Acta haemat. 76 : 60-62(19 86)© 1986 S. Karger AG. Basel

0001-5792/86/0761-0060 $ 2.75/0

Aspergillus Vegetative Endocarditis Complicated with Schizocytic Hemolytic Anemia in a Patient with Acute Lymphocytic Leukemia

Tetsuo Nishiuraa, Yoshiji M iyazakia, Kenji Oritania, Nobuhiko Tominaga*, Yoshiaki Tomiyama3,Shuichi Katagiria, Yoshio Kanayam a*, Takeshi Yonezawa3, Seiichiro Taruia, Tsuyoshi Yam adab,Masami Sakuraib, Hikaru K um eQ, Masahiko Okudairac“ Second D epartm ent o f Internal M edicine, O saka University M edical School; h D epartm ent o f Pathology,O saka University H ospital, O saka; and c D epartm ent o f Pathology, School o f M edicine, K itasato U niversity, K anagaw a, Japan

Key Words. Acute leukemia • Aspergillus • Endocarditis ■ Hemolytic anemia

Abstract, Aspergillus vegetative endocarditis developing in a patient with acute lymphocytic leukemia dur­ing the phase of hematological remission has led to a fatal outcome, complicated with severe hemolytic anemia with red cell fragmentation. Systemic aspergillosis may involve heart valves with underlying disorders, but sel­dom affects intact valves even in severely compromised hosts. Among such rare cases so far reported, onl\ 2 cases have been documented in acute leukemia, despite a huge prevalence of pulm onary and systemic aspergil­losis in hematological malignancies. Our present case is essentially the same as in the preceding two cases in that endocarditis occurred during the hematological remission. These clinical observations may suggest that every leukemic patient suffering from aspergillosis is susceptible to the valvular complication after, rather than during, the period of severe myelosuppression, because platelets play an important role in the formation of throm botic lesions.

Introduction

Among the opportunistic fungi, the most common cause of pneumonia is Aspergillus sp. [ 1 ]. As a result of hematogenous dissemination, the myocardium may be involved in systemic aspergillosis, but the valvular endocardium is seldom affected even in highly im- mune-compromised hosts unless they have underly­ing valvular disorders [2-11 ].

In this case report, we describe an unusual compli­cation of Aspergillus vegetative endocarditis which occurred in a patient with acute lymphocytic leu­kemia (ALL) during the phase of hematological re­mission. This article also deals with the pathogenesis and predisposing factors of this rare but fatal compli­cation.

Case Report

A 68-year-old male with ALL, LI category of FAB classifica­tion, was adm itted to our hospital in early January 1985. He be­cam e feverish 3 weeks after receiving a regimen with vincristine and prednisolone. Broad-spectrum antibiotic treatm ent was in­

itiated (cephem s and am inoglucosides during the entire course of his illness), but the fever persisted and a chest X-ray revealed bila­teral pulm onary infiltrates. Intravenous am photericin B (AM P, to­tal dosage 514.5 mg) was then initiated, together with oral 5-fluoro- cytosine, to reduce the dosage o f AM P because o f his intolerance of the toxicity. But the fever persisted until the patient achieved a com ­plete rem ission. Although the pulm onary shadow was not rem ark­ably im proved, the AM P was discontinued for 1 week because o f a suspect of its hepatic toxicity. On 8th April 1985, a high fever re­curred and a new systolic m urm ur becam e audible at the cardiac apical region, when the tw o-dim ensional (2-D) echocardiography detected only m itral regurgitation w ithout any apparen t vegetative lesions in every valve. M yocardial infarction was considered un­likely since the electrocardiogram and the serum level o f creatine kinase rem ained unchanged. The m urm ur becam e louder with sym ptom s of anem ia and throm bocytopenia developing. Despite the reinstitution of AMP, the condition was further deteriorated and resulted in an occurrence of hem oglobinuria and fragmented erythrocytes on blood smears. He becam e unconscious and died on 15th April 1985. D uring the term inal course, no hem ostatic data suggested dissem inated intravascular coagulation. Postm ortem ex­am ination showed a pair o f vegetative masses on the m itral valve (fig. 1), which had not been detected by our reviewing the videore­cord o f a 2-D echocardiography perform ed one week prior to his death. The m icroscopic study revealed that the vegetation consisted o f a thick sheet o f septate branching hyphae infiltrating the throm ­botic masses and valvular endocardium . Sim ilar organism s were

^ s p e r s i l l i is Vegetative Endocarditis in ALL 61

Fig. 1. H eart opened to show a pair o f vegetations on the m itral valve. The chordae tendineae were rup tured during the postm ortem examination.

also found in the m yocardium and lungs. A lthough no organism grown from these affected lesions, the causative agent was im m uno- histochemically [12] identified as Aspergillus sp. The bone m arrow showed norm al architecture, indicating that he had com plete rem is­sion. Throm boem bolism was absent in any organ exam ined, in ­cluding brain and kidneys, histologically excluding a possibility o f thrombotic throm bocytopenic purpura.

Discussion

A pair of firm and rigid vegetative masses were formed on each leaflet of mitral valve in a patient with ALL during the phase of hematological remis­sion. These invasive lesions affected by Aspergillus sp. could well bring the sudden appearance of heart m ur­mur followed by the development of hemolytic anemia at the terminal course of this patient. This causative organism seated in the left-sided heart valves was presumably disseminated from the pri­mary ’esions in situ despite the antifungal chemother­apy.

Schizocytic hemolytic anemia comprises two cate­gories, microangiopathic hemolytic anemia (MIHA) and macroangiopathic hemolytic anemia (MAHA) [13], Since this case showed no histological evidence

o f M IH A, we considered a possibility o f M AHA, which is usually associated with disordered heart valves or with cardiac surgeries [13]. In contrast, val­vular lesions in infective endocarditis very rarely cause hemolytic anemia [14], In our patient, a rapid growth of vegetative lesions might have given rise to a rapid progression of turbulence of blood flow to cause M A H A [14], since our 2-D echocardiography performed one week prior to his death failed to detect such apparent lesions as found at autopsy. Alterna­tively, the physical property of rigid valvular lesion [15] might be also related to this unusual hemolytic manifestation.

In general, air-borne spores of Aspergillus sp. in­itially colonize in the lung o f compromised hosts and may result in a hematogenous dissemination [1], The myocardium is not infrequently involved in general­ized aspergillosis, but an intact valvular endocardium is seldom affected even in patients with severe under­lying conditions [1, 11]. Although such rare examples of Aspergillus endocarditis affecting norm al heart valves [2-10] have been so far reported, only 2 out of 16 cases are documented in acute leukemias [6, 9], whose incidence appears unproportionately low in view of a huge prevalence of pulmonary and systemic aspergillosis associated with hematological m alignan­cies [16]. The rarity of valvular complications also holds true with disseminated candidiasis in acute leu­kemias [17],

More interestingly, all the reported cases including ours were infected with Aspergillus at the nadir pe­riod, before developing vegetative lesions during the time of hematological remission [6, 9], Considering that platelets act as one o f the major components to form throm botic lesions, the infrequent occurrence of endocarditis in acute leukemia patients could be attri­buted, as Mikulski et al. [6] indicated, to a marked thrombocytopenia during the myelosuppression, in which granulocytopenia apparently renders the p a ­tient especially susceptible to fungal infection.

With the improvement of current anti-leukemic chemotherapy and supportive therapy, the num ber of patients who are susceptible to fungal infection has been paradoxically increasing [1, 18]. In other words, cardiac complication would also gain a high inci­dence in future. However, as this report suggests, once fungal endocarditis occurs, even an extensive use of antifungal agents other than a surgical removal does not seem to have a curative effect [13]. Physicians must be aware that such fatal endocarditis may de­

62 N ishiura et al.

velop after, rather than during, the period of severe myelosuppression in leukemic patients.

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Received: M arch 24, 1986 Accepted: June 1,1986

Dr. Tetsuo N ishiura,The Second D epartm ent o f Internal M edicine, O saka U niversity M edical School,1-1-50 Fukushim a,Fukushim a-ku,O saka 553 (Japan)