It is considered a safe, potent gas commonly used as an analgesic and anaesthetic in obstetrics, dentistry, ambulances and emergency departments. Over the last two decades its recreational use has increased worldwide because of its effects including brief derealization, anxiolysis, analgesia, and euphoria. Misuse or heavy use for a prolonged time may lead to (irreversible) neurological damage due to vitamin B12 deficiency if treatment is delayed. Vitamin B12 deficiency is also associated with TMA, increasing the risk of alveolar haemorrhage due to thrombocytopenia or high pressure locally in the small pulmonary vessels.[27] In our patient dysmorphic erythrocytes were found in urine, which could be explained by anti-GBM glomerulonephritis, however, renal function was spared. Reticulocytes, vitamin B12 or ADAMTS13 were not analysed. Therefore, we cannot conclude whether this has been an adjunctive cause to the bleeding. Another aetiology for the alveolar haemorrhage could be the mechanism of inhalation. Inhalation is usually from balloons filled from non-reusable metal canisters, or more dangerously, from the canister itself, which may lead to negative alveolar pressure and barotrauma leading to damage of the alveolar-capillary membrane.[28] This may in turn lead to circulating anti-GBM antibodies to reach the ABM in a comparable manner as earlier described when damage is induced by other substances. Moreover, pulmonary haemorrhage could have been aggravated by this mechanism.

When anti-GBM disease presents as severe DAH, patients may need mechanical ventilation, which could lead to mechanical stress on lung tissue which might further trigger antigen presentation and worsen symptoms.[29] VV-ECMO as a strategy for bridge-to-recovery should therefore be considered in severe DAH due to anti-GBM disease. The need for anticoagulation in this setting should not be seen as a contra-indication, since VV-ECMO is even feasible with low dosage of anticoagulation or no anticoagulation at all for short periods of time in cases of ongoing alveolar haemorrhage.

Conclusion

Water pipe and tobacco smoking together with inhalation of N₂O may lead to diffuse alveolar haemorrhage due to anti-GBM disease. Although severe lung injury may exist, complete recovery is possible with immunosuppression, plasmapheresis together with mechanical ventilation and VV-ECMO support.

Disclosures

All authors declare no conflict of interest. No funding or financial support was received.

Informed consent was obtained from the patient for the publication of this case report and the accompanying images.