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On-line version ISSN 1678-4642
J. Pneumologia vol.29 no.6 São Paulo Nov./Dec. 2003
Ricardo Henrique de Oliveira Braga TeixeiraI; Marcel HiratsukaII; Flávia Calderini RosaII; Rogério SouzaIII; Carlos Roberto Ribeiro de CarvalhoIV
IIClinical Medicine Resident in the Pulmonology Department
IIIPh.D. , Attending Physician in charge of the Pulmonary Hypertension Group, and TE-SBPT (Specialist, as designated by the Brazilian Society of Pulmonology and Phthisiology)
IVAssociate Professor , Director of the Respiratory ICU, and TE-SBPT (Specialist, as designated by the Brazilian Society of Pulmonology and Phthisiology)
Alveolar hemorrhage leading to respiratory failure is uncommon. Various etiologies have been reported, including systemic lupus erythematosus, which generally presents as pulmonary-renal syndrome. It is believed that the pathogenesis of microangiopathy is related to deposits of immune complexes that lead to activation of cellular apoptosis. We report two cases of alveolar hemorrhage and respiratory failure, both requiring mechanical ventilation. The two cases had opposite outcomes after pharmacological therapy. In one of the cases, the presence of anti-glomerular basement membrane antibodies demonstrates the multiplicity of physiopathological mechanisms that may be involved. This multiplicity of mechanisms provides a possible explanation for the heterogeneous responses to the available treatments.
Key words: Lupus erythematosus systemic/etiology. Lupus nephritis/etiology. Respiratory insufficiency/complications.
used in this paper:
GBM Glomerular basement membrane
SLE Systemic lupus erythematosus
PEEP Positive end-expiratory pressure
ICU Intensive care unit
Diffuse alveolar hemorrhage leading to respiratory failure is uncommon. Various etiologies have been reported, including infections, inhaled toxins, coagulation disorders, Goodpastures syndrome, microscopic polyangiitis and Wegeners granulomatosis, as well as various types of collagenosis, such as scleroderma and systemic lupus erythematosus (SLE).(1,2)
Pulmonary-renal syndrome is characterized by the occurrence of both alveolar hemorrhage and glomerular nephritis and is frequently associated with the presence of antineutrophil cytoplasmic antibodies or anti-glomerular basement membrane (anti-GBM) antibodies. The type of injury, (alveolar, glomerular or both) determines the evolution and prognosis of the syndrome.(1)
A diagnosis of alveolar hemorrhage is made through the identification of acute pulmonary symptoms. Such symptoms include hemoptysis, new alveolar infiltrate (seen in chest radiographs), lower concentrations of hemoglobin and the presence of blood or hemosiderin-laden macrophages in bronchoalveolar lavage fluid, although diagnosis can be made in the absence of some of these symptoms.(1,3)
In SLE patients, diffuse alveolar hemorrhage is quite uncommon, occurring in only about 2% of cases, and is often associated with higher mortality rates. In most cases, concomitant renal involvement is also observed.(3)
We report 2 cases of lupus nephritis-related alveolar hemorrhage treated between June and August of 2002 in the respiratory intensive care unit (Respiratory ICU, Hospital das Clínicas, University of São Paulo School of Medicine).
The patient was an 18-year-old female patient who, due to cutaneous and articular symptoms, had been diagnosed 2.5 years prior with SLE, for which she was being treated with 250 mg of chloroquine/day.
Without consulting a physician, the patient suspended her medication at 1 month prior to admission, consequently developing progressive dyspnea (even during minimal exertion) and muscle weakness. In addition, 4 days before admission, she began to suffer from diuresis. She was taken to the emergency service after an acute attack of dyspnea.
The patient presented with intense pulmonary discomfort, tachypnea (30 breaths per minute), and hypoxemia (88% oxygen saturation in room air). She claimed to have no expectoration. A chest radiograph revealed bilateral alveolar infiltrate and small pleural effusions (Figure 1A). Laboratory tests showed anemia, normal leucocyte counts, impaired renal function and evidence of active inflammation. Since there was no clear evidence of infection, alveolar hemorrhage was suspected.
The patient was transferred to the ICU and submitted to non-invasive ventilation. Intubation was considered necessary due to her worsening condition. Bronchoalveolar lavage was performed and cultures obtained. The cultures tested negative, which is indicative of alveolar hemorrhage. The ventilation was adjusted to allow up to 22 cm H2O of positive end-expiratory pressure (PEEP), with partial response in the oxygenation. Intravenous methylprednisolone was administered as pulse therapy and the chloroquine was maintained. Since the patient did not respond, she was submitted to plasmapheresis for 3 days, and cyclophosphamide was introduced for immunosuppression. After new episodes of bleeding, gamma globulin was administered. However, none of these procedures had any effect on the bleeding episodes, which continued to occur every 3 to 7 days.
Upon admission, the patient had presented compromised renal function, evidenced by disproportionately increased levels of creatinine (urea = 60 mg/dL; creatinine = 2.1 mg/dL). This condition worsened over the course of treatment, despite fluid replacement and the previously described immunosuppression therapy. From day 42 onward, the patient required dialysis. On day 61 of treatment, intracranial hypertension was detected, and computer tomography scans revealed a large area of ischemia in the right cerebral hemisphere, with intense edema and mid-line shift. The patient underwent decompressive craniectomy, but died during the immediate post-operative period.
A 40-year-old female patient had, 17 years earlier, been diagnosed with SLE. Since then, she had been suffering from malar erythema, serositis and arthritis in both the large and small joints. In addition, she had developed renal involvement, including proteinuria and reduced creatinine clearance (40 mL/min). During that time, a renal biopsy was performed, revealing membranous and mesangial glomerulopathy.
Her renal function continued to deteriorate until 5 years prior to her admission to our hospital, at which time partial improvement was achieved through the use of pulse therapy with cyclophosphamide. A regime of mycophenolate mofetil was initiated 2 years later (3 years prior to being admitted to our hospital).
At 1 month before admission to our hospital, her renal function worsened. Proteinuria, dyslipidemia, generalized edema (anasarca), and anuria were all increased and she required hospitalization. Pulse therapy with methylprednisolone was administered, to no effect. She was then given pulse therapy with cyclophosphamide. Again, there was no improvement, and a program of hemodialysis was initiated.
Upon admission to our facilities, the patient presented progressive dyspnea and decreased hemoglobin, as well as alveolar infiltrate in the chest radiograph (Figure 2A). After hemoptysis and a drop in arterial saturation, as well as a severe episode of tachypnea, were observed, the patient was transferred to the ICU. She was intubated and submitted to bronchoscopy with bronchoalveolar lavage, which revealed bleeding. Cytological examination of the bronchoalveolar lavage fluid revealed hemosiderin-laden macrophages, confirming the diagnosis of alveolar hemorrhage.
While in the ICU, ventilation was set at 18 cm H2O of PEEP and a tidal volume of 6 mL/kg, and there were not other bleeding episodes. Ventilation was maintained for 5 days and there was a rapid improvement in her respiratory pattern. She was then extubated and ventilation was maintained through use of an oxygen mask in combination with periods of non-invasive ventilation. Until the patient was discharged from the ICU, she was under monotherapy with prednisone.
Although SLE-related alveolar hemorrhage is quite uncommon (found in only 2% of lupus patients), the prognosis is always negative and the mortality rate is between 70 and 90%.(1,4) Histological studies have shown that, in about 70% of pulmonary biopsies, there is little inflammatory activity and a predominance of hemorrhagic characteristics, whereas, in the remaining 30%, histological changes are compatible with neutrophilic capillaritis or diffuse alveolar damage.(4)
In approximately 75% of SLE-related alveolar hemorrhage cases, immunocomplex deposits have been observed in the alveolar wall.(4) However, other histological studies have shown that most cases are characterized by hemorrhage involving minimal inflammation (with neutrophilic capillaritis in only 7% of cases).(5)
Under electron microscopy, immunocomplex deposits, characteristic of class IV lupus nephritis, are seen in the alveolar wall. In cases involving renal microangiopathy, such deposits are found in the subendothelial region of the glomerular capillary basement membrane. In the literature, most cases of renal microangiopathy have been attributed to class III or IV lupus nephritis. Evidence of microangiopathy is uncommon in class II (mesangial) or V (membranous) lupus nephritis, except when an increase in SLE activity leads to impaired renal function.(3,4)
In our study, both patients presented an acute reduction in renal function. In order to evaluate autoimmunity in these 2 patients, we measured titers of anti-glomerular basement membrane (anti-GBM) antibodies, which are associated with Goodpastures syndrome and are considered to be one of the most prevalent indicators of pulmonary-renal syndrome.
Although anti-GBM titers were undetectable in case 1, it must be taken into consideration that the patient had already been treated with pulse corticosteroid therapy, immunosuppressant drugs and plasmapheresis, all of which may have affected titer determination. In case 2, in which the patient presented class V-type renal lesion, anti-GBM titers were significant. Although, histologically speaking, this is not the most common type of SLE-related microangiopathy, progression to the proliferative type is possible, in which case the impaired renal function would be expected.
However, it is still not possible to identify all factors responsible for the lesion related to the alveolar hemorrhage, or for the SLE-related renal microangiopathy. Neither is it possible to identify which factors might be responsible for the different outcomes in both patients, especially for the differing responses to the immunosuppression therapy. However, similarly divergent patient responses have been seen in other forms of vasculitis involving pulmonary complications.(6)
Nevertheless, the use of protective strategies, such as maintaining low tidal volumes and high levels of PEEP during mechanical ventilation, might be fundamental in treating patients with symptoms of severe respiratory insufficiency. In a study involving respiratory distress syndrome patients, including some with leptospirosis-induced alveolar hemorrhage and other forms of pulmonary vasculitis, the use of such ventilation strategies led to lower mortality rates.(7)
Despite the fact that this condition is rare, early diagnosis and the introduction of measures for respiratory system protection might be beneficial in cases of SLE-related alveolar hemorrhage. In addition, greater understanding of the physiopathology of this condition could lead to the development of more effective pharmacological treatments.
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3. Lee JG, Joo KW, Chung WK, Jung YC, Zheung SH, Yoon HJ, et al. Diffuse alveolar hemorrhage in lupus nephritis. Clin Nephrol 2001;55: 282-8. [ Links ]
4. Hughson MD, He Z, Henegar J, McMurray R. Alveolar hemorrhage and renal microangiopathy in systemic lupus erythematosus. Arch Pathol Lab Med 2001;125:475-83. [ Links ]
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6. Lauque D, Cadranel J, Lazor R, Pourrat J, Ronco P, Guillevin L, et al. Microscopic polyangiitis with alveolar hemorrhage. A study of 29 cases and review of the literature. Groupe d'Etudes et de Recherche sur les Maladies "Orphelines"Pulmonaires (GERM"O"P). Medicine 2000;79: 222-33. [ Links ]
7. Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998;338: 347-54. [ Links ]
Serviço de Pneumologia do HCFMUSP, Av. Dr. Enéas de Carvalho Aguiar, 255, sala 7.079
05403-900 São Paulo, SP
Phone. (11) 3069-7202
Submitted: 28/4/03. Accepted, after revision: 31/7/03
* Study carried out in the Pulmonology Department Respiratory ICU, University of São Paulo School of Medicine, SP