CLINICOPATHOLOGIC CONFERENCE
Systemic Lupus Erythematosus with Postpartum Pulmonary Disease
Stenographic reports, edited by Philip E. Cryer, M.D. and John M. Kissane, M.D., of weekly clinicopathologic conferences held In Barnes and Wohl Hospitals, are published in each issue of the Journal. These conferences are participated in jointly by members of the Departments of Internal Medicine, Radiology and Pathology of Washlngton University School of Medicine. A 22 year old Caucasian woman was admitted to Barnes Hospital on July 17, 1977, because of shortness of breath. She died 17 days later. The patient was overtly well until arthralgias developed in January 1976. Her physician noted a facial rash and swelling of the proximal interphalangeal joints, wrists and knees, and diagnosed systemic lupus erythematosus (SLE). Antinuclear antibodies, with homogeneous and rimmed nuclear staining patterns, were positive at a I:90 serum dilution. After a short course of steroid therapy, the patient felt well. In April 1977, during her sixth month of pregnancy, a urinalysis disclosed 2-t proteinuria and 15 to 20 red blood cells/per high power field (hpf) in the urine sediment. Serum findings included a 3-I positive antinuclear antibody test, with homogeneous and rimmed staining patterns, the presence of anti-DNA antibodies, cryoglobulinemia and depessed complement levels. The creatinine clearance was 98 ml/min, and the urine protein excretion was 0.5 g/24 hours. It was planned to perform a renal biopsy after delivery of her child. Pregnancy and delivery, on July 13, 1977, at another hospital were uneventful. Although the patient complained of cough and substernal chest pain, she was discharged three days postpartum. She experienced increasingly severe, nonpleuritic chest pain and shortness of breath, and her cough became productive of yellow sputum which became blood-tinged and then grossly bloody over the course of one day. She was hospitalized and found to have “pneumonia” and a hematocrit value of 22 per cent. She was given 4 U of blood and transferred to Barnes Hospital on July 17, 1977. Physical findings in the emergency room included a blood pressure of 170/100 mm Hg, a pulse rate of 150/min, a respiratory rate of 361 min and a temperature of 38.7’C. She was in marked respirat&y distress and was deeply cyanotic. There were bilateral pulmonary rales, and a gallop rhythm was noted, but there was no cardiomegaly. The uterus was palpable 4 cm above the symphysis pubis. The neurologic examination was within normal limits.
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Initial laboratory data included a white blood cell count of 41,900/mm3 with a shift to the left; the hematocrit value was 36.8 per cent and the hemoglobin level 12.6 g/dl. The serum creatinine was 4.3 mg/dl and the bicarbonate 11.4 meq/liter. While receiving nasal oxygen at a rate of 4 litersimin, the arterial oxygen tension (PO,) was 22 mm Hg and the pH 7.3 1. Chest roentgenograms revealed diffuse pulmonary infiltrates, greatest at the bases of the lungs. An electrocardiogram showed sinus tachycardia. Examination of the sputum disclosed only a few white blood ceils and bacteria, but there were many red blood cells. The patient was intubated and admitted to the Coronary Care Unit. An episode of ventricular tachycardia was treated by cardioversion. A Swan-Ganz catheter was inserted; the mean pulmonary artery and pulmonary wedge pressures were 23 and 18 mm Hg, respectively. Hydrocortisone, 1.0 g every 6 hours, oxacillin and gentamicin were administered, as were diuretics, to maintain the pulmonary wedge pressure at approximately 10 mm Hg. Positive pressure assisted ventilation, with 100 per cent oxygen, was applied and bronchodilators were also given. Despite pneumothoraces, for which the patient required the insertion of chest tubes, and the subsequent development of subcutaneous emphysema, her respiratory status gradually improved. All bacterial cultures were negative, and the administration of oxacillin and gentamicin was discontinued on the seventh hospital day. Leukocytosis persisted. The pulmonary infiltrates cleared and by the 10th day the arterial PO2 was 70 mm Hg while she was breathing room air. This portion of the patient’s course was complicated by an increase in the serum creatinine to 7.5 mg/dl (hemodialysis was begun) and progressive anemia (a total of 12 U of blood was given). Coagulation studies were initially normal, including a prothrombin time of 90 per cent, but the prothrombin time subsequently decreased to 43 per cent although the partial thromboplastin time remained normal. A few fragmented red blood cells were noted on peripheral blood smears, the platelet count decreased to 27,000/mm3 and fibrin degradation products were present at a 1:8 dilution. Total hemolytic complement (28.5 U), the third component of complement (C3, 58 mg/dl) and the fourth component of complement (C4, 8.4 mg/dl) levels in the serum were low. On July 27, the patient appeared to be doing relatively well and she was transferred from the Coronary Care Unit to the Medical Intensive Care Unit. Subcutaneous emphysema, a few bibasilar rales and pharyngeal ulcerations with overlying white patches were noted. Gram stain and potassium hydroxide study of material from these areas were negative as were fungal cultures. Therapy with hydrocortisone was discontinued and the
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administration
of prednisone,
600 mg every
8 hours,
was begun. Later that day the patient had a grand mal seizure. The arterial PO2 was 52 mm Hg with a pH of 7.50 and a carbon dioxide tension (PCO2) of 36 mm Hg. Neurologic examination, lumbar puncture, computed tomographic scans of the head and an electroencephalogram disclosed no abnormalities. Phenobarbital was administered. On July 30, dyspnea increased and the arterial PO2 decreased despite increased inspired oxygen; diffuse pulmonary infiltrates reappeared on chest films. Because of inspiratory stridor the patient was treated with epinephrine. A nasotracheal aspirate revealed gram-positive cocci and gram-negative rods; a potassium hydroxide preparation was negative. Cultures of the sputum and blood were obtained, and gentamicin, oxacillin and parenteral glucocorticoid therapy was reinstituted. Moderate growth of Enterobacter from the sputum cultures and gram-positive cocci from one blood culture bottle only were subsequently reported. Tracheal intubation was required on July 31. Bronchoscopy showed that the plaque-like lesions extended down the trachea. Transbronchial lung biopsy specimens showed no fungi, bacteria or pneumocystis organisms; however, intranuclear inclusion bodies were seen. The patient was transferred to the Respiratory Intensive Care Unit where positive pressure ventilation with 100 per cent oxygen was required to maintain arterial PO2 above 50 mm Hg. The administration
the of
Adenine Arabinoside (ARA-A), 10 mg/kg every 12 hours, was begun on August 2. Progressive hypotension (despite the infusion of dopamine), acidosis and coma led to the development of an idioventricular rhythm, and the patient died on August 3, 1977 CLINICAL
DISCUSSION
Dr. J. Russell Little: This 22 year old woman was found to have SLE in January 1976. In April 1977, while pregnant, she was found to have proteinuria, microscopic hematuria and low serum complement levels. Renal biopsy was deferred because of the pregnancy. A normal baby was delivered on July 13. Pulmonary symptoms developed, and the patient was admitted to Barnes Hospital with severe hypoxemia, anemia and advancing azotemia on July 17, five days postpartum. Vigorous therapy-including the administration of antibiotics, large doses of glucocorticoids, bronchodilators and diuretics, and the use of assisted ventilation with 100 per cent inspired oxygen-led to clinical improvement with nearly normal arterial PO2 levels and clearing of pulmonary infiltrates. However, on the 10th hospital day a seizure occurred, and pulmonary symptoms, hypoxemia and pulmonary infiltrates recurred. A lung biopsy specimen showed only intranuclear inclu-
SYSTEMIC
LUPUS ERYTHEMATOSUS
WITH POSTPARTUM
PULMONARY
DISEASE
Figure 2. Chest film obtained nine days after admission showing nearly complete resolution of air space disease. Figure lateral lobes.
1. Chest film obtained on admission showing biair-space disease, predominently in the lower
sion bodies. Despite all therapeutic efforts, the patient died 18 days after admission. Dr. Levitt, would you summarize the roentgenographic findings? Dr. Robert Levitt: The chest film taken on admission (Figure 1) demonstrated bilateral air space disease, predominantly in the lower lobes. The differential diagnosis of acute air space disease includes pulmonary exudate, transudate, or hemorrhage. In patients with acute lupus pneumonitis the chest film is characterized by such an air space disease with predilection of the lung bases [ 11. The chest film obtained on day nine (Figure 2) showed nearly complete resolution of the pulmonary infiltrates. Rapid clearing of pulmonary infiltrates in patients with acute lupus pneumonitis treated with corticosteroids has been reported. In one series, the chest film showed complete clearing in one half of the patients who survived the acute illness. In the other half, the disease progressed to chronic interstitial pneumonitis [2]. On the 10th hospital day the patient began to experience dyspnea, and a chest film showed new pulmonary infiltrates. A chest film taken on day 16 (Figure 3) revealed diffuse air space consolidation and extensive subcutaneous emphysema, secondary to a closed tube thoracostomy for pneumothorax. The differential diagnosis of this air space consolidation is unchanged from the differential diagnosis of the chest film obtained on admission. Infectious agents which produce this roentgenographic pattern include Pneumocystis carinii, viral agents and gram-negative bacteria. Dr. Little: I think the films very nicely illustrate what I think was the over-riding feature of this patient’s illness
during her hospitalization here and that is its biphasic nature. That is to say, she presented catastrophically ill with very serious pulmonary disease and then went through a period of marked improvement at which time her chest film was essentially within normal limits, and she was comfortable. After that brief period of dramatic improvement, the overwhelming pulmonary disease recurred and the patient’s general clinical state returned to a condition very much like that with which she had presented initially. It is this biphasic character, along with certain other features of the second phase of her illness, which constitutes for me the major puzzle. Must we entertain other diagnoses beyond that of SLE? Were there at least two or more processes occurring more or less simultaneously, or can we successfully relate all the features of her illness to disease activity consistent with SLE?
Figure 3. Chest film obtained on day 16 reveals diffuse air space consolidation and extension subcutaneous emphysema.
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The first question that I would like to discuss is one which surely must have been very prominent at the time of her admission to Barnes hospital. That is whether or not the pulmonary insufficiency syndrome with which she presented could have been explained on the basis of her underlying SLE. Dr. Atkinson, would you please review the patient’s serologic data available upon admission and direct your attention to whether or not the serologic activity in SLE can be used as an accurate reflection of disease activity, or are there conspicuous dissociations? Also, would you discuss the effects of pregnancy on disease activity in SLE? Dr. John Atkinson: First, regarding the serology, the serologic findings in this patient in most instances correlate with active clinical disease and a relatively poor prognosis. She had high titer, rimmed and homogeneous ANA, markedly increased antibody titers to DNA, decreased complement concentrations and cryoglobulins. There are exceptions to these generalizations because we do see patients with active disease and minimal serologic abnormalities, or minimal disease activity and serologic findings such as those in this patient. However, the serologic results in this case strongly suggest an active disease process and one that in all likelihood is going to become worse. These serologic data, combined with the proteinuria and miscroscopic hematuria, suggest that treatment and careful follow-up are needed. Regarding your second point concerning the relationship between SLE and pregnancy, there are a number of interesting questions to be addressed [2,3]. Dr. Robert Zurier has recently reviewed the subject of SLE and pregnancy [3], and in his article he comments on most of the points which I will now briefly summarize. First, do women with SLE become pregnant? In most studies the fertility rate of women with SLE is similar to that of normal women [4], with the major exception being, as would be expected, patients who have poorly controlled active SLE. Second, will pregnancy make SLE worse? Several studies pertinent to this question have been published [2-lo]. In about one half of the patients there is no marked change in the course of the disease, in about one-third the disease becomes worse (especially during the first trimester), and in a small percentage the disease subsides or diminishes (particularly during the last trimester). However, most frequently an exacerbation occurs in the postpartum state; I will have some more to say about this problem. A third question relates to what effect SLE will have on the baby. In most series there is a definite increase (two-to-three-fold) in prematurity and spontaneous abortion. In well controlled patients, these complications are lower and not unacceptable. In fact, the usual outcome of a pregnancy involving a patient with SLE in remission is an uneventful pregnancy and
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a normal baby. Fourthly, what about the use of corticosteroids in pregnant women? Although in animals these agents cause fetal abnormalities, particularly cleft palate, several hundred babies have been born to women with SLE who were taking 20 mg or more of prednisoneiday; so far, there is no evidence of teratogenie effects of these agents in man. A fifth and very interesting question relates to whether or not the baby will have SLE at birth or a greater risk for the development of SLE. I am not aware of a situation in which the mother had SLE and clinical SLE developed in the baby. Not surprisingly, some babies have positive LE preparations and ANA tests since IgG antibodies cross the placenta. In addition, there has been at least one well documented case of an infant in whom transient skin lesions developed compatible clinically and pathologically with discoid lupus. I am not aware of an increased frequency of SLE in daughters born to mothers with SLE. I would now like to make a few comments concerning the postpartum period. About 30 to 50 per cent of the patients have a major flare in disease activity anywhere from a few days to up until eight weeks after delivery. It is often a severe exacerbation, and the pattern of involvement is no different from what one usually sees in patients with active SLE. In all series, the most common problem was the development or worsening of lupus nephritis. Dr. Little: With the fine image provided with the retrospective vision, would you have handled things differently during this patient’s postpartum exacerbation? Dr. Atkinson: This patient has been presented at at least two other conferences and Grand Rounds, so a number of physicians have discussed her clinical course and treatment program. At the time of her admission it was the belief of the responsible physicians that she had sustained an acute diffuse alveolar injury which was secondary to SLE. Other possibilities were also considered, as will be discussed by Dr. Lefrak. Therapy was immediately instituted with high dose steroids. In retrospect, I believe large quantities were indicated initially but that their administration may have been continued for too long. Perhaps a marked reduction at day 4 or 5, when it was clear that she was improving, would have been the correct manuever. However, at apparently the same time that the decision was made to rapidly taper the dose of steroids to a maintenance dose, the clinical course gradually began to deteriorate and for several days the cause of the change in events (exacerbation of SLE pulmonary disease versus a superinfection) was unclear. Dr. Little: How about antepartum? If you had seen this patient, would you have managed her differently during the last trimester?
SYSTEMIC
Dr. Atkinson: Although we do not have many details during the week immediately preceding delivery, according to both the patient and her obstetrician there were apparently no alterations of note in her clinical course. There are reports of patients who have been * “covered,” because of worsening serologic data or in hopes of preventing a flare of the renal disease, with steroids during delivery and the immediate postpartum period [3, lo]. In view of the outcome in this case, and apparently better results with steroid coverage, more aggressive therapy during the pregnancy and immediate postpartum period may have been indicated. For example, if this patient had not been pregnant, I am sure that the abnormalities of renal function coupled with the serologic findings that were documented at the time of her initial admission to this hospital would have caused her physician to begin corticosteroid therapy. Since there is no convincing evidence of a teratogenic effect of steroids in man, there is no reason to withhold such therapy when the indications for its use are good during pregnancy. Dr. Little: Despite the fact that this patient was febrile immediately postpartum and at the time of her admission to the hospital, I could find no evidence that a pelvic examination was carried out on her either on admission or at any subsequent time. In view of that I do not know what we can say about the possibility that she may have had an infection in her pelvis. I would be just delighted, Dr. Atkinson, if you could tell me that we do not need to worry about her white blood cell count of 42,000/ mm3 because it is a common feature of patients with SLE who present with severe, rapidly progressive activity. Dr. Atkinson: I do not have a novel explanation for this high white cell count. Because of an inexplicable change in the nature of the immune complexes and/or in the host’s milieu associated with the postpartum state, I would hypothesize that in this patient large quantities of immune complexes were deposited in the lung. These complexes initiated an acute inflammatory response which, in turn, produced the acute diffuse alveolar injury pattern. Thus, at least part of the increased white blood cell count was secondary to the host’s response to the pulmonary injury. Many patients with SLE respond quite normally to inflammatory stimuli, and most are not neutropenic. Dr. Little: I will continue to be worried about infection because I do not really know how to explain the leukocytosis. Leaving aside for a moment the strong evidence supporting SLE activity, Dr. LeFrak, I would like to ask you to review the findings in our patient at the time of admission relevant to her pulmonary disease. I would also like to have your comments on two diagnoses of conditions that nobody thought she had, namely, am-
LUPUS ERYTHEMATOSUS
WITH POSTPARTUM PULMONARY
DISEASE
niotic fluid embolism and multiple pulmonary emboli, and your comments on another diagnosis of a condition that everybody agreed she had, namely, the adult respiratory distress syndrome. Dr. Stephen Lefrak: Amniotic fluid embolism is very unlikely. In some series, as many as 10 per cent of all maternal deaths are credited to amniotic fluid embolism. But it is a very acute, catastrophic illness that occurs either during labor or immediately thereafter and is characterized by diffuse bleeding from all orifices. This woman had an apparently normal delivery and went home; the illness gradually developed over four days. Pulmonary embolism is a consideration, but it does not fit the clinical picture. First, it is very unusual for patients with pulmonary emboli to present with pulmonary edema or bilateral pulmonary infiltrates. Second, the Swan-Ganz catheterization data indicate that her modest pulmonary artery hypertension was attributable to cardiac failure. Furthermore, if her severe hypoxemia was due to a massive embolus, I would expect the pulmonary artery pressure to be much higher. The adult respiratory distress syndrome or, as I like to call it, acute alveolar injury, is basically a syndrome characterized by diffuse pulmonary infiltrates, resistant hypoxemia and marked dyspnea. The accumulation of fluid in the alveoli is a central feature of adult respiratory distress syndrome. Normally, the intracapillary hydrostatic pressure is only partially countered by the oncotic pressure and some fluid moves from the capillaries into the interstitial spaces: this normally drains into the lymphatics. The accumulation of large quantities of intraalveolar fluid can be due to a major increase in interstitial fluid (increased capillary hydrostatic pressure, decreased capillary oncotic pressure, decreased lymphatic drainage) or damage to the alveolar epithelial cells, or both. In the patient under discussion, the increment in hydrostatic pressure and the decrement in oncotic pressure were small and there was no reason to suspect lymphatic obstruction. Thus, damage to the alveolar epithelial cells is the most likely explanation for the pulmonary edema. Dr. Little: Most of the time it seems to me that patients with adult respiratory distress syndrome have transudation of fluid without conspicuous bleeding into the alveolar spaces. Our patient, I believe, had extensive intraalveolar bleeding and I would take that to be the cause of her gross hemoptysis. Does that give us any kind of etiologic clues concerning the distinction between those patients who just have intraalveloar edema and those who have bleeding? Dr. Lefrak: It is unusual for people with adult respiratory distress syndrome to have hemoptysis unless they have vasculitis, Goodpasture’s syndrome or idiopathic pulmonary hemosiderosis. On the other hand, let us not
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forget that patients with pulmonary edema are characterized by coughing up pink fluid; one can find blood in their sputum. Patients with mitral stenosis will frequently cough up red blood. But, clearly, if you have gross hemoptysis, we think of different sorts of things. Dr. Little: Dr. Atkinson, I have had a great deal of difficulty knowing how to think about the lung lesions of SLE. Some series would have us believe that the frequency of pulmonary involvement in patients with lupus is extraordinarily high (over 50 per cent) and those are largely series in which pleuritis is included among the criteria used to determine that a patient with SLE has pulmonary involvement. In other series diagnostic criteria are restricted to parenchymal lung disease and indicate that the frequency of lupus lesions is very low. Which is true? And is the pulmonary parenchymal disease in SLE a vasculitis? Dr. Atkinson: Pulmonary
involvement
in SLE is com-
mon. The most common pulmonary clinical manifestations are pleuritis and pleural effusions [2]. Of course, similar pulmonary manifestations occur in rheumatoid arthritis and many other collagen vascular diseases. In autopsy series, ctose to 100 per cent of the patients with SLE have pulmonary involvement. In the patient under discussion, I believe she had an unusual pulmonary manifestation of SLE, acute lupus pneumonitis leading to diffuse alveolar injury. In a recent article the data on 12 patients who presented with this type of picture were reviewed [ 11. Of these 12 patients, six patients died (three of pulmonary insufficiency and one each of pulmonary embolus, nocardial superinfection and central nervous system vasculitis). One patient is alive but has a severe restrictive pulmonary defect, and two other patients continue to have persistent infiltrates. Only three of the 12 patients made a complete recovery. None of the patients was postpartum, and I have been unable to find a case similar to the one under discussion today. Thus, this type of diffuse pulmonic involvement therapy.
is quite uncommon.
It is often lethal despite
Dr. Little:
Among patients who die of SLE, would you say that renal disease still heads the list of critical organ involvement leading to death? Dr. Atkinson: Renal disease is still the most common cause of death. Infections would rank second and central nervous system involvement third. A wide variety of other lethal events in SLE have been described including colonic perforations, pulmonary insufficiency, cardiovascular problems and a number of others. Dr. Little: Lupus lung disease of a noninfectious variety would be very low on the list of causes of death in SLE. Our patient had SLE, severe lung disease and renal failure; suddenly she had a seizure, some abnormal red
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cells on her peripheral smear and recurrence of her pulmonary disease. Dr. Sherman, this patient’s prothrombin time, which was normal on admission, became prolonged during the last few days of her hospital course; she had fibrin split products, and fragmented and helmet cells on her peripheral smear. Surely, she had disseminated intravascular coagulation. Dr. Laurence Sherman: I think that there is a fair likelihood that she had intravascular coagulation. One of the questions is whether or not it was disseminated. If you look at the beginning of this woman’s course, had several risk elements for a thrombotic process. was postpartum and she had SLE. I think there possibility that she had pulmonary thrombi at the
she She is a time
of admission. Obviously, if present, it was a minor part of her respiratory problem. The reason I say that, is that one would suspect that if she had intravascular coagulation it was related to her vasculitis. The major manifestation of her lupus was in the lung and was probably vasculitis. Ordinarily, in connective tissue diseases, when intravascular coagulation and microangiopathic changes occur in a localized manner, they are frequently localized in the kidneys. One sees rapidly advancing renal problems. This was best exemplified in the series of Brain and his co-workers some years ago [ 111. In such circumstances, the fragmentation of the red cells by fibrin leads to release of red cell thromboplastin that would accelerate the clotting system leading to further fibrin deposition, further fragmentation, etc. But the primary event in this sort of situation is most likely a vascular problem. One would suspect that in our current patient, it was localized in the lungs. Even though I raised the possibility of thrombi initially, that possibility is minor. The changes in her blood findings and the vasculitis would make one suspect that her course was complicated towards the end by pulmonary thrombi and that this was secondary to her SLE. Dr. Little: When you say the primary event in this kind of setting is likely to be related to a vasculitic process, do you include immune complex deposition as a primary event leading then to what is referred to as vasculitis, even though sometimes it shows only a minimal local accumulation of inflammatory cells?
Dr. Sherman: Yes. Dr. Little: Do you think we have to worry at all about the presence
of an anticoagulant in this patient? No. Her partial thromboplastin time was normal, and the most consistent abnormal finding in patients with the lupus anticoagulants is a prolonged partial thromboplastin time. Additionally, when present, this does not lead to a problem, such as pulmonary hemorrhage, unless another coagulation disorder is present. Dr. Little: I was hoping that there would be more time
Dr. Sherman:
SYSTEMIC
left for a few comments on the possibility of infection as a superimposed process on our patient’s SLE and also on the consideration of a whole host of other disease processes that could coexist in a person with SLE, conditions such as pulmonary hemosiderosis, Goodpasture’s or Wegener’s diseases. I do not think this patient had any of these. I am also inclined to minimize the many and significant possibilities of infection. I find it appealing to try to relate all the findings in this patient to one diagnosis. As I stated at the outset, there are more similarities than differences in the nature of her pulmonary disease that recurred late in her hospital course with features of her presenting illness. An opportunistic fungus infection could have appeared after that transitory time of improvement, but I am dissuaded by the negative potassium hydroxide preparations and gram stains. I think she probably did have herpesvirus infection throughout her tracheobronchial tree and on her oral mucus membranes. I do not know how one can categorically state that her final pneumonia was not, in fact, overwhelming herpesvirus pneumonia. It seems quite possible that a late occurring, nosocomial herpesvirus led to ‘the recurrence of gross hemoptysis which appeared similar to the findings on her initial presentation but which was, in fact, on a quite different basis. Her episode of stridor and eqiglottitis makes one immediately think of Hemophilus influenzae B infection. However, this organism was not cultured from her throat or blood. She was treated with something less than the ideal antibiotics for that infection. I am inclined, however, to try to rationalize all of her findings with as few diagnoses as possible and would conclude that our patient surely had SLE with immune complex vascular damage in both her lung and kidney. I believe that her kidneys will show proliferate glomerulonephritis and that she had extensive intraalveolar hemorrhage. I believe that she also had disseminated intravascular coagulation and that we will find evidence of venous and arterial thrombosis, not just in her lung but also perhaps in her brain and even her heart. I also believe that our patient did have herpesvirus pharyngitis, tracheobronchitis and bronchopneumonia. But, I think that SLE was the primary disease process and major cause of her death.
LUPUS ERYTHEMATOSUS
WITH POSTPARTUM PULMONARY
DISEASE
Figure 4. Necrofizing fracheobronchifis. Only a few remnants of viable epifhelium remain (arrows). The lumen of this small bronchus is filled with polymorphonuclear leukocytes, fibrin, mucus and cellular debris. Note cartilage in leff lower corner. Magnification X 76; reduced by 28 per cent.
sistent with herpesvirus were evident in residual bits of bronchial epithelium. The membranous exudate was comprised of fibrin and necrotic cell debris with varying numbers of red cells. The lungs were quite heavy; the right weighed 1,300 g, the left 1,250 g. A severe, necrotizing hemorrhagic bronchopneumonia involved all lobes of the lungs and was virtually confluent in the lower lobes. lntranuclear inclusion bodies were present in bronchial epithelium and alveolar lining cells throughout the lungs, especially at the margins of necrotic tissue (Figure 5). In those portions of the lung not affected by necrotizing pneumonitis, marked interstitial edema and extensive, well
PATHOLOGIC DISCUSSION Dr. Joseph Williamson: Unfortunately, the postmortem examination was restricted to the heart, lungs and kidneys. A membranous exudate was present throughout the tracheobronchial tree and formed occlusive plugs in the intrapulmonary branches. Microscopic examination revealed almost complete denudation of respiratory epithelium and extensive necrosis of underlying mucosa (Figure 4). lntranuclear inclusion bodies con-
Figure 5. lnfranuclear viral inclusion body (arrow) lung. Magnification X 760; reduced by 28 per cenf.
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Figure 6. Hyaline membranes and thickened alveolar septums of the lungs. Magnification X 720; reduced by 28 per cent.
developed intraalveolar hyaline membranes were present (Figure 6). The latter are nonspecific changes associated with diffuse alveolar damage [ 121. It is impossible to determine to what extent these changes may be the consequence of viral pneumonitis, lupus vasculitis, lupus pneumonitis, oxygen toxicity or cytotoxic treatment. A few small organizing thromboemboli were present; however, there was no evidence of vasculitis. Postmortem culture of the lungs yielded a heavy growth of herpes simplex virus type I. Peribronchial lymph nodes contained multiple foci of necrosis, and intranuclear inclusion bodies were evident in occasional cells.
Figure 7. Acute vasculitis in the heart. Polymorphonuclear leukocytes, cellular debris and extravasated red cells are present in the upper left portion of the vessel wall. Magnification X 120; reduced by 28 per cent.
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The heart weighed 370 g. Several 3 to 5 mm in diameter plaque-like vegetations consistent with Libman-Sacks endocarditis were present on the endocardium of the right atrium and right ventricle, and on the tricuspid valve. Microscopic examination revealed these vegetations to be comprised of partially organized accumulations of fibrin and platelets with scattered leukocytes. There were no pathologic alterations in the subendocardium underlying these plaques. Thus, although the distribution and microscopic appearance of these vegetations are consistent with Libman-Sacks, they cannot be differentiated microscopically from those of ordinary nonbacterial, thrombotic endocarditis. Examination of the myocardium revealed several examples of acute vasculitis (Figure 7), one of which was associated with focal necrosis of myocardium. The kidneys were of normal size. However, the cortex was pale and there were multiple scattered punctate cortical hemorrhages. Microscopic sections revealed focal, proliferative glomerulitis (Figure 8) involving 30 to 40 per cent of the glomeruli. There were frequent crescent-shaped adhesions between glomerular tufts and Bowman’s capsule. Fibrinoid changes and hyaline thrombi were present in occasional glomeruli. lmmunofluorescent studies demonstrated finely granular deposits of IgG and C3 in capillary loops and in the mesangium. Scattered tubules were filled with red cells. In addition, there was evidence of acute tubular necrosis. The immediate cause of death in this young woman was a necrotizing tracheobronchitis and pneumonitis caused by herpes simplex type I. This finding assumes particular interest because fatal herpes infections are
Figure 6. Glomerulitis with proliferation of Bowman s epithelium and crescent formation (arrow). Note focal mesangial thickening of glomerulus, Magnification X 300; reduced by 28 per cent.
SYSTEMIC LUPUS ERYTHEMATOSUS WITH POSTPARTUM PULMONARY DISEASE
exceedingly rare in adults. They are somewhat more common in children in whom the problem is more often encephalitis. Nash and Foley [ 131 have reported that nine of 97 severely burned patients had evidence of herpes tracheobronchitis at autopsy. However, it appeared doubtful that the herpes infection contributed significantly to the death of these patients. Subsequently, Nash reviewed 1,000 consecutive autopsies at the Massachusetts General Hospital [ 141 and found evidence of respiratory herpes infections in only 10 subjects, half of whom were burn patients. In only three of the IO was the infection extensive enough that it was considered contributory to the death of the patients. Burn patients may be particularly prone to herpes infections; however, Nash noted that practically all the patients with herpes infections in both series had undergone intubation. He hypothesized that the intubation procedure might serve to carry herpesvirus from the oropharynx into the tracheobronchial tree and at the same time produce injury to the epithelial lining of the respiratory tract, thereby increasing its susceptibility
to infection. This is an interesting speculation and suggests an explanation for the biphasic (clinical) character of this patient’s respiratory problems. Her initial respiratory distress at the time of admission may well have been due to postpartum exacerbation of her SLE, with lupus pneumonitis. The appearance of the proliferative glomerular lesions in the kidney at the time of autopsy would be consistent with vasculitis of that duration; the vascular lesions in the heart appeared to be much more recent, on the other hand, and suggest that she still had active vasculitis. The white plaque-like lesions noted in the mouth and pharynx were undoubtedly herpetic and the source of the virus infection which developed in the lower respiratory tract after intubation. The exacerbation of her respiratory symptoms terminally is certainly readily explained by the extensive necrotizing, herpetic, tracheobronchitis and pneumonitis. The large doses of corticosteroids, along with the other medications the patient was receiving during this time, undoubtedly contributed to her vulnerability to infection by the herpesvirus.
REFERENCES 1.
2.
3. 4.
5. 6. 7.
Matthay RA, Schwarz MI, Petty RL, et al.: Pulmonary manifestations of systemic lupus erythematosus. Review of 12 cases of acute lupus pneumonitis. Medicine (Baltimore) 54: 397,1974. Dubois EL: Management of discoid and systemic lupus erythematosus. Lupus Erythematosus (Dubois EL, ed), Los Angeles, University of Southern California Press, 1974, p 612. Zurier RB: Systemic lupus erythematosus and pregnancy. Clin Rheum Dis 1: 613, 1975. Fraga A, Mintz G, Orozco J, et al.: Sterility and fertility rates, fetal wastage and maternal morbidity in systemic lupus erythematosus. Arth Rheum 1: 293, 1974. Friedman R, Rutherford J: Pregnancy in lupus erythematosus. Obstet Gynecol 8: 60 1, 1956. Estes D, Larson DL: Systemic lupus erythematosus and pregnancy. Clin Obstet Gynecol 8: 307. 1965. Madsen, JR, Anderson GV: Lupus erythematosus and pregnancy. Obstet Gynecol 18: 492, 1961.
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13. 14.
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Garsenstein M, Pollak VE, Kark RM: Systemic lupus erythematosus and pregnancy. N Engl J Med 267: 165, 1962. Mund, A, Simson L, Rothfield MF: Effect of pregnancy on the course of systemic lupus erythematosus. JAMA 183: 917, 1963. McGee CD, Makowski EL: Systemic lupus erythematosus in pregnancy. Am J Obstet Gynecol 107: 1008, 1970. Brain MC, Baker LR, McBride JA, et al.: Treatment of patients with microangiopathic haemolytic anemia with heparin. Br J Haemat 15: 603, 1968. Katzenstein ALA, Bloor CM, Leibow AA: Diffuse alveolar damage-the role of oxygen, shock and related factors. Am J Pathol 85: 210, 1976. Nash G, Foley FD: Herpetic infection of the middle and lower respiratory tract. Am J Clin Pathol 54: 857, 1970. Nash G: Necrotizing tracheobronchitis and bronchopneumonia consistent with herpetic infection. Hum Pathol 3: 283, 1972.
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Systemic Lupus Erythematosus with Postpartum Pulmonary Disease
Stenographic reports, edited by Philip E. Cryer, M.D. and John M. Kissane, M.D., of weekly clinicopathologic conferences held In Barnes and Wohl Hospitals, are published in each issue of the Journal. These conferences are participated in jointly by members of the Departments of Internal Medicine, Radiology and Pathology of Washlngton University School of Medicine. A 22 year old Caucasian woman was admitted to Barnes Hospital on July 17, 1977, because of shortness of breath. She died 17 days later. The patient was overtly well until arthralgias developed in January 1976. Her physician noted a facial rash and swelling of the proximal interphalangeal joints, wrists and knees, and diagnosed systemic lupus erythematosus (SLE). Antinuclear antibodies, with homogeneous and rimmed nuclear staining patterns, were positive at a I:90 serum dilution. After a short course of steroid therapy, the patient felt well. In April 1977, during her sixth month of pregnancy, a urinalysis disclosed 2-t proteinuria and 15 to 20 red blood cells/per high power field (hpf) in the urine sediment. Serum findings included a 3-I positive antinuclear antibody test, with homogeneous and rimmed staining patterns, the presence of anti-DNA antibodies, cryoglobulinemia and depessed complement levels. The creatinine clearance was 98 ml/min, and the urine protein excretion was 0.5 g/24 hours. It was planned to perform a renal biopsy after delivery of her child. Pregnancy and delivery, on July 13, 1977, at another hospital were uneventful. Although the patient complained of cough and substernal chest pain, she was discharged three days postpartum. She experienced increasingly severe, nonpleuritic chest pain and shortness of breath, and her cough became productive of yellow sputum which became blood-tinged and then grossly bloody over the course of one day. She was hospitalized and found to have “pneumonia” and a hematocrit value of 22 per cent. She was given 4 U of blood and transferred to Barnes Hospital on July 17, 1977. Physical findings in the emergency room included a blood pressure of 170/100 mm Hg, a pulse rate of 150/min, a respiratory rate of 361 min and a temperature of 38.7’C. She was in marked respirat&y distress and was deeply cyanotic. There were bilateral pulmonary rales, and a gallop rhythm was noted, but there was no cardiomegaly. The uterus was palpable 4 cm above the symphysis pubis. The neurologic examination was within normal limits.
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Initial laboratory data included a white blood cell count of 41,900/mm3 with a shift to the left; the hematocrit value was 36.8 per cent and the hemoglobin level 12.6 g/dl. The serum creatinine was 4.3 mg/dl and the bicarbonate 11.4 meq/liter. While receiving nasal oxygen at a rate of 4 litersimin, the arterial oxygen tension (PO,) was 22 mm Hg and the pH 7.3 1. Chest roentgenograms revealed diffuse pulmonary infiltrates, greatest at the bases of the lungs. An electrocardiogram showed sinus tachycardia. Examination of the sputum disclosed only a few white blood ceils and bacteria, but there were many red blood cells. The patient was intubated and admitted to the Coronary Care Unit. An episode of ventricular tachycardia was treated by cardioversion. A Swan-Ganz catheter was inserted; the mean pulmonary artery and pulmonary wedge pressures were 23 and 18 mm Hg, respectively. Hydrocortisone, 1.0 g every 6 hours, oxacillin and gentamicin were administered, as were diuretics, to maintain the pulmonary wedge pressure at approximately 10 mm Hg. Positive pressure assisted ventilation, with 100 per cent oxygen, was applied and bronchodilators were also given. Despite pneumothoraces, for which the patient required the insertion of chest tubes, and the subsequent development of subcutaneous emphysema, her respiratory status gradually improved. All bacterial cultures were negative, and the administration of oxacillin and gentamicin was discontinued on the seventh hospital day. Leukocytosis persisted. The pulmonary infiltrates cleared and by the 10th day the arterial PO2 was 70 mm Hg while she was breathing room air. This portion of the patient’s course was complicated by an increase in the serum creatinine to 7.5 mg/dl (hemodialysis was begun) and progressive anemia (a total of 12 U of blood was given). Coagulation studies were initially normal, including a prothrombin time of 90 per cent, but the prothrombin time subsequently decreased to 43 per cent although the partial thromboplastin time remained normal. A few fragmented red blood cells were noted on peripheral blood smears, the platelet count decreased to 27,000/mm3 and fibrin degradation products were present at a 1:8 dilution. Total hemolytic complement (28.5 U), the third component of complement (C3, 58 mg/dl) and the fourth component of complement (C4, 8.4 mg/dl) levels in the serum were low. On July 27, the patient appeared to be doing relatively well and she was transferred from the Coronary Care Unit to the Medical Intensive Care Unit. Subcutaneous emphysema, a few bibasilar rales and pharyngeal ulcerations with overlying white patches were noted. Gram stain and potassium hydroxide study of material from these areas were negative as were fungal cultures. Therapy with hydrocortisone was discontinued and the
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administration
of prednisone,
600 mg every
8 hours,
was begun. Later that day the patient had a grand mal seizure. The arterial PO2 was 52 mm Hg with a pH of 7.50 and a carbon dioxide tension (PCO2) of 36 mm Hg. Neurologic examination, lumbar puncture, computed tomographic scans of the head and an electroencephalogram disclosed no abnormalities. Phenobarbital was administered. On July 30, dyspnea increased and the arterial PO2 decreased despite increased inspired oxygen; diffuse pulmonary infiltrates reappeared on chest films. Because of inspiratory stridor the patient was treated with epinephrine. A nasotracheal aspirate revealed gram-positive cocci and gram-negative rods; a potassium hydroxide preparation was negative. Cultures of the sputum and blood were obtained, and gentamicin, oxacillin and parenteral glucocorticoid therapy was reinstituted. Moderate growth of Enterobacter from the sputum cultures and gram-positive cocci from one blood culture bottle only were subsequently reported. Tracheal intubation was required on July 31. Bronchoscopy showed that the plaque-like lesions extended down the trachea. Transbronchial lung biopsy specimens showed no fungi, bacteria or pneumocystis organisms; however, intranuclear inclusion bodies were seen. The patient was transferred to the Respiratory Intensive Care Unit where positive pressure ventilation with 100 per cent oxygen was required to maintain arterial PO2 above 50 mm Hg. The administration
the of
Adenine Arabinoside (ARA-A), 10 mg/kg every 12 hours, was begun on August 2. Progressive hypotension (despite the infusion of dopamine), acidosis and coma led to the development of an idioventricular rhythm, and the patient died on August 3, 1977 CLINICAL
DISCUSSION
Dr. J. Russell Little: This 22 year old woman was found to have SLE in January 1976. In April 1977, while pregnant, she was found to have proteinuria, microscopic hematuria and low serum complement levels. Renal biopsy was deferred because of the pregnancy. A normal baby was delivered on July 13. Pulmonary symptoms developed, and the patient was admitted to Barnes Hospital with severe hypoxemia, anemia and advancing azotemia on July 17, five days postpartum. Vigorous therapy-including the administration of antibiotics, large doses of glucocorticoids, bronchodilators and diuretics, and the use of assisted ventilation with 100 per cent inspired oxygen-led to clinical improvement with nearly normal arterial PO2 levels and clearing of pulmonary infiltrates. However, on the 10th hospital day a seizure occurred, and pulmonary symptoms, hypoxemia and pulmonary infiltrates recurred. A lung biopsy specimen showed only intranuclear inclu-
SYSTEMIC
LUPUS ERYTHEMATOSUS
WITH POSTPARTUM
PULMONARY
DISEASE
Figure 2. Chest film obtained nine days after admission showing nearly complete resolution of air space disease. Figure lateral lobes.
1. Chest film obtained on admission showing biair-space disease, predominently in the lower
sion bodies. Despite all therapeutic efforts, the patient died 18 days after admission. Dr. Levitt, would you summarize the roentgenographic findings? Dr. Robert Levitt: The chest film taken on admission (Figure 1) demonstrated bilateral air space disease, predominantly in the lower lobes. The differential diagnosis of acute air space disease includes pulmonary exudate, transudate, or hemorrhage. In patients with acute lupus pneumonitis the chest film is characterized by such an air space disease with predilection of the lung bases [ 11. The chest film obtained on day nine (Figure 2) showed nearly complete resolution of the pulmonary infiltrates. Rapid clearing of pulmonary infiltrates in patients with acute lupus pneumonitis treated with corticosteroids has been reported. In one series, the chest film showed complete clearing in one half of the patients who survived the acute illness. In the other half, the disease progressed to chronic interstitial pneumonitis [2]. On the 10th hospital day the patient began to experience dyspnea, and a chest film showed new pulmonary infiltrates. A chest film taken on day 16 (Figure 3) revealed diffuse air space consolidation and extensive subcutaneous emphysema, secondary to a closed tube thoracostomy for pneumothorax. The differential diagnosis of this air space consolidation is unchanged from the differential diagnosis of the chest film obtained on admission. Infectious agents which produce this roentgenographic pattern include Pneumocystis carinii, viral agents and gram-negative bacteria. Dr. Little: I think the films very nicely illustrate what I think was the over-riding feature of this patient’s illness
during her hospitalization here and that is its biphasic nature. That is to say, she presented catastrophically ill with very serious pulmonary disease and then went through a period of marked improvement at which time her chest film was essentially within normal limits, and she was comfortable. After that brief period of dramatic improvement, the overwhelming pulmonary disease recurred and the patient’s general clinical state returned to a condition very much like that with which she had presented initially. It is this biphasic character, along with certain other features of the second phase of her illness, which constitutes for me the major puzzle. Must we entertain other diagnoses beyond that of SLE? Were there at least two or more processes occurring more or less simultaneously, or can we successfully relate all the features of her illness to disease activity consistent with SLE?
Figure 3. Chest film obtained on day 16 reveals diffuse air space consolidation and extension subcutaneous emphysema.
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The first question that I would like to discuss is one which surely must have been very prominent at the time of her admission to Barnes hospital. That is whether or not the pulmonary insufficiency syndrome with which she presented could have been explained on the basis of her underlying SLE. Dr. Atkinson, would you please review the patient’s serologic data available upon admission and direct your attention to whether or not the serologic activity in SLE can be used as an accurate reflection of disease activity, or are there conspicuous dissociations? Also, would you discuss the effects of pregnancy on disease activity in SLE? Dr. John Atkinson: First, regarding the serology, the serologic findings in this patient in most instances correlate with active clinical disease and a relatively poor prognosis. She had high titer, rimmed and homogeneous ANA, markedly increased antibody titers to DNA, decreased complement concentrations and cryoglobulins. There are exceptions to these generalizations because we do see patients with active disease and minimal serologic abnormalities, or minimal disease activity and serologic findings such as those in this patient. However, the serologic results in this case strongly suggest an active disease process and one that in all likelihood is going to become worse. These serologic data, combined with the proteinuria and miscroscopic hematuria, suggest that treatment and careful follow-up are needed. Regarding your second point concerning the relationship between SLE and pregnancy, there are a number of interesting questions to be addressed [2,3]. Dr. Robert Zurier has recently reviewed the subject of SLE and pregnancy [3], and in his article he comments on most of the points which I will now briefly summarize. First, do women with SLE become pregnant? In most studies the fertility rate of women with SLE is similar to that of normal women [4], with the major exception being, as would be expected, patients who have poorly controlled active SLE. Second, will pregnancy make SLE worse? Several studies pertinent to this question have been published [2-lo]. In about one half of the patients there is no marked change in the course of the disease, in about one-third the disease becomes worse (especially during the first trimester), and in a small percentage the disease subsides or diminishes (particularly during the last trimester). However, most frequently an exacerbation occurs in the postpartum state; I will have some more to say about this problem. A third question relates to what effect SLE will have on the baby. In most series there is a definite increase (two-to-three-fold) in prematurity and spontaneous abortion. In well controlled patients, these complications are lower and not unacceptable. In fact, the usual outcome of a pregnancy involving a patient with SLE in remission is an uneventful pregnancy and
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a normal baby. Fourthly, what about the use of corticosteroids in pregnant women? Although in animals these agents cause fetal abnormalities, particularly cleft palate, several hundred babies have been born to women with SLE who were taking 20 mg or more of prednisoneiday; so far, there is no evidence of teratogenie effects of these agents in man. A fifth and very interesting question relates to whether or not the baby will have SLE at birth or a greater risk for the development of SLE. I am not aware of a situation in which the mother had SLE and clinical SLE developed in the baby. Not surprisingly, some babies have positive LE preparations and ANA tests since IgG antibodies cross the placenta. In addition, there has been at least one well documented case of an infant in whom transient skin lesions developed compatible clinically and pathologically with discoid lupus. I am not aware of an increased frequency of SLE in daughters born to mothers with SLE. I would now like to make a few comments concerning the postpartum period. About 30 to 50 per cent of the patients have a major flare in disease activity anywhere from a few days to up until eight weeks after delivery. It is often a severe exacerbation, and the pattern of involvement is no different from what one usually sees in patients with active SLE. In all series, the most common problem was the development or worsening of lupus nephritis. Dr. Little: With the fine image provided with the retrospective vision, would you have handled things differently during this patient’s postpartum exacerbation? Dr. Atkinson: This patient has been presented at at least two other conferences and Grand Rounds, so a number of physicians have discussed her clinical course and treatment program. At the time of her admission it was the belief of the responsible physicians that she had sustained an acute diffuse alveolar injury which was secondary to SLE. Other possibilities were also considered, as will be discussed by Dr. Lefrak. Therapy was immediately instituted with high dose steroids. In retrospect, I believe large quantities were indicated initially but that their administration may have been continued for too long. Perhaps a marked reduction at day 4 or 5, when it was clear that she was improving, would have been the correct manuever. However, at apparently the same time that the decision was made to rapidly taper the dose of steroids to a maintenance dose, the clinical course gradually began to deteriorate and for several days the cause of the change in events (exacerbation of SLE pulmonary disease versus a superinfection) was unclear. Dr. Little: How about antepartum? If you had seen this patient, would you have managed her differently during the last trimester?
SYSTEMIC
Dr. Atkinson: Although we do not have many details during the week immediately preceding delivery, according to both the patient and her obstetrician there were apparently no alterations of note in her clinical course. There are reports of patients who have been * “covered,” because of worsening serologic data or in hopes of preventing a flare of the renal disease, with steroids during delivery and the immediate postpartum period [3, lo]. In view of the outcome in this case, and apparently better results with steroid coverage, more aggressive therapy during the pregnancy and immediate postpartum period may have been indicated. For example, if this patient had not been pregnant, I am sure that the abnormalities of renal function coupled with the serologic findings that were documented at the time of her initial admission to this hospital would have caused her physician to begin corticosteroid therapy. Since there is no convincing evidence of a teratogenic effect of steroids in man, there is no reason to withhold such therapy when the indications for its use are good during pregnancy. Dr. Little: Despite the fact that this patient was febrile immediately postpartum and at the time of her admission to the hospital, I could find no evidence that a pelvic examination was carried out on her either on admission or at any subsequent time. In view of that I do not know what we can say about the possibility that she may have had an infection in her pelvis. I would be just delighted, Dr. Atkinson, if you could tell me that we do not need to worry about her white blood cell count of 42,000/ mm3 because it is a common feature of patients with SLE who present with severe, rapidly progressive activity. Dr. Atkinson: I do not have a novel explanation for this high white cell count. Because of an inexplicable change in the nature of the immune complexes and/or in the host’s milieu associated with the postpartum state, I would hypothesize that in this patient large quantities of immune complexes were deposited in the lung. These complexes initiated an acute inflammatory response which, in turn, produced the acute diffuse alveolar injury pattern. Thus, at least part of the increased white blood cell count was secondary to the host’s response to the pulmonary injury. Many patients with SLE respond quite normally to inflammatory stimuli, and most are not neutropenic. Dr. Little: I will continue to be worried about infection because I do not really know how to explain the leukocytosis. Leaving aside for a moment the strong evidence supporting SLE activity, Dr. LeFrak, I would like to ask you to review the findings in our patient at the time of admission relevant to her pulmonary disease. I would also like to have your comments on two diagnoses of conditions that nobody thought she had, namely, am-
LUPUS ERYTHEMATOSUS
WITH POSTPARTUM PULMONARY
DISEASE
niotic fluid embolism and multiple pulmonary emboli, and your comments on another diagnosis of a condition that everybody agreed she had, namely, the adult respiratory distress syndrome. Dr. Stephen Lefrak: Amniotic fluid embolism is very unlikely. In some series, as many as 10 per cent of all maternal deaths are credited to amniotic fluid embolism. But it is a very acute, catastrophic illness that occurs either during labor or immediately thereafter and is characterized by diffuse bleeding from all orifices. This woman had an apparently normal delivery and went home; the illness gradually developed over four days. Pulmonary embolism is a consideration, but it does not fit the clinical picture. First, it is very unusual for patients with pulmonary emboli to present with pulmonary edema or bilateral pulmonary infiltrates. Second, the Swan-Ganz catheterization data indicate that her modest pulmonary artery hypertension was attributable to cardiac failure. Furthermore, if her severe hypoxemia was due to a massive embolus, I would expect the pulmonary artery pressure to be much higher. The adult respiratory distress syndrome or, as I like to call it, acute alveolar injury, is basically a syndrome characterized by diffuse pulmonary infiltrates, resistant hypoxemia and marked dyspnea. The accumulation of fluid in the alveoli is a central feature of adult respiratory distress syndrome. Normally, the intracapillary hydrostatic pressure is only partially countered by the oncotic pressure and some fluid moves from the capillaries into the interstitial spaces: this normally drains into the lymphatics. The accumulation of large quantities of intraalveolar fluid can be due to a major increase in interstitial fluid (increased capillary hydrostatic pressure, decreased capillary oncotic pressure, decreased lymphatic drainage) or damage to the alveolar epithelial cells, or both. In the patient under discussion, the increment in hydrostatic pressure and the decrement in oncotic pressure were small and there was no reason to suspect lymphatic obstruction. Thus, damage to the alveolar epithelial cells is the most likely explanation for the pulmonary edema. Dr. Little: Most of the time it seems to me that patients with adult respiratory distress syndrome have transudation of fluid without conspicuous bleeding into the alveolar spaces. Our patient, I believe, had extensive intraalveolar bleeding and I would take that to be the cause of her gross hemoptysis. Does that give us any kind of etiologic clues concerning the distinction between those patients who just have intraalveloar edema and those who have bleeding? Dr. Lefrak: It is unusual for people with adult respiratory distress syndrome to have hemoptysis unless they have vasculitis, Goodpasture’s syndrome or idiopathic pulmonary hemosiderosis. On the other hand, let us not
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forget that patients with pulmonary edema are characterized by coughing up pink fluid; one can find blood in their sputum. Patients with mitral stenosis will frequently cough up red blood. But, clearly, if you have gross hemoptysis, we think of different sorts of things. Dr. Little: Dr. Atkinson, I have had a great deal of difficulty knowing how to think about the lung lesions of SLE. Some series would have us believe that the frequency of pulmonary involvement in patients with lupus is extraordinarily high (over 50 per cent) and those are largely series in which pleuritis is included among the criteria used to determine that a patient with SLE has pulmonary involvement. In other series diagnostic criteria are restricted to parenchymal lung disease and indicate that the frequency of lupus lesions is very low. Which is true? And is the pulmonary parenchymal disease in SLE a vasculitis? Dr. Atkinson: Pulmonary
involvement
in SLE is com-
mon. The most common pulmonary clinical manifestations are pleuritis and pleural effusions [2]. Of course, similar pulmonary manifestations occur in rheumatoid arthritis and many other collagen vascular diseases. In autopsy series, ctose to 100 per cent of the patients with SLE have pulmonary involvement. In the patient under discussion, I believe she had an unusual pulmonary manifestation of SLE, acute lupus pneumonitis leading to diffuse alveolar injury. In a recent article the data on 12 patients who presented with this type of picture were reviewed [ 11. Of these 12 patients, six patients died (three of pulmonary insufficiency and one each of pulmonary embolus, nocardial superinfection and central nervous system vasculitis). One patient is alive but has a severe restrictive pulmonary defect, and two other patients continue to have persistent infiltrates. Only three of the 12 patients made a complete recovery. None of the patients was postpartum, and I have been unable to find a case similar to the one under discussion today. Thus, this type of diffuse pulmonic involvement therapy.
is quite uncommon.
It is often lethal despite
Dr. Little:
Among patients who die of SLE, would you say that renal disease still heads the list of critical organ involvement leading to death? Dr. Atkinson: Renal disease is still the most common cause of death. Infections would rank second and central nervous system involvement third. A wide variety of other lethal events in SLE have been described including colonic perforations, pulmonary insufficiency, cardiovascular problems and a number of others. Dr. Little: Lupus lung disease of a noninfectious variety would be very low on the list of causes of death in SLE. Our patient had SLE, severe lung disease and renal failure; suddenly she had a seizure, some abnormal red
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cells on her peripheral smear and recurrence of her pulmonary disease. Dr. Sherman, this patient’s prothrombin time, which was normal on admission, became prolonged during the last few days of her hospital course; she had fibrin split products, and fragmented and helmet cells on her peripheral smear. Surely, she had disseminated intravascular coagulation. Dr. Laurence Sherman: I think that there is a fair likelihood that she had intravascular coagulation. One of the questions is whether or not it was disseminated. If you look at the beginning of this woman’s course, had several risk elements for a thrombotic process. was postpartum and she had SLE. I think there possibility that she had pulmonary thrombi at the
she She is a time
of admission. Obviously, if present, it was a minor part of her respiratory problem. The reason I say that, is that one would suspect that if she had intravascular coagulation it was related to her vasculitis. The major manifestation of her lupus was in the lung and was probably vasculitis. Ordinarily, in connective tissue diseases, when intravascular coagulation and microangiopathic changes occur in a localized manner, they are frequently localized in the kidneys. One sees rapidly advancing renal problems. This was best exemplified in the series of Brain and his co-workers some years ago [ 111. In such circumstances, the fragmentation of the red cells by fibrin leads to release of red cell thromboplastin that would accelerate the clotting system leading to further fibrin deposition, further fragmentation, etc. But the primary event in this sort of situation is most likely a vascular problem. One would suspect that in our current patient, it was localized in the lungs. Even though I raised the possibility of thrombi initially, that possibility is minor. The changes in her blood findings and the vasculitis would make one suspect that her course was complicated towards the end by pulmonary thrombi and that this was secondary to her SLE. Dr. Little: When you say the primary event in this kind of setting is likely to be related to a vasculitic process, do you include immune complex deposition as a primary event leading then to what is referred to as vasculitis, even though sometimes it shows only a minimal local accumulation of inflammatory cells?
Dr. Sherman: Yes. Dr. Little: Do you think we have to worry at all about the presence
of an anticoagulant in this patient? No. Her partial thromboplastin time was normal, and the most consistent abnormal finding in patients with the lupus anticoagulants is a prolonged partial thromboplastin time. Additionally, when present, this does not lead to a problem, such as pulmonary hemorrhage, unless another coagulation disorder is present. Dr. Little: I was hoping that there would be more time
Dr. Sherman:
SYSTEMIC
left for a few comments on the possibility of infection as a superimposed process on our patient’s SLE and also on the consideration of a whole host of other disease processes that could coexist in a person with SLE, conditions such as pulmonary hemosiderosis, Goodpasture’s or Wegener’s diseases. I do not think this patient had any of these. I am also inclined to minimize the many and significant possibilities of infection. I find it appealing to try to relate all the findings in this patient to one diagnosis. As I stated at the outset, there are more similarities than differences in the nature of her pulmonary disease that recurred late in her hospital course with features of her presenting illness. An opportunistic fungus infection could have appeared after that transitory time of improvement, but I am dissuaded by the negative potassium hydroxide preparations and gram stains. I think she probably did have herpesvirus infection throughout her tracheobronchial tree and on her oral mucus membranes. I do not know how one can categorically state that her final pneumonia was not, in fact, overwhelming herpesvirus pneumonia. It seems quite possible that a late occurring, nosocomial herpesvirus led to ‘the recurrence of gross hemoptysis which appeared similar to the findings on her initial presentation but which was, in fact, on a quite different basis. Her episode of stridor and eqiglottitis makes one immediately think of Hemophilus influenzae B infection. However, this organism was not cultured from her throat or blood. She was treated with something less than the ideal antibiotics for that infection. I am inclined, however, to try to rationalize all of her findings with as few diagnoses as possible and would conclude that our patient surely had SLE with immune complex vascular damage in both her lung and kidney. I believe that her kidneys will show proliferate glomerulonephritis and that she had extensive intraalveolar hemorrhage. I believe that she also had disseminated intravascular coagulation and that we will find evidence of venous and arterial thrombosis, not just in her lung but also perhaps in her brain and even her heart. I also believe that our patient did have herpesvirus pharyngitis, tracheobronchitis and bronchopneumonia. But, I think that SLE was the primary disease process and major cause of her death.
LUPUS ERYTHEMATOSUS
WITH POSTPARTUM PULMONARY
DISEASE
Figure 4. Necrofizing fracheobronchifis. Only a few remnants of viable epifhelium remain (arrows). The lumen of this small bronchus is filled with polymorphonuclear leukocytes, fibrin, mucus and cellular debris. Note cartilage in leff lower corner. Magnification X 76; reduced by 28 per cent.
sistent with herpesvirus were evident in residual bits of bronchial epithelium. The membranous exudate was comprised of fibrin and necrotic cell debris with varying numbers of red cells. The lungs were quite heavy; the right weighed 1,300 g, the left 1,250 g. A severe, necrotizing hemorrhagic bronchopneumonia involved all lobes of the lungs and was virtually confluent in the lower lobes. lntranuclear inclusion bodies were present in bronchial epithelium and alveolar lining cells throughout the lungs, especially at the margins of necrotic tissue (Figure 5). In those portions of the lung not affected by necrotizing pneumonitis, marked interstitial edema and extensive, well
PATHOLOGIC DISCUSSION Dr. Joseph Williamson: Unfortunately, the postmortem examination was restricted to the heart, lungs and kidneys. A membranous exudate was present throughout the tracheobronchial tree and formed occlusive plugs in the intrapulmonary branches. Microscopic examination revealed almost complete denudation of respiratory epithelium and extensive necrosis of underlying mucosa (Figure 4). lntranuclear inclusion bodies con-
Figure 5. lnfranuclear viral inclusion body (arrow) lung. Magnification X 760; reduced by 28 per cenf.
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Figure 6. Hyaline membranes and thickened alveolar septums of the lungs. Magnification X 720; reduced by 28 per cent.
developed intraalveolar hyaline membranes were present (Figure 6). The latter are nonspecific changes associated with diffuse alveolar damage [ 121. It is impossible to determine to what extent these changes may be the consequence of viral pneumonitis, lupus vasculitis, lupus pneumonitis, oxygen toxicity or cytotoxic treatment. A few small organizing thromboemboli were present; however, there was no evidence of vasculitis. Postmortem culture of the lungs yielded a heavy growth of herpes simplex virus type I. Peribronchial lymph nodes contained multiple foci of necrosis, and intranuclear inclusion bodies were evident in occasional cells.
Figure 7. Acute vasculitis in the heart. Polymorphonuclear leukocytes, cellular debris and extravasated red cells are present in the upper left portion of the vessel wall. Magnification X 120; reduced by 28 per cent.
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The heart weighed 370 g. Several 3 to 5 mm in diameter plaque-like vegetations consistent with Libman-Sacks endocarditis were present on the endocardium of the right atrium and right ventricle, and on the tricuspid valve. Microscopic examination revealed these vegetations to be comprised of partially organized accumulations of fibrin and platelets with scattered leukocytes. There were no pathologic alterations in the subendocardium underlying these plaques. Thus, although the distribution and microscopic appearance of these vegetations are consistent with Libman-Sacks, they cannot be differentiated microscopically from those of ordinary nonbacterial, thrombotic endocarditis. Examination of the myocardium revealed several examples of acute vasculitis (Figure 7), one of which was associated with focal necrosis of myocardium. The kidneys were of normal size. However, the cortex was pale and there were multiple scattered punctate cortical hemorrhages. Microscopic sections revealed focal, proliferative glomerulitis (Figure 8) involving 30 to 40 per cent of the glomeruli. There were frequent crescent-shaped adhesions between glomerular tufts and Bowman’s capsule. Fibrinoid changes and hyaline thrombi were present in occasional glomeruli. lmmunofluorescent studies demonstrated finely granular deposits of IgG and C3 in capillary loops and in the mesangium. Scattered tubules were filled with red cells. In addition, there was evidence of acute tubular necrosis. The immediate cause of death in this young woman was a necrotizing tracheobronchitis and pneumonitis caused by herpes simplex type I. This finding assumes particular interest because fatal herpes infections are
Figure 6. Glomerulitis with proliferation of Bowman s epithelium and crescent formation (arrow). Note focal mesangial thickening of glomerulus, Magnification X 300; reduced by 28 per cent.
SYSTEMIC LUPUS ERYTHEMATOSUS WITH POSTPARTUM PULMONARY DISEASE
exceedingly rare in adults. They are somewhat more common in children in whom the problem is more often encephalitis. Nash and Foley [ 131 have reported that nine of 97 severely burned patients had evidence of herpes tracheobronchitis at autopsy. However, it appeared doubtful that the herpes infection contributed significantly to the death of these patients. Subsequently, Nash reviewed 1,000 consecutive autopsies at the Massachusetts General Hospital [ 141 and found evidence of respiratory herpes infections in only 10 subjects, half of whom were burn patients. In only three of the IO was the infection extensive enough that it was considered contributory to the death of the patients. Burn patients may be particularly prone to herpes infections; however, Nash noted that practically all the patients with herpes infections in both series had undergone intubation. He hypothesized that the intubation procedure might serve to carry herpesvirus from the oropharynx into the tracheobronchial tree and at the same time produce injury to the epithelial lining of the respiratory tract, thereby increasing its susceptibility
to infection. This is an interesting speculation and suggests an explanation for the biphasic (clinical) character of this patient’s respiratory problems. Her initial respiratory distress at the time of admission may well have been due to postpartum exacerbation of her SLE, with lupus pneumonitis. The appearance of the proliferative glomerular lesions in the kidney at the time of autopsy would be consistent with vasculitis of that duration; the vascular lesions in the heart appeared to be much more recent, on the other hand, and suggest that she still had active vasculitis. The white plaque-like lesions noted in the mouth and pharynx were undoubtedly herpetic and the source of the virus infection which developed in the lower respiratory tract after intubation. The exacerbation of her respiratory symptoms terminally is certainly readily explained by the extensive necrotizing, herpetic, tracheobronchitis and pneumonitis. The large doses of corticosteroids, along with the other medications the patient was receiving during this time, undoubtedly contributed to her vulnerability to infection by the herpesvirus.
REFERENCES 1.
2.
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The American Journal of Medicine
Volume 84
1055
