Hemophagocytosis Secondary to Mycoplasma pneumoniae Infection

KULWANT GILL, M.D. A patient with hemophagocytosis secondary to Mycoplasma pneumon- THOMAS J. MARRIE, M.D., F.R.C.P.(C.) iae is described. This adds another entity to the already protean

Halifax, Nova Scotia, Canada manifestations of M. pneumoniae infection.

From the Departments of Medicine and Microbi- ology, Dalhousie University’and Victoria General Hospital, Halifax, Nova Scotia, Canada. Re- quests for reprints should be addressed to Dr. Thomas J. Marrie, Room 4090 A.C.C., Victoria General Hospital, 1278 Tower Road, Halifax, Nova Scotia, B3H 2Y9, Canada. Manuscript sub- mitted March 14, 1986, and accepted March 27, 1986.

In recent years, it has been increasingly recognized that reactive histio- cytic proliferation with prominent hemophagocytosis can occur in pa- tients with infections and malignancies. This so-called virus-associated hemophagocytosis [l] complicates other infectious diseases, including tuberculosis [2], typhoid fever [3], brucellosis [4], leishmaniasis [5], and Q fever [6]. Histiocytic hemophagocytosis has also been described in patients with malignancies, especially T cell lymphomas [7]. I’ve de- scribe a patient with transient hemophagocytosis, caused by bone mar- row histiocytes, that was secondary to Mycoplasma pneumoniae infec- tion.

CASE REPORT

A 27-year-old white man was admitted to the Victoria General Hospital with fever and a rash. He was well until one week before admission, when malaise, excessive fatigue, backache, anorexia, and nausea with occa- sional vomiting developed. Two days before admission, he experienced chills and rigors followed by fever. One day before admission, he noticed a maculopapular rash, which first appeared on the dorsum of hands and feet and became generalized overnight. His only medication was acetylsalicy- clic acid for symptomatic relief of fever and backache. There was’no history of similar illness among his close contacts.

Physical examination at the time of admission revealed an acutely ill, alert man with an oral temperature of 40.5’%, a pulse of 120 beats/minute, blood pressure of 120/60 mm Hg, and a respiratory rate of 22/minute. There was a generalized erythematous maculopapular rash with target lesions. The lips and oral mucosa were ulcerated. Bullous lesions were present in his external ear canals. There was no lymphadenopathy or hepatosplenomegaly.

Laboratory tests revealed a white blood cell count of 3.9 X log/liter with 54 percent segmented neutrophils, 33 percent bands, 11 percent lympho- cytes, 1 percent monocytes, and 1 percent eosinophils. The hemoglobin level was 129 g/liter and the platelet count was 78 X log/liter. The results of initial chest radiography were normal. The serum creatinine level was slightly elevated at 133 PM/liter. The serum glutamic oxaloacetic transami- nase level was 40 IU/ml and the lactic dehydrogenase level was 482 IU/ml. Partial thromboplastin time was increased at 37.5 seconds; prothrombin time was normal. There was proteinuria of 1 g/liter. The diagnosis was

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probable M. pneumoniae infection and treatment with erythromycin was started after blood and throat culture specimens were obtained.

The patient remained febrile with temperatures up to 40.5OC. His respiratory rate increased to 30 to 40/minute, and crackles were noted at both lung bases. He became confused on the third day of his hospitalization. The serum glutamic pyruvic transaminase level increased to 108 IU/ml, serum glutamic oxaloacetic transaminase level in- creased to 249 IU/ml, lactic dehydrogenase level increased to 614 IU/ml, and creatine phosphokinase level was elevat- ed to 776 IU/ml. The platelet count remained low at 78 X log/liter. The platelet-associated IgG was normal at a level of 2.7 pg/platelet. Bone marrow aspiration revealed normal cellularity with normal maturation of myeloid, erythroid, and megakaryocytic series. There was an increased number of benign-looking histiocytes with prominent erythrophagocy- tosis, thrombophagocytosis, and leukophagocytosis (Fig- ure 1). Results of blood and urine cultures were negative. A stool test for enteroviruses was negative by both culture and direct electron microscopic examination. Tests for antinuclear antibodies had negative results, as did tests for cold agglutinins. On the fourth day of admission, the patient started therapy with hydrocortisone sodium succinate, 100 mg intravenously every six hours. There was marked im- provement over the next few days. He became afebrile and respirations returned to normal within three days. The ste- roid dosage was gradually tapered, and he was discharged from the hospital 10 days after admission. At the time of his discharge, his hemoglobin level was 147 g/liter, platelet count was 446 X log/liter, and white blood cell count was 9.4 X log/liter. Liver function test results and partial throm- boplastin time had returned to normal levels. Convalescent titers for M. pneumoniae revealed a diagnostic eight-fold increase to 1:256 from acute titers of less than 1:32. Antibody titers to adenovirus, cytomegalovirus, and Ep- stein-Barr virus were absent or unchanged. The reagin screen test for syphilis had a negative result.

COMMENTS

Disorders of histiocytic proliferation with prominent he- mophagocytosis have been classified [ 1,8] into benign, or reactive and malignant, depending upon the morphologic features, sites of involvement, presence of infection, and course of the disease. Histiocytic medullary reticulosis, which was originally described by Scott and Robb-Smith [9] in 1939, is a fatal disorder of histiocytic proliferation that manifests malignant characteristics. The disease has been renamed malignant histiocytosis [IO]. Proliferating histiocytes in this disorder have a high ratio of nucleus to cytoplasm, large nuclei with nuclear chromatin, promi- nent nucleoli, and basophilic cytoplasm. However, hemo- phagocytosis in malignant histiocytosis is usually ob- served in patients with more benign-looking histiocytes that are thought to be reactive.

In reactive hemophagocytic syndromes seen in associ-

Figure 1. Photomicrograph of bone marrow aspiration specimen showing a macrophage containing a leukocyte (small arrow) and multiple erythrocytes (kwge arrows) (original magnification X I, 000, reduced by 50 percent).

ation with viral [ 1,8,1 l] and other infections [2-61, histio- cytes are morphologically benign; they have a dense nuclear chromatin, indistinct nucleoli, and a high ratio of cytoplasm to nucleus. The pathogenesis of reactive his- tiocytic hemophagocytic syndrome is poorly understood. Increased phagocytic activity of histiocytes or damaged cell membranes may play a role.

Injury to red blood cells in vitro by exposure to physio- logic saline solution [ 121, dialdehydes [ 131, heat [ 141, or malarial parasites [ 151 results in erythrophagocytosis. This phenomenon has been suggested as a biologic test for any injury to the red blood cell membrane [ 161. Eryth- rophagocytosis has been shown to occur both in vivo [ 171 and in vitro in patients with sickle cell anemia. An immune mechanism may be important in inducing erythrophago- cytosis in this setting in that elevated quantities of mem- brane-bound IgG have even been found in these red blood cells [18]. We cannot invoke this as the explanation for the hemophagocytosis in our patient because the platelet- associated IgG level was normal. Murray et al [ 191, in a review of the many manifestations of M. pneumoniae infections in adults, were able to find three reports of thrombocytopenia complicating this illness as reported by Hers and Masurel [20], but they did not give any details of these cases [20].

The prognosis in patients with reactive hemophagocy- tic syndromes is good. Hemophagocytosis is potentially reversible in most patients; however, six of the patients described by Risdall and his co-authors [I] and the patient described by Wilson and his co-authors [21] died from their infections.

ACKNOWLEDGMENT

We thank Dr. S. Krikler for the photomicrographs.

HEMOPHAGOCYTOSIS AND MYCOPLASMA INFECTION-GILL and MARRIE

March 23. 1987 The American Journal of Medicine Volume 82 689

HEMOPHAGOCYTOSIS AND MYCOPLASMA INFECTION-GILL and MARRIE

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