There is a general lack of understanding of the gap between, on the one hand, the “air side”, where the effective drug-related receptors are located and, on the other hand, the vascular compartment. When administered intravenously biological drugs like FVIIa do not reach the receptors in the alveoli, because they do not pass the alveolo-capillary membrane. “Biologics” refer to biologically manufactured drugs, similar to endogenously key signaling proteins, like FVIIa.
Traditionally, biologics are administered intravenously with the hope that a sufficient concentration of the drug reaches the specific receptors. This requires a high systemic concentration of the drug and is associated with a higher risk of adverse systemic effects than local application at the target site.
The syndrome of diffuse bleeding DAH
The diffuse alveolar hemorrhage (DAH) syndrome has a number of clinical characteristics similar to a number of well-pulmonary documented conditions like acute respiratory distress syndrome (ARDS), acute lung insufficiency (ALI), and bronchiolitis obliterans organizing pneumonia (BOOP) ().
Diffuse alveolar hemorrhage related to pulmonary receptors in perspective
For many years it has been known that even the air side of the lung has receptors. Rose et al made a functional study of the granulocyte macrophage colony stimulating factor (GM-CSF) receptor, documenting that it was necessary to inhale the drug in order to reach the receptor on the air side (). Intravenous administration of GM-CSF had no effect on the alveolar macrophages whereas the inhaled drug increased the number of macrophages with no interference with systemic monocytes.1
Figure 1 Local pulmonary administration of FVIIa into the airways ensures that the drug reaches its alveolar receptor TF. However, most importantly, taking into account the separation between the two compartments the “air side” and the “systemic (more ...)
In the normal airspace the hemostatic balance is skewed toward anticoagulation due to increased expression of plasminogen activator and low expression of tissue factor (TF). As soon as the lungs are exposed to an inflammatory process, the anticoagulatory state will swiftly be turned into a procoagulatory state – a primitive host defense reaction in order to stop the invasiveness of bacteria and to hinder bacterial multiplication and dissemination.2
On the air side a whole host of receptors are placed. The complex cross talk between the dynamic receptor expression and the overall effect is hard to predict. It is known that pulmonary receptors ensure pulmonary host defense, ie, the TF and GM-CSF-receptors, both placed on the airside isolated from the blood side.3
The different biologics must fulfill certain qualities in order to be able to penetrate the biological membranes. First of all the molecular size must be small, most likely smaller than 15–20 kDa, like insulin with a molecular size of 8 kDa. Secondly, the drug must be lipophilic in order to cross the alveolo-capillary membrane to reach the peripheral airways. However, no newly developed therapeutic recombinant drug fulfills the low size criteria in as much as all the wild type proteins are all hydrophilic FVIIa and GM-CSF.
Pathophysiology of DAH
DAH is characterized by damage to the alveolar-capillary basement membrane allowing red blood cells to enter the alveolar spaces. Most frequently DAH is a symptom of pulmonary capillaritis as seen in autoimmune diseases or after hematopoietic stem cell transplant (HSCT). DAH may also occur as a result of diffuse alveolar damage in acute respiratory distress syndrome/acute lung injury (ARDS/ALI). Further the damage may be the result of physicochemical factors like blast lung injury (BLI), toxic drug effects (eg, cytotoxic drugs, crack cocaine inhalation), and radiation therapy ().
Figure 2 The DAH syndrome is the common denominator of multiple diseases and conditions. DAH is the general alveolar response to multiple underlying diseases and conditions. The syndrome DAH manifests itself in three subsets: the acute catastrophic DAH, the chronic (more ...)
Epidemiology of DAH
In hematological stem cell transplantation (HSCT) recipients, DAH is an infrequent cause of death both in early and late phases after transplantation.5
DAH after HSCT is a devastating complication that carries an overall mortality of 16%–70%.7
As a result of life-threatening multiple organ dysfunctions, 15%– 40% of HSCT recipients receive intensive care unit support, the majority of whom require mechanical ventilation.9
The mortality rate of HSCT recipients receiving invasive ventilation used to exceed 90%.10
Although more recent studies have shown improvement in outcome, the mortality rate of HSCT recipients receiving mechanical ventilation is still high.10
It is estimated that 50,000 HSCT procedures took place in 2007 in the USA, and 80,000 worldwide, and that 25%–40% of HSCT recipients are admitted to the medical intensive care unit (ICU) for the management of pulmonary complications to HSCT.7
A considerable number of patients will also develop DAH due to other causes than HSCT, eg, infections, bronchoscopy, autoimmune diseases, HIV (Kaposi’s sarcoma), and transplantations, ie, DAH has been reported in 75% of patients with Kaposi’s sarcoma,18
in 66% of patients with SLE,19
5%–10% of patients with Goodpasture syndrome.20
Fatal DAH has been reported in approximately 10%–41% of lung autopsies of HSCT patients that succumbed to HSCT related complications.6
Further, DAH is reported to develop in 40% of patients admitted to the ICU for respiratory failure (ARDS/ALI). The annual incidence of ARDS/ ALI in the USA and EU admitted to ICU is over 500,000 patients.
The syndrome of DAH
The multiple causes of DAH are shown in 22
together with the treatment of the underlying cause of DAH and symptomatic treatment of the ongoing alveolar bleeding. Formerly, the management strategy was limited to the optimization of each of the specific diseases and underlying disorders as a prophylactic measure toward prevention of DAH syndrome. Most of such prophylactic interventions have been treatment with steroids, anti-infective measures, eg, anti-cytomegalovirus pneumonia therapy, plasmapheresis, platelet transfusion, and coagulation factors. These interventions are alone focused on prophylaxis of the stereotype syndrome alveolar bleeding.
Overview of diseasesyndromes and other causes leading to DAH and the classical options of treatment
The diagnosis of DAH
The algorithmic scheme is depicted in , based on the fact that the signs and symptoms are a common denominator of DAH, ARDS and BOOP: acute pulmonary insufficiency with reduced O2 transport capacity and confluent opacities on chest film. It is imperative to distinguish between the specific diagnoses of these conditions, and in as much as they have a very high mortality, it is of utmost importance to diagnose correctly because the specific therapies are different. The key to the diagnosis, as it appears in , is the finding of (i) a macroscopically progressively hemorrhagic aliquot in a series of bronchoalveolar lavage fluid (BALF) findings that denote a severe DAH syndrome, or (ii) measurements of an increased hemoglobin concentration in the BALF corresponding to a slow bleeding (pulmonary hemosiderosis), or (iii) absence of bloody return in the BALF excluding the DAH diagnosis. The remaining two conditions are separated by a simple flow-cytometry (FC) on the BALF, where the BOOP is characterized by abundant inflammatory cells, and the ARDS diagnosis is based on a BALF without inflammatory cells and without bloody return.
Figure 3 The diagnostic algorithm for DAH, BOOP and ARDS. The clinical signs and symptoms of DAH, ALI/ARDS and BOOP are identical, ie, chest film with confluent opacities, acute pulmonary insufficiency with reduced O2 transport capacity. It is imperative to separate (more ...)
DAH in childhood and adolescence
DAH occurs in any age group secondary to the same underlying diseases and conditions. However, the major difference is that the DAH syndrome is characterized by microscopic alveolar bleeding with chronic transfusion need. Hemoptysis is seldom. The chronic erythrocyte intraalveolar bleeding often surpasses the metabolic clearance of iron originating from the erythrocyte metabolism of the alveolar macrophage. This leads to an alveolar iron overload. These patients don’t have a considerable acute mortality, but a severely reduced long term life-expectancy due to pulmonary fibrosis secondary to accumulated iron in the alveolar space.
The idiopathic pulmonary hemosiderosis syndrome (IPH) is a DAH condition, however, without known underlying cause, ie, the incidence and prevalence of IPH is unknown. There are approximately 500 cases reported in the literature, primarily in children (80%). The etiology of IPH is not clear, in spite of many theories. Clinically, the signs and symptoms of IPH are identical to other microalveolar bleedings like the acquired pulmonary hemosiderosis secondary to known underlying diseases, ie, exacerbations concomitantly with cough, dyspnea to fulminant respiratory failure. The chronic state is accompanied with variable degrees of iron deficiency anemia, present in most patients. Spirometry shows a restrictive pattern due to pulmonary fibrosis in the chronic condition. Lung biopsies from both IPH and secondary pulmonary hemosiderosis patients often show severe thickening of the alveolar wall and hemosiderin-loaded alveolar macrophages that also appear in sputum.
The blast lung injury – a dynamic process with a “window of opportunity”
A blast lung injury (BLI) is based on the disruption of the alveolo-capillary membrane after an explosion, with a significant pressure wave entailing diffuse alveolar bleeding ().23
Table 3 Overview of BLI – a dynamic condition23
Based on the pathophysiology, BLI can be characterized into distinct phases of a dynamic process ().24
This leads to (i) diffuse bleeding and (ii) hemolysis which quantitatively surpasses the clearance rate of free iron (Fe++
) from the alveoli unless the diffuse alveolar bleeding is stopped early.
Table 4 After a major blast the three phases have their own distinct problems24–26
It seems that there is a “window of opportunity” of 3 hours in which the BLI is reversible (). If the hemorrhage is not brought to a halt, the severity of the pulmonary dysfunction increases over the next 4 days into irreversible BLI and fatal pulmonary failure. The BLI occurs when soldiers in the battlefield or the civilian population are exposed to bomb attacks. Inhalation of FVIIa is an obvious measure to treat the BLI within the window of opportunity, which could be an indication for use of FVIIa in respect to the military and homeland use, because BLI affects soldiers in the battlefield as well as victims of terror attacks.
Diffuse alveolar hemorrhage – the treatment paradigm
BLI – signs, symptoms and outcome
BLI secondary to high explosives causes life-threatening dysfunction of the lungs of soldiers exposed to a blast. The incidence of BLI is not known, but may be as high as 1000–5000 persons annually.
There are to date no reports of the prevalence of DAH in blast lungs because it is a military secret. BLI may occur in the absence of any external signs of trauma, as seen in a series of 517 blast casualties, where approximately 20% were immediately fatal.23
Treatment of DAH
Hitherto the separation between symptomatic intervention towards life threatening DAH and the optimization of the underlying disease has not been properly addressed – a fact which has caused confusion concerning the discussion of the best way to administer FVIIa as an intravenous infusion or as an airway deposition, ie, as a BALF administration or as an inhalation ().
Figure 4 It is essential to separate cause and the effect of DAH. It is important to separate the treatment of multiple underlying causes of DAH from the common complicating denominator DAH syndrome, because the latter is simply treated with local pulmonary FVIIa. (more ...)
A common denominator for these studies is that the trials generally have only a very small number of patients included, thereby evading proper statistical evaluation.27
In 2006 a study was published with a sufficient number of patients to reach a statistical significant effect of local FVIIa. Before this time treatment was a mixed intervention of questionable effect with steroids, anti-infective measures, plasmapheresis, platelet transfusion, and intravenous infusion of FVlla and other procoagulation factors in spite of the fact that DAH bleeding is not due to factor deficiency.29
As late as in 2011 it is still suggested that treatment of DAH should be based “on the underlying cause of hemorrhage, with corticosteroids as a mainstay of therapy in most cases”,22
despite of the first series of a systematic treatment of DAH with local intrapulmonary FVIIa in 2006.31
This study documented an effect of administering a small intrabronchial dose of FVIIa. The effect of intrabronchial lavage with a simple saline solution of FVIIa demonstrated (i) that no patient succumbed after the treatment due to alveolar bleeding, (ii) a significantly improved oxygen gas exchange (P
= 0.024), and (iii) a balanced hemostasis (P
= 0.031). These findings were subsequently reproduced by three later publications from three independent centers using the identical treatment protocol, however, each study had only a few patients included.32
None of the four studies adverse effects (AE) were reported, probably because there was no detectable transmembraneous FVIIa passage from the air side into the blood as evaluated by the prothrombin time. The pathophysiological understanding of the mechanism of action, the marked effect, and the fact that no patients died or were encountering adverse effects as a consequence of the local treatment with FVIIa was most likely the reason for being granted the orphan drug (OD) designation in both Europe (European Medicines Agency [EMEA]), Canary Wharf, London and secondly in the USA (Food and Drug Administration [FDA], Virginia, USA) in spite of the theoretical risk of intra-alveolar thrombotic complications, when treating DAH with FVIIa as a pulmonary deposition.22
However, the systemic administration of FVIIa for off-label use for the treatment of uncontrollable life-threatening hemorrhage has been increasing since the introduction of FVIIa (NovoSeven®
, Novo Nordisk A/S, Bagsværd, Denmark),35
but concomitantly a concern for potential thromboembolic complications has equally been increasing, especially after the publication of several meta-analyses recommending caution due to ongoing reports of fatal complications.36
A suggestion for the treatment of the three conditions, DAH, pulmonary hemosiderosis and blast lung injury, is shown in 31
based on published documentation.
Patients suffering from chronic DAH as IPH, often children, are at present generally placed on high-dose steroids, and then weaned to the lowest dose that keeps them from having exacerbations. The use of chronic high dose steroids is problematic because the treatment induces multiple adverse effects both in children but also in the adolescent. The 5-year mortality rate in pediatric patients ranges from 24% to 60%.38
Since no treatment is known at present to be effective, clinical trials with inhaled FVIIa are warranted. It is suggested that the end point could be a fall in numbers of hemosiderin-loaded macrophages in sputum combined with reduced transfusion need. Since FVIIa has a very high degree of efficacy in DAH and is without adverse effects, inhaled FVIIa in a small low daily dose will most likely serve as a prophylactic measure. Such a treatment scheme could make invasive procedures like single-lung transplantation superfluous as this treatment has shown no lasting effect because IPH recurred.38
However, to date no information on treatment of pulmonary hemosiderosis and BLI has been published. In as much as pulmonary hemosiderosis and BLI share the same pathophysiological background alveolar bleeding, treatment suggested in is an extrapolation from the published effective dose in DAH.
Every time the clinician encounters a condition where no documentation exists it should be considered whether the disease is worse than the treatment. In the case of using air side treatment of FVIIa in microalveolar bleeding, inhalation by a simple inhalation device seems to be the treatment of choice, ensuring swift deposition of FVIIa into the alveolar space, without the need for invasive procedures such as bronchoscopy. Using a micropump nebulizer ensures that there will not be any interference with the active site of the FVIIa molecule. The only documented case of inhalation of FVIIa by a micropump where the DAH has been treated with success was a patient with Wegener’s granulomatosis.31
The patient had been extubated a few hours earlier after a bout of hemoptysis and had presented with recurrence of the DAH through bloody tinged expectorate. Instead of reintubation she was treated with an FVIIa dose of 50 μg/kg BWT inhaled via a jet nebulizer. After 5 minutes the patient spontaneous exclaimed that the dyspnea had defervesced, and there were no further episodes of DAH.