Pulmonary aspergillosis and central nervous system hemorrhage as complications of autoimmune hemolytic anemia treated with corticosteroids. (Case Report).

Abstract

Warm, active antibody adult autoimmune hemolytic anemia is the most common form of hemolytic anemia not related to drug therapy. Mortality in adult autoimmune hemolytic anemia is related to the inability to successfully treat patients' underlying disease, or the infectious complications of splenectomy and prolonged steroid therapy. Predisposing factors for invasive aspergillosis are neutropenia and steroid therapy. We present a fatal case of aspergillosis complicating a nonneutropenic case of warm active antibody adult autoimmune hemolytic anemia treated with prolonged steroid therapy.

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The most frequently encountered form of non-drug-related adult autoimmune hemolytic anemia (AIHA) is disease caused by immunoglobulin (Ig) G warm, active antibodies (WAA). (1) Unlike pediatric AIHA, the adult form of the disease is more often associated with underlying lymphoproliferative, autoimmune, or infectious diseases. (1,2) When treatment of the underlying disease is not possible or folate supplements fail to permit adequate bone marrow compensation for hemolysis, steroid therapy is instituted. (1) Infectious complications have most often been the result of steroid therapy or splenectomy. Adult AIHA has a higher mortality because of the presence of a serious underlying disease or complications of therapy. (3) We report a fatal case of steroid-treated AIHA complicated by pulmonary aspergillosis and a cerebral hemorrhage without evidence of central nervous system invasion by the fungus.

Discussion

AIHA seems to be different diseases in adults and children. (1,2) Pediatric AIHA is fairly common, is rarely associated with underlying disease, and may spontaneously resolve or readily respond to steroids. Splenectomy is seldom required for treatment (1,2) Pediatric AIHA may appear in infancy or childhood, is usually preceded by a nonspecific viral illness, has a sudden and severe onset, and has a male predominance. (1) Immune thrombocytopenia associated with AIHA (Evans syndrome) is seen in both adult and pediatric patients, although more commonly in childhood, and may be more difficult to treat. (1,2) Pediatric disease has a 9 to 29% mortality, usually from severe anemia or hemorrhage from thrombocytopenia. Chronic and adult disease has a higher mortality because of the inability to treat serious underlying diseases or complications of therapy. (3)

Further classification separates AIHA into those with 1) cold-active antibodies (CAA), 2) mixed CAA and WAA, and 3) WAA, (1,2) CAA (usually IgM antibodies against red blood cell [RBC] I antigen, rarely IgG, IgA antibodies, or mixed IgM-IgG antibodies seen in infectious mononucleosis) increase titers and RBC binding as temperatures approach 0[degrees]C. (1) Twenty percent of AIHA is caused by CAA.(1) CAA (causing cold agglutinin disease) may be idiopathic or secondary to lymphoproliferative, autoimmune, or infectious diseases (ie, Mycoplasma pneumnoniae, mononucleosis, or other viruses). (1) Paroxysmal cold hemoglobinuria is a form of CAA disease caused by a cold-active IgG hemolysin (Donath-Landsteiner antibody) and is seen in patients infected with syphilis, measles, mumps, and other viruses. (1)

Up to 35% of patients with WAA have small concentrations of CAA that agglutinate normal RBCs at 20[degrees]C. (2) Rare patients with WAA have cold-active IgM antibody with highest activity at 4[degrees]C and varying activity through 37[degrees]C. (1)

More than 70% of patients with AIHA (excluding drug-induced disease) have isolated WAA. These antibodies are usually IgG with peak activity at 37[degrees]C, may or may not fix complement, and cause hemolysis of RBCs in the spleen. (1) WAA AIHA may be idiopathic; secondary to lymphoproliferative diseases, autoimmune diseases, malignancies, viral infections, or immune deficiencies; or drug induced. (1)

Drug-induced AIHA may be a manifestation of the following:

1. Drug binding to the RBC membrane and antibody attaching to the drug ("drug absorption mechanism-penicillin type ")

2. "Neoantigen," formation of a trimolecular complex of drug and specific alloantigen on the RBC interacting with antibody (neoantigen mechanism-quinidine/slibophen type)

3. Autoimmune hemolysis in which antibodies bind to the RBC membrane in a manner indistinguishable from sporadic AIHA. It is caused by drugs inducing autoimmune RBC antibodies (autoimmune mnechanism-[alpha]-methyldopa type) (1)

Steroids, splenectomy, and plasmapheresis are generally unsuccessful in the treatment of cold agglutinin disease. When treatment is necessary, immunosuppressive therapy (usually chlorambucil or cyclophosphamide) has had the most success, with transfusion reserved for severe cases. Treatment of WAA AIHA or mixed WAA and CAA AIHA, when necessary, consists of treatment of the secondary disorder if possible, and folate replacement when necessary. When the bone marrow can no longer compensate for the hemolysis, glucocorticoids are the initial therapy of choice. Transfusion or splenectomy may become necessary. When these modalities fail, immunosuppressive drugs have resulted in a 40 to 60% response rate. Plasmapheresis has had limited success. Intravenous immunoglobulin administration has had mixed clinical results. Danazol and steroids, vinca-loaded platelets, and thymectomy in infants have also been attempted. (1)

Infectious complications of AIHA have been most often associated with treatment, particularly steroid therapy and splenectomy. (1,3) Aspergillosis has infrequently been reported as a complication of AIHA. (2) Aspergillus species are ubiquitous fungi infecting humans after inhalation of conidia. (4,5) Conidia are killed by alveolar macrophages. (6,7) Those that escape the macrophages and convert to the invasive mycelial form are killed by polymorphonuclear leukocytes.

Corticosteroids impair conidicidal activity of macrophages and neutrophils. (8,9) Mechanisms. include suppression of mobility, adherence, chemotaxis, superoxide production, release of lactoferrin and lysozyme, phagocytosis, and expression and function of the Fc receptors. (9) In animal models, corticosteroids inhibit the capacity of alveolar macrophages to restrict the invasive process of Aspergillus species. (9) There is in vitro evidence that these effects may be reversed by treatment with granulocyte colony-stimulating factor and interferon-[gamma]. (9) In fact, glucocorticoids may inhibit antimicrobial activity of macrophages without affecting their responsiveness to interferon[gamma]. (10) There is in vivo evidence that granulocyte colony-stimulating factor may antagonize triazole antifungal agents when given to hydrocortisone immune-suppressed mice. (5)

Hydrocortisone has been shown to increase the in vitro growth rate of human (pathogenic) isolates of A. fumigatus, and laboratory isolates of A.flavus, A. oryzae, and A. nigerby 30 to 40%. (8) Ergosterol increased the growth rate by 21%. No significant effect was seen with testosterone, estradiol, or progesterone. (8)

Conclusion

The principal risk factors for invasive and disseminated aspergillosis are neutropenia and steroid therapy. (5,7,8) Infection, one of the two principal complications of AIHA, is the result of steroid treatment. Our case raises the question of whether antifungal prophylaxis or presumptive treatment should be considered in the nonneutropenic AIHA patient being treated with hydrocortisone or other steroids.

Accepted October 1, 2002

References

(1.) Thomas AT. Autoimmune hemolytic anemias, in Lee GR, Foerster J, Lukens J, Paraskevas F, Greer JP, Rodgers GM (eds): Wintrobe's Clinical Hematology. Philadelphia, Lippincott Williams & Wilkins, 1999, vol 1, ed 10, pp 1233-1263.

(2.) Friedmann AM, King KE, Sirey RS, Resar LM, Casella JF. Fatal autoimmune hemolytic anemia in a child due to warm-reactive immunoglobulin M antibody. J Pediatr Hematol Oncol 1998;20:502-505.

(3.) Schreiber AD. Hemolytic anemias: autoimmune, in Goldman L, Bennett JC, Drazen JM, Gill GN, Griggs RC, Kokko JP, et al (eds): Cecil Textbook of Medicine. Philadelphia, W.B. Saunders Co., 2000, ed 21, pp 876-882.

(4.) Denning DW. Aspergillus species, in Mandell GL, Bennett JE, Dolin R (eds): Mandell, Douglas, and Bennett's Principles and Practice of infections Diseases. Philadelphia, Churchill Livingstone, 2000, ed 5, pp 2674-2685.

(5.) Graybill JR, Bocanegra R, Najvar LK, Loebenberg D, Luther MF. Granulocyte colony-stimulating factor and azole antifungal therapy in murine aspergillosis: role of immune suppression. Antimicrob Agents Chemother 1998;42:2467-2473.

(6.) Levitz SM, Diamond RD. Mechanisms of resistance of Aspergillus fumigatus conidia to killing by neutrophils in vitro. J Infect Dis l985;152:33-42.

(7.) Schaffner A, Douglas H, Braude A. Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytes in resistance to Aspergillus: Observations on these two lines of defense in vivo and in vitro with human and mouse phagocytes. J Clin Invest 1982;69:617-631.

(8.) Ng TTC, Robson GD, Denning DW. Hydrocortisone-enhanced growth of Aspergillus spp: Implications for pathogenesis. Microbiology 1994; 140:2475-2479.

(9.) Roilides E, Uhlig K, Venzon D, Pizzo PA, Walsh TJ. Prevention of corticosteroid-induced suppression of human polymorphonuclear leukocyte-induced damage of Aspergillus fumigatus hyphae by granulocyte colony-stimulating factor and [gamma]-interferon. Infect Immun 1993;61:4870-4877.

(10.) Schaffner A. Therapeutic concentrations of glucocorticoids suppress the antimicrobial activity of human macrophages without impairing their responsiveness to [gamma]-interferon. J Clin Invest 1985;76:1755-1764.

RELATED ARTICLE: Key Points

* Aspergillosis is infrequently reported as a complication in autoimmune hemolytic anemia.

* Mortality associated with autoimmune hemolytic anemia is related to inability to treat underlying disease, infectious complications, and long-term steroid therapy.

* Principal risk factors of aspergillosis are neutropenia and steroid therapy.

Case Report

A 31-year-old Filipino woman of Asian descent was in good health until 2 months before admission, when she developed pharyngitis for which she was treated in a walk-in clinic with oral azithromycin. The patient had no previous history of allergies, rarely used alcohol, smoked cigarettes 1 pack per day but stopped when she became ill, and never used illicit drugs. Her father had coronary artery disease. While taking this antibiotic, the patient developed fatigue, lethargy, and loss of appetite. Two weeks after her initial visit, she returned, was sequentially treated with oral levofloxacin and gatifloxacm, and was self-administering undetermined quantities of acetaminophen for the entire course of her illness. Routine laboratory studies on the last visit to the walk-in clinic revealed abnormal liver function studies, but she failed to return to the clinic as requested. Seven weeks after becoming ill, she presented to another hospital's emergency room with progressive weakness, jaundice, Key Points and poor or al intake. She was admitted and diagnosed with hemolytic anemia. She was treated with steroids but developed sinus tachycardia and an altered mental status. The patient's initial hemoglobin was 7.0 g/dl and hematocrit was 21%, which fell to a hemoglobin of 5.0 g/dl and hematocrit of 16%. Computed tomography of the head and lumbar puncture were normal. Intravenous immunoglobulin and haloperidol were administered, and the patient was subsequently transferred on the sixth hospital day to our institution for plasmapheresis. At the time of transfer, she was receiving a reduced dose of hydrocortisone (80 mg IV every 12 hours), ampicillin-sulbactam, metoprolol, and famotidine.

On admission, the patient was lethargic but able to follow commands and only complained of shortness of breath and nausea. On physical examination, the patient's oral temperature was 36.l[degrees]C (97[degrees]F), blood pressure 125/92 mm Hg supine, pulse rate 132 beats/mm, and respiratory rate 31 breaths/mm while receiving 2 L/min of oxygen by nasal cannula. The patient was pale and had scattered wheezes on auscultation. Except for lethargy, the neurologic examination was nonfocal.

Initial laboratory values were white blood cell count of 11,700/[mm.sup.3] with 69% neutrophils, platelet count 168,000/ [mm.sup.3], hemoglobin 4.8 g/dl, and hematocrit 14.3%. The patient's admission chemistry studies revealed a blood urea nitrogen 43 mg/dl, creatinine 1.5 mg/dl, total bilirubin 1.5 mg/dl, alanine aminotransferase 68 U/L, aspartate aminotransferase 146 U/L, alkaline phosphatase 310 U/L, amylase 233 U/L, and lipase 197 U/L. There was a positive direct antiglobulin test (direct Coombs test). An elution study showed a warm IgG panagglutinin. No alloantibodies were present.

During her hospital course, the patient received supportive therapy and was transfused with 4 U of packed red blood cells without adverse reaction. She was treated with hydrocortisone 80 mg IV every 12 hours, ampicillin-sulbactam, heparin for deep vein thrombosis prophylaxis, haloperidol, famotidine, and antihypertensive agents. Her creatinine rose to 1.7 mg/dl.

The patient was given LV hydration, daily IV immunoglobulin 0.5 g/kg, and hydrocortisone 80 mg IV every 12 hours. By the fifth hospital day, the patient had dramatically improved with normal mentation and limited walking. Rehabilitation was begun, and the patient was transferred from the intensive care unit to a step-down telemetry unit. On the morning of hospital day 8, the patient deteriorated neurologically. She became comatose. Her left pupil dilated to 4 mm, and she assumed bilateral decorticate posturing and was hyperreflexic. Computed tomography of the head showed a massive left frontal intracerebral bleed (Fig. 1). She was intubated, and a sputum culture taken from the endotracheal tube grew Kiebsiella pneumoniae. Later that same day neurologic reevaluation was consistent with brain death. The patient died the next day.

Postmortem examination revealed multifocal necrotizing pneumonia, severe acute pancreatitis, and extensive peripancreatic and retroperitoneal fat necrosis. Invasive hyphae consistent with Aspergillus species were identified in lung tissue. Culture of lung tissue grew Aspergillus and Candida species. Examination of the brain showed a large recent intracerebral hemorrhage (Fig. 2).

From the Departments of Medicine and Pathology, St. Francis Medical Center, Seton Hall University School of Graduate Medical Education, Trenton, NJ.

Reprint requests to Dennis J. Cleri, MD, Director, Internal Medicine Residency Program, St. Francis Medical Center, 60 1 Hamilton Avenue, Room B-158, Trenton, NJ 08629-1986. Email: [e-mail]

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