ANNALS O F CLINICAL AND LABORATORY SCIENCE, Vol. 19, No. 6Copyright © 1989, Institute for Clinical Science, Inc.

Cyclic Neutropenia: A Case of Asymptomatic Appendicitis*

KENNETH R. G O LD SCH N EID ER , P h .D . and FARIPOUR A. FOROUHAR, M .D.

Pathology Department, University o f Connecticut Health Center,

Farmington, CT 06032

ABSTRACT

A seven year old boy with a history of cyclic neutropenia (CN) was adm itted to the hospital after developing fever and chills following a bicy­cle accident. After admission, he had a rapidly deteriorating hospital course leading to shock and death. At autopsy, acute appendicitis with resultant peritonitis and sepsis was diagnosed. The peculiar clinical and microscopic aspects of this case will be presented and contrasted with the more usual signs and symptoms of this cyclic disease.

Introduction

Cyclic neu tropen ia (CN) is a clinical sy n d ro m e of p e rio d ic a lly o c c u rr in g fever, ap h th o u s s to m a titis , m alaise, chills, and often pharyngitis, lym pha­denitis, and headache. U nderlying the symptoms is a granulopoietic disorder that results in levels of blood polymor­phonuclear leukocytes (PMNs) that cycle betw een normal levels and low to zero w ith a periodicity of approximately 2 1 days. The nadir lasts about three to five days. At this tim e, the marrow shows a num ber of granulocyte precursors that develop as far as th e m etam yelocyte stage, b u t no fu rth e r. In te resting ly , m any of th e p re c u rso rs have b e e n rep o rted to be abnorm al and contain

* Send reprint requests to: Faripour A. Forouhar, M .D., Director, Anatomic Pathology, University of Connecticut Health Center, Farmington, CT 06032.

autophagic vacuoles. The marrow of CN patien ts in the neutropenic phase has been said to contain nuclear dust from destroyed PMN precursors . 27 Although these two observations have been dis­puted, o ther ultrastructural abnormali­ties have been seen elsew here . 26

Following the neutropenia, these p re­cursors develop as a wave during which tim e the symptoms clear. The unique characteristic of cyclic neutropenia (CN) is its periodicity, allowing regular blood counts to d ifferen tia te effectively this d isease from aplastic anem ia or drug- induced granulocytopenia. No genetic link has b e e n e s ta b lish e d , a lth o u g h sev era l fam ilial cases have b e e n r e ­po rted . 7-33 The disease is generally one of morbidity, not mortality. Deaths have been reported, however, owing to infec­tious causes. 1,4,33 Although there are two types, adult-onset and child-onset, only the latter will be discussed here.

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4 3 0 GOLDSCHNEIDER AND FOROUHAR

Case H istory and Pathologic FindingsThis case is one of an eight year old white male

who had a history of CN, with polymorphonuclear (PMN) levels dipping to zero at the nadir of his cycles. He presented in the emergency room after suffering a cardiopulmonary arrest at home approxi­mately 48 hours after a bicycle accident. He had complained of fever and shaking chills the night prior to arrival. The symptoms were of sudden onset, with no prodrome.

At autopsy, the patient was diagnosed as having had appendicitis that ruptured, leading to peritonitis and septic shock with subsequent cardiopulmonary

arrest. The m icroscopic findings consisted of an intense inflammatory reaction in the appendix com­prising numerous lymphocytes and sporadic macro­phages and plasma cells with a fibrous exudate over the serosa (figure 1). Areas of necrosis were appar­ent, and Gram staining revealed Gram (+ ) cocci and Gram ( —) rods. No PMNs were present, a finding that is consistent with his complete blood count (table I).

The patient had a “mushy spleen”. There was attenuation of the white pulp with congestion of the red pulp. There was a large number of plasma cells (figure 2). The marrow showed reduced myelopoesis, (M:E) ratio of approximately 1:1. There was a slight

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F ig u r e 1. S e ro s a l involvement of the appen­dicitis. There is complete absence of neu troph ils . T he inflam m atory cells a re ly m p h o c y te s an d plasma cells. (100 x ).

F ig u r e 2 . S p l e e n w ith ex ten siv e p lasm a cell in f iltra te (400 x ).

CYCLIC NEUTROPENIA: CASE OF ASYMPTOMATIC APPENDICITIS 431TABLE I

Complete Ante-Mortem Blood Count and D if fe re n tia l Obtained in the Emergency Room

Total White Blood CellNeutrophilsBandsLymphocytesMoncytesBasophilsPlatelets

8/000 per yl 0 percent0 percent

51 percent 48 percent

1 percent 20 ,0 0 0 per yl

reduction in the number of megakaryocytes. There were a fair number of promyelocytes and metamye­locytes, as well as a few band forms. Mature neutro­phils w ere not p resen t (figure 3). An occasional eosinophil was noted.

An additional diagnosis was made of a large hema­toma of the inner thigh.

Discussion

The patient was highly predisposed to s e v e re co m p lic a tio n s to a com m on enough childhood mishap. The absence of marrow PMN reserves left the patient susceptible to infection. The appearance of the appendix, com pletely devoid of PMNs, underscores the patient’s lack of first line in flam m atory defense . The serosal involvement indicated a perito­nitis in the region of the appendix and cecum. The raised num ber of leukocytes

suggested that an inflammatory response was m ounted. It is notew orthy that 97 percent of them were lymphocytes, indi­cating an absolute lymphocytosis. This attem pt was ineffective and sepsis fol­lowed, suggested anatom ically by the “mushy spleen” containing many plasma cells and an attenuated white pulp. The p a tie n t’s hem atom a followed from his accident. The ex ten t of the bruising, however, was probably aggravated by the patient’s throm bocytopenia (20,000 pe r (xl). The low p la te le t count could have been either a part of the patient’s cyclic neutropenia or a result of dissemi­nated intravascular coagulation subse­quent to a long term infection.

A similar set of symptoms was seen in a CN patient who died from Clostridium sphenoides gastroenteritis.14 This patient had abdominal cramps, fever of 39.3°C, w h ich fad ed w ith tim e . T he w hole course from onset to death was 29 hours, a p p ro x im a te ly th e sam e as for ou r patient. A second patient was reported to have superficial ulcerations of the colon (as view ed via a colostomy) that came and went with his neutropenic epi­sodes.15 Such ulcerations could provide

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- . :4É> m. A %, F ig u r e 3. Hypocellu-

cytes (400 x ).

lar bone marrow showing reduced M :E ratio and

* » A * lack of m ature granulo-

4 3 2 GOLDSCHNEID ER AND FOROUHAR

footholds on the road to peritonitis for ordinarily non-invasive organisms such as the C. sphenoides seen in one fatal case . 14

The most curious aspect of our case is the lack of sym ptom s. As m entioned, fever, chills, m alaise, e tc . a re usual sym ptom s found in th e n e u tro p e n ic phase of CN. Not only w ere there no sym ptom s for the appendicitis, th ere w ere none for the underly ing disease either. By its oddity, this case may shed light upon the pathophysiology of pain, fever, and on the relationship betw een granulopoiesis and the other blood lines.

Cyclic neutropenia has been studied extensively in relationship to production of other blood cell types. Generally, CN is believed to be a stem cell problem that leaves granulocytes arrested at the m eta­myelocyte stage in the bone marrow. It is not a problem of peripheral sequestra­tion or of sh o rte n e d cell ha lf life as shown by animal m odels . 8 9 Additionally, monocytes and lymphocytes have been observed to cycle in a pattern up to 180° off from the neutrophil periodicity .5,13 In fact, frank monocytosis has been noted in several patients .25 Furtherm ore, a rise in B and pre-B lymphocytes has been asso­ciated with the production of a hormonal factor found in the urine of cyclic neu- tropenics that stim ulates the prolifera­tion of pre-B cells . 21 In grey collie dogs (the animal models for CN), the propor­tion of B cells is increased, and the per­centage of the subtypes of T lymphocytes is a lte re d . 30 W hether or no t the rises and/or alterations in these other leuko­cyte lines are compensatory to the lack of first line defense or an inherent part of the disease remains unclear.

There have been a num ber of hypoth­eses posed to explain th e etiology of cyclic neutropenia. These include both positive28,32 and negative12 feedback by m atu re an d /o r dy ing n e u tro p h ils on d ev e lo p in g g ran u lo cy te p rec u rso rs .

Lymphocytes, too, have been proposed to play an inhibitory role on granulocyto- poiesis in C N . 19

One intriguing possible etiology of CN is tha t the problem may be w ith the monocytes and not the neutrophils. One study suggested that interruption of the cycling of the neutrophils did not halt the cycling of the monocytes .29 In an in vitro study, m onocytes w ere found to produce a granulocyte colony forming agent that could raise PMN levels . 6 F u r­ther evidence would be required to sup­port this theory, bu t there is enough evi­dence at present to suggest that although CN is billed as a neutrophil disorder, it is m ore likely a disorder of multiple blood cell lines.

As m entioned, fever is a normal com­ponent of the clinical picture of CN. This fact contrasts with the classical thinking th a t PM N s are th e p ro d u ce rs o f an endogenous pyrogen (EP) that is stim u­lated by Gram (+ ) bacteria, endotoxins, an d v a rio u s o th e r s t im u li . 2 R e c e n t experim ents have dem onstrated that the results of the classic experiments were due to contam ination of the PM N cul­ture by monocytes and m acrophages . 11,18 Monocytes were subsequently shown to p ro d u ce E P at levels 10 to 30 tim es higher than PM Ns .3,18

The E P has been dem onstrated to be In terleukin-1, which has been hypothe­sized to act via a central m ediator sug­gested to be prostaglandin E l . 10 These findings support the observations that CN patients have fever even with the com plete absence of neutrophils bu t in the presence of relative or absolute mono­cytosis. W hy our pa tien t was afebrile m ight be exp lained by rev iew ing his com plete blood count (CBC) and noting that monocytes comprised only two per­cent of his total white cells (table I). W hy he had a lack of monocytes is unclear and contrasts with the normal cyclic neutro­penia p icture. It is possible that what

CYCLIC NEUTROPENIA: CASE O F ASYMPTOMATIC APPENDICITIS 433

monocytes there had been were quickly overw helm ed by the infection. This final b u rs t of m onocytic activity may have perhaps resulted in the fever that even­tually developed im m ediately prior to the patient’s demise.

The second enigma of our case is the lack of pain accompanying the patient’s appendicitis. Several mediators such as p rostag landin E2 and leuko triene B4 play a role in local pain transduction. Both are produced by leukocytes. The LTB4, C5a, and other mediators depend on PM N s in th e ir ro le as hypera lge- sics. 22-24 W ithout PMNs to produce this key m ediator, one w ould expect little pain to be produced under conditions that would otherwise elicit this reaction. That our patient was without pain, even when on the verge of appendiceal rup­ture is consistent with the lim ited physi­ological response of which the cyclic neutropenic is capable.

W ith such a lim ited understanding of the pathophysiology of CN, no obvious treatm ent comes to mind. Splenectomy has been tried , although CN is no t a problem of splenic sequestration. Lith­ium carbonate has been used effectively in the grey collie dog ; 1617 however, its efficacy has b e e n u n ev en in hum an pa tien ts . 20,31 Prednisilone and p redn i­sone, too, have been explored . 29,34 No one trea tm en t has had m ore than spo­radic success. Supportive and prophylac­tic antibiotic therapy remains the main­stay o f CN therapy . As in o u r case, com p lica tions to CN can b reak th e “rules” governing clinical symptomatol­ogy. The clinician, therefore, m ust be very aware of the condition of the patient having this interesting and complex dis­ease.

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4 3 4 GOLDSCHNEID ER AND FOROUHAR

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