Fatal adult respiratory distress syndrome in a patient with Lyme disease.
Kirsch M, Ruben FL, Steere AC, Duray PH, Norden CW, Winkelstein A. JAMA1988 May 13; 259(18): 2737-9
www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract
Case
A 67-year-old woman who lived on a farm near Pittsburgh first noted lethargy, weakness, lower-extremity stiffness, and myalgias on May 16, 1986, one week after a weekend trip to the Maryland shore. Soon thereafter, a dry cough, swelling of her hands, fever, anorexia, and a rash on her extremities and trunk developed. Although she had no known history of a tick bite, a presumptive diagnosis of Rocky Mountain spotted fever was made, and a two-week course of tetracycline hydrochloride, 250 mg orally four times a day, was prescribed.
Because of persistent symptoms, she was referred to Montefiore Hospital in Pittsburgh. Examination showed a maculopapular eruption on her trunk and hands. Although antibody titers for Rocky Mountain spotted fever were negative, both the IgM and IgG antibody titers in response to the Lyme disease spirochete Borrelia burgdorferi were markedly elevated (Table), as determined by enzyme-linked immunosorbent assay.2 She completed her tetracycline course without improvement in her condition.
She was admitted to the hospital on June 17, 1986. Her temperature was 16.7oC. Liver function test results were abnormal (lactic dehydrogenase [LDH], 419 U/L; aspartate aminotransferase [ASAT], 639 U/L; alanine aminotransferase [ALAT], 418 U/L; and alkaline phosphatase, 223 U/L), but results of the remainder of the admission studies, including a serum VDRL test, chest roentgenogram, and electrocardiogram, were unremarkable. A skin biopsy specimen revealed nonspecific inflammatory changes. Because of the lack of response to tetracycline, she was given a ten-day course of intravenous penicillin G potassium, 5 million U every six hours. Her fevers resolved, and her rash, joint complaints, and liver enzyme abnormalities improved (LDH, 338 U/L; ASAT, 184 U/L; ALAT, 111 U/L; and alkaline phosphatase, 198 U/L). She was discharged on June 28.
At home, her rash worsened, and periorbital edema developed. Her constitutional symptoms persisted, and she was readmitted to the hospital five days later. Examination revealed an oral temperature of 38.1oC, a pulse rate of 112 beats per minute, and respirations of 20/min. In addition to the maculopapular rash and periorbital edema, there was moderate swelling and tenderness over the carpal and interphalangeal joints. There was no muscle tenderness or pedal edema, and the lungs were clear. The white blood cell count was 6.0 x 109/L (6.0 x 103/mm3); the erythrocyte sedimentation rate (Wintrobe) was 47 mm/h; and liver and muscle enzyme concentrations were elevated (LDH, 508 U/L; ASAT, 429 U/L; ALAT, 162 U/L; alkaline phosphatase, 286 U/L; and creatine kinase, 279 U/L). A chest roentgenogram showed atelectasis at the left base (Fig 1). The level of immune complexes was shown to be elevated by the C1q binding assay result of 36% (norms), <13%) and by the Raji cell assay result of 315 mg of aggregated human gamma globulin equivalents per liter (normal, <50 mg of aggregated human gamma globulin equivalents per liter). Serum cryoglobulins were absent. Antinuclear antibody was present in low titer (1:10), and rheumatoid factor was positive (1:40). The level of the C3 component of complement was mildly decreased, at 0.85 g/L (35 g/dl) (normal range, 1.15 to 1.85 g/L [115 to 185 mg/dl]). Titers for hepatitis A, hepatitis B, cytomegalovirus, Epstein-Barr virus, Trichinella, Legionella pneumophila, and febrile agglutinins were negative. The patient was given a second course of intravenous penicillin C potassium, 5 million U every six hours, and enteric coated aspirin 650 mg orally every four hours.
Initially, her rash, edema, and arthralgias improved, but her marked lethargy and dry cough persisted. On her tenth day in the hospital, bibasilar rales were noted, and a chest roentgenogram demonstrated new findings of bibasilar atelectasis with bilateral peripheral infiltrates. Prednisone therapy, 20 mg orally three times a day, was begun. While her rash and edema improved, her liver and muscle enzyme abnormalities worsened. An abdominal computed tomographic scan showed a nonhomogeneous liver and was otherwise unremarkable.
Four days later, her oral temperature rose to 38.9oC, and her respirations were 34/mm. Increased rales were present bilaterally. An arterial blood gas test done while the patient was breathing 35% 02 showed the following values: Arterial oxygen pressure, 68 mm Hg; arterial carbon dioxide pressure, 27 mm Hg; and pH, 7.55. The white blood cell count was 12.4 x 109/L (12.4 10 103/mm3), with 0.04 (4%) band forms. A chest roentgenogram showed diffuse, bilateral, patchy infiltrates (Fig 1). Blood and urine cultures showed no growth. Lyme disease antibody titers were still markedly elevated (Table). Immunoblotting demonstrated IgG antibodies against at least 14 polypeptides of B burgdorferi, including the 31-kilodalton outer-membrane component. Nafcillin and tobramycin therapy was started empirically.
On the following day, during bronchoalveolar lavage, the patient became tachypnoic and cyanotic and underwent intubation. A chest roentgenogram now showed bilateral central infiltrates. The patient was given intravenous trimethoprim with sulfamethoxazole, and nafcillin therapy was discontinued. She became increasingly more hypoxemic, requiring a positive end-expiratory pressure of 15 cm H2O and a fraction of inspired oxygen in the range of 0.8 to 0.9. On her 19th day in the hospital, an open-lung biopsy specimen revealed severe, acute, diffuse alveolar damage, compatible with the adult respiratory distress syndrome (ARDS). There was no evidence of tumor, infection, or vasculitis. She became progressively more hypoxemic and hypotensive, and she died six days later.
Pathologic Findings
The cause of death was diffuse alveolar damage of the lungs (ARDS). Additional findings were cardiomegaly (370 g with borderline right ventricular hypertrophy (0.3 cm), fatty liver (1600 g), and acute tubular necrosis of the kidneys. Lymph nodes showed a transformed lymphocytic response, and, when Dieterle silver stain was used,3 spirochetes compatible with B burgdorferi infection were demonstrated (Fig 2). Lung tissue was submitted for virus isolation and was found to be negative for influenza A and B, parainfluenza, respiratory syncytial virus, adenovirus, and coxoackievirus. Antibodies to Leptospira canicola and Leptospira icterohaemorrhoragiae antibodies were present at less than 1:8 by complement fixation testing and were not detectable by direct agglutination testing using serum from July 21, 1986, three days before the patient died.
Comment
After the first description of Lyme disease in 1975, the clinical spectrum was expanded to include cardiac and neurologic features. This disorder is now recognized to be a multisystemic disease that triggers a complex immune response to a spirochetal infection.
The patient described herein presented with cough, fever, a diffuse rash, and myositis, and she also had abnormal liver function test results. Her hospital course was essentially characterized by progressive respiratory failure and fatal ARDS. Levels of IgM and IgG antibodies were markedly increased in response to B burgdorferi, the agent that causes Lyme disease. This level of titers has been shown to exhibit cross-reactivity in patients with syphilis or relapsing fever. We excluded syphilis with a nonreactive VDRL test and relapsing fever with immunoblotting studies. Antibodies were demonstrated to 14 polypeptides of B burgdorferi, including the 31-kilodalton polypeptide, a pattern thought to be specific for Lyme disease. In addition, lymph node sections examined after the patients death demonstrated spirochetes morphologically compatible with B burgdorferi. We are confident that the serologic and histologic evidence described supports the diagnosis of Lyme disease.
The clinical features of our patient were, however, highly atypical for Lyme disease. Her rash was generalized and prominent on her hands. This distribution has not previously been reported in Lyme disease and contrasts with erythema chronicum migrans, the unique clinical marker for this disorder. Although mild hepatitis has been described,markedly abnormal liver enzyme levels, myositis, and edema of the hands and face are not characteristic of Lyme disease. Most important was her progressive and fatal respiratory failure. The only respiratory symptom described in human Lyme disease is a nonproductive cough, although spirochetes have been demonstrated in the lungs of experimentally infected hamsters. Since it is recognized that ARDS follows a wide variety of predisposing conditions we believe that Lyme disease triggered this fatal complication.
How can we explain our patients variant clinical syndrome? This case is atypical in its presentation, course, response to therapy, and outcome. This patient received a course tetracycline followed by two courses of high-dose intravenous penicillin, without improvement. Both of these antibiotic regimens are considered to be established antispirochetal therapy for Lyme disease. This suggests that the spirochete was particularly virulent, that the host defenses were impaired, or that the disease state no longer solely depended on live spirochetes for its expression. We do not believe that our patient was immunocompromised. The mechanism by which B burgdorferi causes Lyme disease is still under study. It is unclear whether certain manifestations of Lyme disease require a live spirochete for continued disease activity or whether they result from immune-mediated mechanisms. Although spirochetes were identified in lymph nodes, the transformed lymphocytic response, the presence of circulating immune complexes and the progression of disease despite antibiotic treatment indicate an immune-mediated disease.
Lyme disease has become a prevalent and serious infection. In addition to chronic arthritis, this disease has been shown to be the cause of fatal myocarditis, panophthalmitis leading to blindness,1 fetal death, and central nervous system syndromes suggestive of demyelination.To these complications we add respiratory failure and ARDS, which are refractory to known therapy. Although Lyme disease is endemic in the Northeast, the Midwest, and the Far West of the United States, it has been reported throughout the country.
With an incubation period that ranged from three to 12 day and no documented tick bite, we are uncertain whether our patient contracted the disease in Maryland or in western Pennsylvania.
We urge physicians throughout the United States to consider the multisystemic features of Lyme disease and to recognize its lethal potential.
