Hypereosinophilic syndrome

Hypereosinophilic syndrome (HES) is an infiltrative disease of eosinophils affecting multiple organs, including the lung. Hypereosinophilic syndrome differs from acute and chronic eosinophilic pneumonia clinically and usually necessitates treatment with alkylating agents and/or corticosteroids. We describe two patients with HES and pulmonary involvement. One of our patients developed the adult respiratory distress syndrome thought to be a complication of the HES. Aggressive treatment of HES in both cases combined with intensive support in the patient with ARDS resulted in prolonged survival.

The hypereosinophilic syndrome (HES) is a disorder affecting multiple organ systems and is caused by infiltration of tissues by mature eosinophils.[1-4] The inciting event is unknown, although an extreme form of the disease is a manifestation of eosinophilic leukemia. The Philadelphia chromosome has been found in many of these cases.[5] The previously dismal prognosis for idiopathic HES has improved since 1976 with the advent of treatment regimens using hydroxyurea, cytarabine (cytosine arabinoside), or vincristine and corticosteroids.[6-10]

Proposed criteria establishing a diagnosis of HES include the following: (1) peripheral eosinophilia greater than 1.5 x [10.sup.9]/[mm.sup.3]; (2) duration of disease greater than 6 months or earlier death; (3) documented multiorgan system dysfunction; and (4) exclusion of other causes of eosinophilia.[1,2] Affected individuals are usually men aged 20 to 50 years, but there is no racial or ethnic predilection. Several tissues and organs may be affected; the most critically involved are the heart and central nervous system.[2] The lung is affected resulting in nocturnal cough, productive sputum, wheezing, and dyspnea raising the suspicion of reactive airways disease. However, physiologic testing reveals no airflow limitation.[3] Radiographs have demonstrated focal or diffuse infiltrates, and atelectasis and pleural effusion can occur. Pulmonary hypertension has also been described in association with the HES.[4] Postmortem examination of lung usually shows infiltration by eosinophils. Edema, vascular congestion, thrombosis, and lung infarcts may also be observed. Hilar adenopathy has been reported rarely.[4] Adult respiratory distress syndrome (ARDS) has been described in both the acute and chronic form of eosinophilic pneumonia; however, eosinophilic pneumonia differs substantially both clinically and with regard to treatment for HES. We are not aware of the occurrence of ARDS with HES.

We describe a patient with HES who developed ARDS as a manifestation of her HES and was successfully treated with conventional chemotherapy and aggressive intensive care support. Further, we describe a second case of HES with lung involvement and review pulmonary involvement in HES.

CASE REPORTS

CASE 1

A 48-year-old Hispanic woman was thought to have chronic myelogenous leukemia with eosinophilia or HES. One month prior to hospital admission, her leukocyte count was 100,000/[mm.sup.3]; hydroxyurea therapy had been started. One day prior to transfer, her leukocyte count was 70,000/[mm.sup.3] with 43 percent eosinophils, platelet count was 127,000, hemoglobin was 14.8 g/dl, and hematocrit was 41.8 percent. Two days previously, weakness of the left arm and right leg had developed and was accompanied by altered mental status. She was transferred for further treatment.

The medical history was significant for hypertension and asthma; she had undergone cholecystectomy and hysterectomy. Medications included clonidine and prochlorperazine (Compazine) in addition to hydroxyurea. She was allergic to codeine. Cigarette smoking (20 pack-years) had been discontinued 1 month previously.

Examination showed a mildly overweight white woman who was afebrile with blood pressure of 132/62mm Hg and pulse of 116. She was disoriented to place and time and had decreased responsiveness. Gaze was preferentially to the right and dysconjugate although extraocular movements appeared normal. Weakness was evident in the left arm and left and right leg with increased muscle tone in the right leg. Reflexes were increased on the left. Bilateral Babinski signs were present and she withdrew from painful stimuli. The neck was supple, lungs were clear, and results of the cardiac examination were normal. There was evidence for diffuse abdominal tenderness without rebound tenderness.

Laboratory analysis was pertinent for an elevated leukocyte count of 56,600/[mm.sup.3] with 40 percent eosinophils and hypokalemia of 2.9 mEq/L. Results of other chemistry studies and urinalysis were unremarkable. Chest radiograph showed normal lung parenchyma with some haziness of the left costophrenic angle; the ECG revealed only nonspecific ST- and T-wave changes. She underwent a head computed tomographic (CT) scan that showed neither hemorrhage nor edema, but lesions were present in the right occipital and left parietal lobes and were interpreted as infarcts. Lumbar puncture was unrevealing. Upper and lower gastrointestinal endoscopy revealed gastric and colonic ulcerations. Biopsy specimens showed eosinophilic infiltration consistent with HES. Echocardiography demonstrated decreased left ventricular function with mild mitral and tricuspid regurgitation. No vegetations were seen. Magnetic resonance imaging (MRI) of the brain showed extensive white and gray matter disease that was most severe in the posterior circulation and was believed to be compatible with HES (Fig 1). Bone marrow biopsies were performed on two occasions for cytogenetic cultures. Marked increases in eosinophil numbers were noted.

Treatment with hydroxyurea, 1.5 g every day, and prednisone, 25 mg four times a day, continued. On the eighth hospital day, a urinary tract infection with Escherichia coli was treated with trimethoprim-sulfa. She was asymptomatic and afebrile.

Five days later, she experienced a diminution in her mental status, which had improved while in the hospital. A head CT scan showed no change, although a lumbar puncture showed pleocytosis; a chest radiograph showed a left upper lobe infiltrate. Apnea (greater than 10 s) and hypoxic respiratory failure (arterial blood gas on room air: pH, 7.44; [PaO.sub.2], 46; [Pco.sub.2], 34 percent; saturation, 84 percent) resulted in transfer to the medical ICU where she was intubated and mechanically ventilated. Treatment with piperacillin sodium and gentamicin, which was begun empirically, was changed to ceftazidime when E coli resistant to trimethoprim-sulfa grew from the cerebrospinal fluid.

When transferred from the ward, her chest radiograph revealed diffuse bilateral alveolar infiltrates compatible with pulmonary edema (Fig 2) and she was coughing up orange-pink frothy material. Edema fluid protein was greater than 92 percent of the serum protein (total protein, 4.6; pulmonary edema fluid protein, 4.2). Edema fluid was obtained within 1 h of intubation. A Swan-Ganz pulmonary artery catheter was placed. Swan-Ganz catheter measurements documented noncardiogenic pulmonary edema: right artrial pressure, 5 mm Hg; pulmonary artery systolic/pulmonary artery diastolic, 48/21 mm Hg; pulmonary catheter wedge pressure, 10 mm Hg; cardiac output, 4.6 L/min; and systemic vascular resistance, 1443 dynes*se*/[cm.sup.5]. A bronchoalveolar lavage (BAL) was performed. Gram stain was negative. Analysis of BAL fluid revealed sheets of eosinophils (greater than 75 percent) (Fig 3). Semiquantitative cultures yielded less than [10.sup.3] colonies of coagulase-negative staphylococci and 1 CFU of Candida species.

Pressor support using dopamine and dobutamine continued for 1 week. Hydroxyurea therapy was stopped and intravenous methylprednisoline sodium succinate (Solu-Medrol) was administered intravenously at 60 mg four times a day. The leukocyte count progressively declined from 28,000 with 25 percent eosinophils to 10,000 with 6 percent eosinophils.

Aggressive multisystem support continued. Weaning from mechanical ventilation was accomplished gradually over 10 days and was facilitated by tracheostomy. An MRI of the spine, electromyogram, and nerve conduction velocity were normal. Chest radiograph had normalized. Bone marrow biopsy specimen showed marked reductions in eosinophils. When the patient was discharged to a rehabilitation center 49 days after hospital admission, her leukocyte count was 14,300 with 3 percent eosinophils. Two years after hospital admission, she remains in remission with maintenance therapy, using corticosteroids and cytotoxic agents.

CASE 2

A 31-year-old black man was diagnosed as having eosinophilic pneumonia (bilateral interstitial pneumonia) in 1987 when he was found to have pulmonary eosinophilia on bronchoscopy (peripheral leukocyte count 14,800 with 51 percent eosinophils) and open lung biopsy (negative for granulomas or vasculitis). He was treated with oral corticosteroids for 5 months; at that time, he was symptomless and steroid therapy was tapered over several months. He remained well without receiving steroids for 3 years.

In December 1990, he developed cough and hemoptysis with radiographic pneumonia believed once again to be secondary to eosinophilia and was treated with oral corticosteroids. He initially responded and 3 months later the steroid dose had been tapered to every other day (20 mg). At that time, however, he experienced plantar dysesthesias (tingling) that progressed and then involved the calf muscle with pain. During an emergency evaluation, he had the acute onset of left facial numbness, dysarthria, pain in the left arm, and left frontal headache. These symptoms resolved over 30 to 60 s except the plantar dysesthesia. Simultaneously on examination he was hypotensive and tachycardic. Chest radiograph showed left upper lobe and left lower lobe infiltrates. He was admitted to the hospital and was begun on a regimen of stress-dose corticosteroids and subsequently developed fever to 38.3 [degrees] C orally. Empiric therapy with parenteral cefoperazone was initiated and he was transferred for further evaluation.

The medical history was insignificant; he never smoked and drank alcohol minimally. There was no occupational exposure in his job as a navigator.

On physical examination he was afebrile and the vital signs were normal. Lung examination revealed dullness over the right posterior chest. There was no egophony, wheezes, or rhonchi noted. Subjective tingling over the left foot was described, but sensation was intact. Otherwise, the findings from the examination were not contributory.

Chest radiograph revealed left upper and lower lobe interstitial/alveolar infiltrates (Fig 4). The leukocyte count was 18,100 with 13 percent eosinophils. Oxygenation was normal. Results of all other laboratory tests were normal. The day following transfer, his leukocyte count was 14,500 with 42 percent eosinophils while receiving intravenous steroids and antimicrobials. Bone marrow biopsy specimen showed increased eosinophilic precursors. A karyotype did not reveal the Philadelphia chromosome. All cultures remained negative, but he was treated for an adequate duration for possible bacterial pneumonia.

Despite continued steroid use, his peripheral eosinophilia persisted; hydroxyurea therapy was begun (1.0 g daily) with an initial dissolution of the eosinophilia. A pericardial and pleural effusion were documented on echocardiography. Fluid was not obtained for analysis. An MRI scan revealed increased uptake in the right temporal lobe consistent with HES.

Clinically there was difficulty over several months in continuing control of the eosinophilia; however, ultimately control was achieved with hydroxyurea. Nineteen months later, he is doing well while receiving therapy and continues to work full time.

DISCUSSION

Our first patient represents an example of ARDS occuring in the setting of HES. Although this patient had evidence of Gram-negative meningitis, the marked eosinophilia on the BAL suggests that the ARDS was at least in part caused by the HES. Other organ systems involved in this patient included the gastrointestinal tract, central nervous system, heart, and bone marrow. To our knowledge, this is the first report of ARDS occurring in the setting of the HES. The second patient represents HES manifesting itself with pulmonary and central nervous system disease. The initial presentation of this patient suggested chronic eosinophilic pneumonia, although the findings on bone marrow examination, the central nervous system findings, and the clinical course and response to therapy support a diagnosis of HES.

Eosinophilic infiltration of critical organ systems, particularly the heart and central nervous system,[11] is responsible for the protean clinical manifestations of HES. Prior to 1976, the outlook for HES was grave. After the use of chemotherapeutic agents such as hydroxyurea,[6-10] a more favorable course has been reported. Using a clinical grading system espoused by Schooley et al,[2] the requirement for treatment or expectation of treatment response may be cautiously predicted. A more aggressive disease course has been observed when cardiac or neurologic dysfunction is initially present. Using the criteria of Schooley et al, case 1 was deemed a candidate or cytotoxic therapy and steroids although a positive response could not be adequately predicted. In addition, her condition had worsened despite previous administration of hydroxyurea and prednisone. Leukopharesis was considered briefly,[12] but ultimately corticosteroid dosage was increased and hydroxyurea therapy was abandoned temporarily.

Hyperinfection with Strongyloides stercoralis should be considered in any patient with high eosinophil counts and pulmonary disease. Infestation/infection with Strongyloides was not proven in either case.

In 1968, Hardy and Anderson[1] defined HES. Further refinement occurred with the exclusion of identifiable etiologies.[13] Although case 1 had not had disease for 6 months, organ system infiltration had been documented and death could certainly have occurred at several points in her hospital course. Differentiation of HES from eosinophilic leukemia may be difficult to establish in the absence of the Philadelphia chromosome; we were unable to demonstrate its presence despite two attempts. Evidence for other myeloproliferative disease such as polycythemia rubra vera was also absent.[14]

Pulmonary involvement has been frequently observed in HES and may consist of focal or diffuse infiltrates.[3] Antemortem BAL analyses of patients with HES are lacking although many data are available in patients with chronic or acute eosinophilic pneumonia. ARDS has been described as occurring in chronic eosinophilic pneumonia and a delayed response to corticosteroids has been seen, although recovery thereafter has been rapid.[15] Severe hypoxemia necessitating mechanical ventilation in the presence of diffuse infiltrates and BAL evidence for eosinophils has been described in an acute form of eosinophilic pneumonia, but differs from HES in the immediate response to corticosteroids and prolonged state of remission as well as absence of involvement of other organ systems.[16] To our knowledge, ARDS has not been described previously in HES.[17-24] Infiltration of the meninges and brain

parenchyma by eosinophils may have potentiated the risk for secondary bacterial meningitis. As stated earlier, it is possible that the ARDS occurring in case 1 was the result of a sepsis syndrome complicating the meningitis; however, we believe that this potential cause was unlikely due to the results of the BAL (culture negativity and preponderance of eosinophils).

Although the mechanism whereby eosinophilic infiltration of the lung causes ARDS is unknown, it appears that ARDS can occur in the HES with multiorgan involvement as well as in acute and chronic eosinophilic pneumonia. Early BAL in these patients may serve to discriminate ARDS secondary to HES from other etiologies and help guide appropriate management.

REFERENCES

[1] Hardy WR, Anderson RE. The hyperosinophilic syndromes. Ann Intern Med 1968; 68:1220-28

[2] Schooley RT, Flaum MA, Gralnick HR, Fauci AS. A clinicopathologic correlation of the idiopathic hypereosiniphilic syndrome: II. Clinical manifestations. Blood 1981; 58:1021-26

[3] Spry CJF. The hypereosinophilic syndrome: clinical features, laboratory findings and treatment. Allergy 1982; 37:539-51

[4] Alfaham MA, Ferguson SD, Sihra B, Davies J. The idiopathic hypereosinophilic syndrome. Arch Dis Child 1987; 62:601-13

[5] Gruenwald H, Kidssoglou KA, Mitus WJ, Dameshek W. Philadelphia chromosome in eosinophilic leukemia. Am J Med 1965; 39:1003-10

[6] Parrillo JE, Fauci AS, Wolff SM. Therapy of the hypereosinophilic syndrome. Ann Intern Med 1978; 89:167-72

[7] Flaum MA, Schooley RT, Fauci AS, Gralnick HR. A clinicopathologic correlation of the idiopathic hypereosinophilic syndrome: I. hematologic manifestations. Blood 1981; 58:1012-20

[8] Van Slyck EJ, Adamson TC III. Acute hypereosinophilic syndrome. JAMA 1979; 242:175-76

[9] Eakin DL, Gill DP, Weiss GB. Response of hypereosinophilic syndrome to 6-thioguanine and cytarabine. Cancer Treat Rep 66:545-47, 1982

[10] Edwards D, Wald JA, Dobozin BS, Kirkpatrick CH. Troleandomycin and methylprednisone for treatment of the hypereosinophilic syndrome. N Engl J Med 1987; 317:573-74

[11] Martin-Gonzales E, Yebra M, Garcia-Merino A, Liano H. Neurologic dysfunction in the idiopathic hypereosinophilic syndrome. Ann Interm Med 1986; 104:448-49

[12] Blacklock HA, Cleland JF, Tan P, Pillai VM. The hypereosinophilic syndrome and leukapheresis. Ann Intern Med 1979; 91:650-51

[13] Chusid MJ, Dale DC, West BD, Wolff SM. The hypereosinophilic syndrome. Medicine 1975; 54:1-27

[14] Varon D, Wetzler M, Berrebi A. Hypereosinophilic syndrome associated with polycythemia vera. Arch Intern Med 1986; 146:1440-41

[15] Ivanick MJ, Donohue JF. Chronic eosinophilic pneumonia, a cause of ARDS. South Med J 1986; 79:686-90

[16] Allen JN, Pacht ER, Gadek JE, Davis WB. Acute eosinophilic pneumonia as a reversible course of non infectious respiratory failure. N Engl J Med 1989; 317:569-73

[17] Brandstetter RD. The adult respiratory distress syndrome--1986 Heart Lung 1986; 15:155-64

[18] Norwood SH, Civetta JM. The adult respiratory syndrome. Surg Gynecol Obstet 1985; 161:497-508

[19] Hudson DL. Causes of the adult respiratory distress syndrome: clinical recognition. In: Bone RC, ed. Clinics chest medicine. Philadelphia: WB Saunders Co, 1982; 195

[20] Fowler AA, Hanman RF, Good JT, Benson KN, Baird M, Eberle DJ, et al. Adult respiratory distress syndrome: risk with common predispositions. Ann Intern Med 1983; 98:593

[21] Petty, Ashbaugh D. The adult respiratory distress syndrome: clinical features, factors influencing prognosis and principles of management. Chest 1971; 60:233-39

[22] Petty TL. Adult respiratory distress syndrome: definition and historical perspective. In: Bone RC, ed. Clinics Chest Medicine. Philadelphia: WB Saunders Co, 1982; 3-7

[23] Baumann WR, Jung RC, Koss M, Boylen CT, Navarro L, distress syndrome: a prospective analysis from a large metropolitan hospital. Crit Care Med 1986; 14:1-4

[24] Schale DJ. The adult respiratory distress syndrome--20 years on. Thorax 1987; 42:641-45

COPYRIGHT 1994 American College of Chest Physicians
COPYRIGHT 2004 Gale Group