Alveolar hemorrhage associated with lupus nephritis
Print version ISSN 0102-3586
J.
Pneumologia vol.29 no.6 São Paulo Nov./Dec. 2003
CASE REPORT
Ricardo
Henrique de Oliveira Braga TeixeiraI; Marcel HiratsukaII;
Flávia Calderini RosaII; Rogério SouzaIII; Carlos Roberto
Ribeiro de CarvalhoIV
ABSTRACT
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.
Abbreviations
used in this paper:
GBM – Glomerular basement membrane
SLE – Systemic lupus erythematosus
PEEP – Positive end-expiratory pressure
ICU – Intensive care unit
Introduction
Diffuse
alveolar hemorrhage leading to respiratory failure is uncommon. Various
etiologies have been reported, including infections, inhaled toxins,
coagulation disorders, Goodpasture’s syndrome, microscopic polyangiitis and Wegener’s 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).
Case reports
Case 1
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.
Case 2
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.
Discussion
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 Goodpasture’s 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.
References
1. Bosch X,
Font J. The pulmonary-renal syndrome: a poorly understood clinicopathologic
condition. Lupus 1999;8:258-62. [ Links ]
2. Bar J,
Ehrenfeld M, Rozenman J, Perelman M, Sidi Y, Gur H. Pulmonary-renal syndrome in
systemic sclerosis. Semin Arthritis Rheum 2001; 30:403-10. [ Links ]
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 ]
5. Specks U.
Diffuse alveolar hemorrhage syndromes.Curr Opin Rheumatol 2001;13:12-7. [ Links ]
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 ]
