Leptospirosis

The literature on diffuse alveolar hemorrhage heavily emphasizes the causal role of vasculitides. We present a patient with diffuse alveolar hemorrhage caused by leptospirosis. Although the pathology in leptospirosis occurs secondary to a vasculitic process, this disease is not listed as a cause of diffuse alveolar hemorrhage in the review literature. In the right clinical scenario, the disease should be considered in a patient presenting with diffuse alveolar hemorrhage.

Key words: diffuse alveolar hemorrhage; hemoptysis; interstitial nephritis; leptospirosis; pulmonary hemorrhage; vasculitis

Abbreviations: ALT = alanine transaminase; AST = aspartate transaminase; EIA = enzyme-linked immunoassay

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The syndrome of diffuse alveolar hemorrhage consists of hemoptysis, bilateral airspace opacification on the chest radiograph, and a decreased hematocrit secondary to bleeding from the pulmonary microvasculature into the alveolar space. Many reviews divide its causes into those associated with vasculitis and those from other factors, (1-5) while others focus solely on the vasculitides. (6-12) Few, however, include an important cause of pulmonary hemorrhage--leptospirosis.

CASE REPORT

A 46-year-old homeless man complained of 5 days of nausea, watery diarrhea, myalgias, dizziness, and headache. While ill, he had little oral intake and spent most of his time sleeping in the woods. His temperature was 38.2[degrees]C (100.7[degrees]F), and his BP was 58/20 mm Hg while standing. Laboratory results were as follows: sodium, 133 mEq/L; bicarbonate, 21 mEq/L; BUN, 17 mg/dL; and creatinine, 1.5 mg/dL. Liver test results were as follows: aspartate transaminase (AST), 35 U/L (normal < 37 U/L); alanine transaminase (ALT), 24 U/L (normal < 40 U/L); alkaline phosphatase, 70 U/L (normal < 117 U/L); and total bilirubin, 2.6 mg/dL, with a direct component of 0.6 mg/dL. WBC count was 11.9 x [10.sup.3]/[micro]L, hematocrit was 40.2%, and platelets were 167 x [10.sup.3]/[micro]L. Urinalysis revealed 1+ protein, 3+ blood, 9 to 30 RBCs, 0 to 4 WBCs, and no casts.

After volume repletion, the patient felt significantly better and his serum creatinine level decreased to 1.1 mg/dL: however, on hospital day 3 the serum creatinine level rose to 1.6 mg/dL despite adequate oral intake. That night, his temperature was 39[degrees]C (102.2[degrees]F). A chest radiograph demonstrated bilateral patchy infiltrates (Fig 1). interpreted as a multilobar pneumonia. He received ceftriaxone and azithromycin.

[FIGURE 1 OMITTED]

The following day, he had multiple episodes of hemoptysis (< 100 mL total) and required intubation for hypoxemia. His chest radiograph demonstrated diffuse bilateral infiltrates (Fig 2). Pulmonary artery catheterization showed a normal pulmonary capillary wedge pressure, and bronchoscopy revealed a RBC count in the lavage fluid that increased with each successive sample, suggesting alveolar hemorrhage. Bacterial, mycobacterial, viral, and fungal culture findings of the fluid were negative.

[FIGURE 2 OMITTED]

Laboratory studies that day were as follows: serum bicarbonate, 20 mEq/L; BUN, 32 mg/dL; creatinine, 3.1 mg/dL; and WBC count, 3.6 x [10.sup.3]/[micro]L. The hematocrit, which was 30.5% on day 2 following IV hydration, was now 27%. AST and ALT had risen to 78 U/L and 62 U/L, respectively, while the total bilirubin was 3.7 mg/dL. Alkaline phosphatase was 223 U/L, and creatine phosphokinase was 411 U/L with normal creatine kinase-MB and troponin levels. Urine output remained normal, but urinalysis revealed 11 to 30 WBCs and 0 to 3 RBCs per high-power field, 2+ protein, 3+ blood, coarse granular casts, and red cell casts. A renal biopsy showed acute tubulointerstitial nephritis with hemorrhagic features, but no evidence of glomerulonephritis. The patient received a course of systemic corticosteroids and a change in antibiotics to levofloxacin for possible Legionella infection.

The patient's respiratory and renal function improved, but on day 8 his AST and ALT, which had normalized 2 days earlier, rose to 133 U/L and 121 U/L, respectively. Total bilirubin, which had also decreased after rising earlier in the hospital admission, was 6.8 mg/dL. The patient received oral doxycycline, 100 mg bid, for possible leptospirosis, confirmed later by positive serologies: IgM of 135 enzyme-linked immunoassay (EIA) units and IgG of 39 EIA units (normal < 20 EIA units).

Chest CT scan on day 13 showed diffuse airspace disease involving all lobes with bilateral ground-glass opacities. The patient revealed that while in the woods, he had seen rats, and several times, after dropping food onto the dirt where the animals had been, he had picked it up and eaten it. After continued improvement, he was discharged with instructions to complete a 14-day course of doxycycline.

DISCUSSION

Leptospirosis, a zoonosis caused by spirochetes from the species Leptospira interrogans, occurs worldwide, but is commoner in tropical regions. Wild or domestic animals, including rats, mice, sheep, cattle, pigs, dogs, raccoons, and goats, are its reservoir. (13,14) Infected animals, even immunized ones, excrete the organism in the urine, and it can persist for several months in the environment with suitable temperature (28 to 32[degrees]C), moisture, and pH (neutral to slightly alkaline). (15-17) Humans become infected from direct contact with the urine of infected animals or from exposure to soil, water, or other matter contaminated with it. Those with occupational risk include farmers, ranchers, loggers, trappers, veterinarians, flee-field laborers, and sewer workers. Recreational activities such as swimming, canoeing, hunting, and trail-biking may also involve contact with the organism. (17,18) The spirochetes enter the host through abraded skin or intact mucous membranes and travel to the liver where they reproduce. After an incubation period of 2 to 30 days (usually 5 to 14 days), leptospiremia occurs, spreading organisms to all parts of the body including the meninges. (17,19,20)

Leptospirosis produces numerous clinical findings, but two general patterns occur. In the less severe and generally nonfatal form, often called anicteric leptospirosis and accounting for 90% of cases, the illness commonly begins abruptly and includes headache, myalgias, conjunctival suffusion and other ocular abnormalities, fever, nausea, vomiting, rash, and meningismus. Epistaxis or other minor bleeding can occur, as can myocarditis. In addition to these features, the more severe form of leptospirosis, called icteric leptospirosis or Weil disease, causes jaundice, renal impairment, and major hemorrhagic complications. Laboratory abnormalities include leukocytosis and thrombocytopenia. Myositis may cause elevated muscle enzymes. In icteric leptospirosis, the serum bilirubin typically remains < 20 mg/dL, although values as high as 60 to 80 mg/dL can occur. Transaminases are also usually elevated but rarely exceed 200 U/L. (17) In 20 to 40% of icteric cases, renal impairment develops, accompanied by elevations in BUN (typically < 100 mg/dL) and creatinine (usually 2.0 to 8.0 mg/dL), as well as proteinuria, hematuria, and pyuria. (17) Fatalities, significantly more frequent in the icteric form, typically arise from renal, cardiac, or respiratory failure. Both mild and severe cases often have a biphasic pattern, with an initial "leptospiremic" period and a subsequent "immune" phase marked by antibody production and urinary excretion of leptospira. (17,21,22) This sequence occurred with our patient. The first phase usually lasts 4 to 9 days, followed by 1 to 3 symptom-free days, and then the second phase of fever and other features, especially aseptic meningitis.

Several laboratory methods establish the diagnosis. Early in the disease, cultures of blood, urine, and even cerebrospinal fluid can grow the spirochete in special media. Alternatively, demonstrating the presence of IgM-class antibodies or a fourfold rise in IgG titers between acute and convalescent sera by EIA (17,21) is diagnostic. Penicillin is the usual therapy, (23) but doxycycline is also effective in shortening the illness (24) and in preventing infection in high-risk circumstances. (25)

Pulmonary symptoms occur in both the nonicteric and icteric forms, including chest pain secondary to myositis (18) or with a pleuritic character. (26) Cough develops in up to 57 to 63% of cases. (27,28) Many case reports, (19,26) clinical series, and descriptions of outbreaks document the frequent occurrence of hemoptysis and diffuse pulmonary hemorrhage. Fourteen cases of pulmonary hemorrhage occurred among 75 patients (19%) in the Seychelles, and all six deaths were from this cause. (29) In a 1987 epidemic in Korea, 37 of 93 patients (40%) with leptospirosis had hemoptysis, massive in all 5 patients who died. (30) Hemoptysis occurred in 50% of 168 cases in China between 1959 and 1960 (27) and 13% of 115 patients hospitalized with severe leptospirosis in Brazil. (21)

Radiographic findings commonly accompany pulmonary symptoms but may occur without them. In one series, 82% of patients with hemoptysis had abnormal chest radiographic findings,l" These changes appear as early as 24 h after symptoms begin, although more commonly 3 to 9 days later.23 Three radiographic patterns occur: (1) small "snowflake-like" nodular densities corresponding to areas of alveolar hemorrhage, (2) large confluent consolidations, and (3) a diffuse, ill-defined ground-glass pattern that may represent resolving hemorrhage? Serial radiographs may show progression from a nodular pattern to confluent consolidation, a sequence seen in our patient (Figs 1, 2).

Leptospira cause disease through a toxin-mediated process by inducing vascular injury, particularly a small-vessel vasculitis. (31-34) The specific toxin responsible remains unidentified, but possibilities include outer membrane proteins, (35) membrane glycolipoproteins, (36) hemolysins, (37) and lipopolysaccharides. (38) The vasculitis producing pulmonary hemorrhage primarily affects capillaries. (31,33) Diffuse petechiae involve the lung parenchyma, pleural surfaces, and tracheobronchial tree. Microscopic examination usually demonstrates areas of intra-alveolar and interstitial hemorrhage, but other findings, including pulmonary edema, fibrin deposition, hyaline membrane formation, and proliferative fibroblastic reactions, are frequent. (31) Leptospira are uncommon in the lung tissue, (33,34) although leptospiral antigen is present at sites of tissue injury. (39) Inflammatory infiltrates are generally not prominent. (31,39) Electron microscopic studies reveal the primary lesion as damage to the capillary system: endothelial cells swell and detach from the basement membrane leaving areas of exposed interstitium, even in areas free of hemorrhage. (33,34,39)

Although vasculitis is the primary mechanism of pulmonary hemorrhage in leptospirosis, this disease is generally absent from differential diagnoses in reviews on diffuse alveolar hemorrhage. In the proper setting, clinicians should consider this infection in patients with that syndrome, especially since the clinical features of leptospirosis are nonspecific and the histopathologic findings similar to the other causes of pulmonary capillaritis that produce diffuse alveolar hemorrhage.

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* From the Department of Medicine (Dr. Luks), University of Washington, Seattle; and Divisions of Pulmonary and Critical Care Medicine (Dr. Lakshminarayanan) and General Internal Medicine (Dr. Hirschmann), Veterans Affairs Medical Center, Seattle, WA.

Manuscript received April 3, 2002; revision accepted July 11, 2002.

Work for this article was performed at the Veterans Affairs Medical Center and the University of Washington Medical Center in Seattle, WA.

Correspondence to: Jan v. Hirschmann, MD, Veterans Affairs Medical Center, 1600 South Columbia Way, Seattle, WA 98108; e-mail: pepsi@u.washington.edu

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