**4.1 Diffuse alveolar hemorrhage**

DAH is a severe and life-threatening pulmonary complication of aPL. Inflammatory damage to the pulmonary microcirculation, namely to alveolar arterioles, capillaries, and venules, with subsequent necrotic changes and secondary hemorrhage, define the disorder [53]. A microscopic pathoanatomical picture typically reveals capillaritis with interstitial neutrophilic infiltrate, thrombi in small muscular pulmonary arteries, myointimal thickening, and the remodeling of the muscular pulmonary arteries and arterioles [53, 54]. The condition is rare and appears in less than 1% of all aPL-positive patients, though it is considerably more frequent and clinically relevant in those with CAPS, affecting 5–10% [54–57]. Both genders are affected, but males constitute approximately 2/3 of cases with primary APS, whereas women dominate the group with APS secondary to SLE [54]. The patients with DAH are more likely to have a higher titer of aPL and suffer from other comorbidities associated with aPL than those without DAH. Cardiac valve disease, pulmonary hypertension, livedo reticularis, skin ulcers, CNS involvement (stroke or seizure), and pregnancy complications are among the reported concomitant disorders [54, 57].

Several pathomechanisms are likely to participate in the damage of the alveolar structures in DAH in aPL-positive patients. aPL-mediated activation of endothelial cells, resulting in the increased expression of tissue factor, platelet, and complement activation with C5a-mediated neutrophil recruitment and the subsequent lung tissue injury is likely behind thrombi formation in the pulmonary microcirculation. aPL-induced systemic inflammatory response syndrome with the excessive cytokine activation (e. g. tumor necrosis factor-α, interleukin-1, interleukin-6, interleukin-18, macrophage migration inhibitory factor) as well as L-ficolininduced lung injury and interstitial neutrophilic infiltration lead to the loss of the integrity of the alveolar-capillary basement membrane. Disruption of alveolar structure and its veins through the combination of inflammation and thrombosis result in the extravasation of red blood cells into the alveoli [58].

The usual clinical presentation of DAH includes fever, chest pain, cough with hemoptysis, and dyspnea with the signs of hypoxemic respiratory failure [4]. However, not all symptoms, including hemoptysis, need to be present in every case. The symptoms are not specific and appear in other pulmonary diseases such as pulmonary embolism, pneumonia, and pulmonary edema. The complex differential diagnostics is of utmost importance. Laboratory and complementary tests are critical for the distinction of DAH. Anemia, aPL positivity, high diffusing capacity for carbon monoxide in pulmonary function tests, patchy or perihilar opacities on the chest X-ray and signs of hemorrhage, ground-glass infiltrates, and reticular interstitial opacities on pulmonary CT scans belong to the typical findings. Bronchoscopy with bronchoalveolar lavage and biopsy can document alveolar hemorrhage, exclude infections, and provide biological material for cytologic and histologic evaluation. Lung biopsy remains the gold standard for the definitive diagnosis, albeit the patient′s condition and benefit–risk ratio should be evaluated before the procedure. As mentioned above, DAH is quite frequently associated with CAPS. Treating physicians should actively search for its signs in all cases.

Immune suppression remains the mainstay of the therapy. High-dose corticosteroids are the preferred initial treatment. The use of other immunosuppressives remains without a clear consensus due to the rarity of the condition and limited clinical data. However, available clinical data support the combined immune suppression (corticosteroids plus another immunosuppressive agent) over monotherapy with corticosteroids. The combined therapy seems to improve the clinical outcome and rate of long-term remission. Cyclophosphamide and rituximab have been showing encouraging results, whereas mycophenolate mofetil and azathioprine seem to be less effective [4]. Other therapeutic modalities that could be beneficial, especially in the presence of underlying CAPS, include plasma exchange and IVIg.
