Immune Thrombocytopenia: A Rare Presenting Manifestation of Tuberculosis

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1 Americn Journl of Hemtology 67: (2001) Immune Thrombocytopeni: A Rre Presenting Mnifesttion of Tuberculosis M.W. Ghobril* nd M.A. Albornoz Mercy Ctholic Medicl Center, Drby, Pennsylvni We report the cse of 49 yer-old mle who presented with immune thrombocytopeni (ITP)-induced epistxis nd generlized purpur. During the sme hospitliztion the ptient ws lso found to hve clinicl, microbiologicl, histologicl, nd roentgenogrphic evidence of disseminted mycobcteril tuberculosis (TB). The hemtologicl nd infectious bnormlities, which did not respond to high-dose intrvenous corticosteroids nd immune globulin (IVIg), resolved fter nti-tuberculous tretment. Herein we review the chrcteristics of this rrely documented ssocition. Am. J. Hemtol. 67: , Wiley-Liss, Inc. Key words: tuberculosis; immune thrombocytopenic purpur; idiopthic thrombocytopenic purpur INTRODUCTION Over the pst decde in the United Sttes (US), TB hs been recognized s public helth burden of incresing proportions. A totl of 18,361 cses were reported in the US in 1998, which, for tht yer, represented n incidence of 6.8 per 100,000. The ltter is figure well over the 3.5 per 100,000 ntionl gol estblished for the yer 2000 [1]. Though myrid of hemtologicl derngements hve been described in TB, nemi, leukocytosis, nd pncytopeni hve been most frequently cited [2]. When thrombocytopeni occurs in TB it does so most commonly vi non-immunologic mens, typiclly mnifesting in the context of pncytopeni tht develops secondry to grnulomtous infiltrtion of the bone mrrow. A cusl ssocition between TB nd ITP is extrordinrily rre, with our cse representing the thirteenth such report nd only the second cse documented in the US. CASE REPORT 2001 Wiley-Liss, Inc. A 49-yer-old previously helthy Africn-Americn mle with history of well-controlled hypertension ws dmitted with new-onset cute severe epistxis nd rsh. The ptient, who dmitted to n unquntified involuntry weight loss over 2-month period, described 2 3 dy history of generlized purpuric lesions nd dyspne. The physicl exmintion reveled blood pressure of 106/51, pulse 120/min nd regulr, nd temperture of 100 F orlly. The ptient ppered cutely ill but firly well nourished. Other thn generlized nontender, nonplpble purpuric lesions most evident in the extremities nd trunk, the reminder of the physicl exmintion ws norml. The initil complete blood count reveled white blood cell count /l with 75.4% grnulocytes, 13.1% lymphocytes, 11.1% monocytes, 0.3% eosinophils, nd 0.1% bsophils, hemoglobin 5.7 g/dl with MCV of 70.5 nd MCH of 22.7, nd pltelet count /l. A peripherl smer ws remrkble for pucity of pltelets. Iron level ws 38. Fibrinogen level ws 436 (norml: ) mg/dl. The following lbortory studies were norml or negtive: PT/PTT, Chem 12, fibrin degrdtion products (FDP), ANA, rheumtoid fctor, nti-pltelet specific ntibodies, HIV, nd multiple blood cultures. A bone mrrow biopsy reveled mild hypercellulrity of ll cell lines with norml mturtion of myeloid nd erythroid precursors. Megkryocytes were incresed in number with norml morphology. No grnuloms were detected. A chest X-ry demonstrted bilterl pleurl effusions nd diffuse bilterl interstitil infiltrtes tht were more pronounced in the left upper lobe without miliry chnges. Computed *Correspondence to: Michel W. Ghobril, M.D., 772 Providence Rod, Apt. B402, Aldn, PA E-mil: ghobril@hotmil.com Received for publiction 16 June 2000; Accepted 15 December 2000

2 140 Cse Report: Ghobril nd Albornoz Fig. 1. Lymph node biopsy shows necrotizing lymphdenitis with cseting grnuloms nd inflmmtory cells. Fig. 2. Lymph node biopsy under oil mgnifiction revels multinucleted gint cell with tuberculous bcillus (rrow). tomogrphy of the chest, bdomen, nd pelvis reveled bilterl interstitil lung infiltrtes, mssive right nd smll left pleurl effusions, multiple smll spce occupying lesions in the liver nd spleen, nd medistinl, thorcobdominl pr-ortic nd bilterl externl ilic nd inguinl denopthy. The ptient ws dmitted to the intensive cre unit, where he demonstrted persistent low-grde fevers nd intermittent hemodynmic instbility. The pltelet count dropped to /l nd did not respond to severl courses of high-dose intrvenous corticosteroids nd 5-dy course of IVIg. The ptient required multiple pltelet trnsfusions. Eleven dys fter hospitliztion, the ptient ws found to hve bilterl inguinl lymphdenopthy. Histopthologicl nlysis of right inguinl lymph node reveled necrotizing lymphdenitis with cseting grnuloms nd rre cid-fst bcilli (Figs. 1 nd 2). Sputum cultures were sterile. However, culture of the lymph node biopsy grew TB. A thorcentesis ws performed, nd the pleurl fluid reveled glucose 51, protein 4.0, LDH 790, nd no mlignnt cells. Pleurl fluid AFB smers nd cultures were both negtive. The ptient ws strted on isonizid 300 mg od, ethmbutol 800 mg od, rifmpin 600 mg od, pyrzinmide 500 mg tid, nd pyridoxine 50 mg od. The ptient ws dischrged 3 weeks fter dmission febrile nd with disppernce of the inguinl lymphdenopthy. A complete blood count t dischrge demonstrted white blood cell /l, hemoglobin 8.0 g/dl, nd pltelet count of /l. Two months fter dischrge, the ptient, who ws in stble helth nd with pltelet

3 Cse Report: Immune Thrombocytopeni 141 TABLE I. Chrcteristics of TB-relted ITP cses reported in the literture Author Country of report Number of ptients Age/sex Rce Pthology Anti-pltelet ntibodies Ndir pltelet count Other tretment modlities nd pltelet response Response to nti-tuberculous therpy Perez de Llno et l., 1998 [4] Spin 1 27/M Pulmonry TB Tlbot et l., 1998 [5] Austrli 1 74/F Benglese Medistinl nodl TB Hernndez-Mrver, 1996 [6] Al-Mjed et l., 1995 [7] Ysud et l., 1994 [8] Pvithrn et l., 1993 [9] Boots et l., 1992 [10] Singh et l., 1986 [11] Jurk et l., 1983 [12] Spin 1 70/M Cucsin Disseminted TB Sudi Arbi 9 Jpn 1 b c c Disseminted TB (3) Abdominl bscess (3) Pulmonry TB (3) Pulmonry TB c /l Prednisone & IVIg -Poor response /l Prednisolone & IVIg -Improvement /l Methylprednisolone & IVIg Rnged from (4 to 21) 10 9 /l -Incresed from (8 to 21) 10 9 /l Prednisone in ll ptients Cyclophosphmide in 1 ptient -Poor response /l IVIg & splenectomy -Improvement Indi 1 36/M TB lymphdenitis /l Prednisolone d Austrli 1 20/M Thi Pulmonry TB Detected /l IVIg d Indi 1 16/F TB lymphdenitis /l Prednisolone d USA 2 30/F Koren Pulmonry TB Detected /l Steroids d splenectomy & Vincristine 2/M Koren TB lymphdenitis Detected /l Chi et l., 1978 [13] UK 1 24/F Indin TB Spleenitis < /l Prednisone & splenectomy Cockcroft et l., 1976 [14] (6 months fter delivery) Cnd 1 74/F Chinese Miliry TB & SIADH Levy et l., 1964 [15] Cnd 1 27/F Greek TB lymphdenitis -No response to either < /l Prednisone d & Vincristine /l Methylprednisolone -Increse from (8 to 43) 10 9 /l c Dt not mentioned in the report or test not performed. b 7 femles nd 2 mles. Ages: 28, 40, 42, 47, 50, 51, 51, 55, nd 65 yers. c Unble to extrct dt secondry to lnguge brrier. d Strted simultneously with the nti-tuberculous tretment.

4 142 Cse Report: Ghobril nd Albornoz count of /l, ws found to hve bnorml liver functions thought to be secondry to isonizid. A liver biopsy ws performed which reveled foci of chronic lobulr inflmmtion, rre non-cseting grnuloms, nd no evidence of cid-fst bcilli or mlignnt cells. Cultures of the liver specimen were not performed. Despite multiple ttempts to contct the ptient, he ws subsequently lost to follow-up. DISCUSSION ITP is reltively common immune-driven disorder tht clssiclly occurs in two forms: childhood vriety tht is cute, without gender predilection, post-virl nd self-limited, nd the dult form tht tends to be chronic, femle-predominnt, nd most frequent between the 2 nd nd 4 th decdes [3]. In pproximtely 50% of cses of ITP no underlying etiology is discovered. Systemic lupus erythemtosus, lymphoprolifertive disorders, especilly chronic lymphocytic leukemi nd Hodgkin s lymphom, HIV infection, nd medictions represent the most common secondry cuses of ITP. The two principl dignostic criteri for ITP re thrombocytopeni in the context of n otherwise norml blood count nd norml peripherl smer nd the exclusion of conditions cpble of inducing thrombocytopeni. The ssocition between TB nd ITP is exceedingly rre. To our knowledge, only 12 such reports hve been described in the world literture (Tble I) [4 15]. An immune bsis for TB-induced ITP ws supported by the presence of either pltelet ntigen specific ntibodies or pltelet surfce membrne IgG in two of the 12 reports [10,12] nd by slutry response in some of the cses to immunomodulting tretments [5,8]. It hs been postulted tht the nti-pltelet ntibodies generted in some cses of TB-relted ITP re secreted by lymphocytes borne of clonl prolifertion tht is set in motion by the host s exposure to the tuberculous pthogen [12]. However, nd s highlighted in the Americn Society for Hemtology s 1996 guidelines for the dignosis nd mngement of ITP [16], the bsence of nti-pltelet ntibodies in no wy invlidtes the dignosis of ITP. In fct, nti-pltelet ntibodies were lbeled s n unnecessry test for the routine evlution of ptients presenting with ITP. These guidelines lso considered the pltelet-ssocited IgG ssy s both n unnecessry nd inpproprite test nd further concluded tht dignostic gold stndrd nd definitive therpeutic strtegy were lcking. All ptients with TB-relted ITP cited in Tble I responded to medicl therpy. Though vluble informtion regrding clinicl dt, post-tretment lbortory vlues, tretment specifics, nd long-term follow-up ws unvilble in mny of the reports, the bsence of recurrent thrombocytopeni fter the withdrwl of corticosteroids nd/or IVIg in ll cses nd the poor response to immunomodulting therpies lone in most of the ptients strongly support the etiologic role of TB in producing ITP nd reinforces the need for nti-tuberculous therpy in ll ptients with TB-relted ITP. As Tble I illustrtes, the mjority of ptients were femle nd of Middle Estern nd Asin descent. And though TB-relted ITP ws distributed cross ll ge groups, it occurred most commonly between the 3 rd nd 8 th decdes of life. Pulmonry TB represented the most common clinicl presenttion hving occurred in 33% of cses, followed eqully t 19% by disseminted TB nd lymphdenitis. Eighty-one nd 35% of ptients presented with pltelet count under /lnd /l, respectively. The highest pltelet counts t presenttion were seen in 3 of the 4 ptients with tuberculous lymphdenitis. Lstly, slient chrcteristic tht our cse shred with most reports of TB-relted ITP ws n initil filure to identify TB s puttive cuse of thrombocytopeni. Though mny questions concerning the pthophysiology, clinicl significnce, nd tretment of TB-relted ITP remin unnswered, s the incidence of this worldwide disese continues to increse, we feel it is importnt tht the medicl community recognize TB s tretble secondry cuse of ITP. ACKNOWLEDGMENT We re deeply grteful to Dr. Smi Rouf Henein from the Deprtment of Pthology for her vluble ssistnce. REFERENCES 1. Morbid Mortl Weekly Rep 1999;48(33): Glsser RM, Wlker RI, Herion JC. The significnce of hemtologic bnormlities in ptients with tuberculosis. Arch Intern Med 1970;125(4): George JN, Rskob GE. Idiopthic thrombocytopenic purpur. Dignosis nd mngement. Am J Med Sci 1998;316(2): Perez de Llno LA, Soiln del Cerro JL, Grci Pis MJ. Immune thrombocytopenic purpur s presenting form of miliry tuberculosis. Arch Broncho-Pneumol 1998;34(8): Tlbot S, Dowling A, Dowling JP, Fuller A, Schwrz M. Medistinl nodl tuberculosis presenting s immune thrombocytopeni. Aust NZ J Med 1998;28(4): Hernndez-Mrver D, Pelez J, Pinill J, Nvrro FH. Immune thrombocytopenic purpur due to disseminted tuberculosis. Act Hemtol 1996;96(4): l-mjed SA, l-momen AK, l-kssimi FA, l-zeer A, Kmbl AM, Bgil H. Tuberculosis presenting s immune thrombocytopenic purpur. Act Hemtol 1995;94(3): Ysud Y, Mtsubr Y, Wtnbe S, Htkenk R, Funtsu T. A cse of intrctble pulmonry tuberculosis complicted by idiopthic thrombocytopenic purpur. Nippon Kyobu Gek Gkki Zsshi 1994;42(12): Pvithrn K, Vijylekshmi N. Thrombocytopenic purpur with tuberculous denitis. Indin J Med Sci 1993;47(10);

5 Cse Report: Immune Thrombocytopeni Boots RJ, Roberts AW, McEvoy D. Immune thrombocytopeni complicting pulmonry tuberculosis. Cse report nd Investigtion of mechnism. Thorx 1992;47(5): Singh SP, Misr GC, Prusty PK, Ds RK. Tuberculr lymphdenitis with purpur. J Indin Med Assoc 1986;84(8): Jurk SS, Aster R, Swf H. Immune thrombocytopeni ssocited with tuberculosis. Clin Peditr 1983;22(4): Chi YC, Mchin SJ. Tuberculosis nd severe thrombocytopeni. Br J Clin Prct 1979;33(2): Cockcroft DW, Donevn RE, Coplnd GM, Ibbott JW. Miliry tuberculosis presenting with hypontremi nd thrombocytopeni. Cn Med Assoc J 1976;115(9): Levy M, Cooper BA. Thrombocytopenic purpur ssocited with tuberculous lymphdenitis. Cn Med Assoc J 1964;90: George JN, Woolf SH, Rskob GE, Wsser JS, Aledort LM, Bllem PJ, Blnchette VS, Bussel JB, Cines DB, Kelton JG, Lichtin AE, McMilln R, Okerbloom JA, Regn DH, Wrrier I. Idiopthic thrombocytopenic purpur: prctice guideline developed by explicit methods for the Americn Society of Hemtology. Blood 1996;88(1):3 40.