Immune thrombocytopenia (ITP) related to Mycoplasma pneumoniae infection is a rare condition and usually associated with a severe clinical course. We here report a case of a young man with a clinical diagnosis of severe ITP secondary to M. pneumoniae infection. The clinical features, therapy and outcome are presented

Almeida, Raquel

Baptista, António Martins

Evangelista, Vasco

Gouveia, Catarina

European Journal of Case Reports in Internal Medicine

Catarina Gouveia

Vasco Evangelista

Raquel Almeida

António Martins Baptista

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Immune Thrombocytopenia Associated with Mycoplasma pneumoniae Infection

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European Journalof Case Reports inInternal MedicineDOI: 10.12890/2018_000817 European Journal of Case Reports in Internal Medicine © EFIM 2018Doi: 10.12890/2018_000817- European Journal of Case Reports in Internal Medicine - © EFIM 2018Immune Thrombocytopenia Associated with Mycoplasma pneumoniae InfectionCatarina Gouveia, Vasco Evangelista, Raquel Almeida, Antonio Martins BaptistaBeatriz Ângelo Hospital, Loures, PortugalReceived: 13/12/2017 Accepted: 18/12/2017Published: 22/01/2018How to cite this article: Gouveia C, Evangelista V, Almeida R, Martins Baptista A. Immune thrombocytopenia associated with Mycoplasma pneumoniae infection. EJCRIM 2018;5: doi:10.12890/2018_000817.Conflicts of Interests: The Authors declare that there are no competing interests.This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseABSTRACTImmune thrombocytopenia (ITP) related to Mycoplasma pneumoniae infection is a rare condition and usually associated with a severe clinical course. We here report a case of a young man with a clinical diagnosis of severe ITP secondary to M. pneumoniae infection. The clinical features, therapy and outcome are presented.LEARNING POINTS• Immune thrombocytopenia (ITP) related to Mycoplasma pneumoniae infection is a rare condition.• ITP secondary to M. pneumoniae infection appears to be associated with a more severe and refractory clinical course.•	 It	remains	unclear	whether	specific	anti-Mycoplasma antibiotic therapy is associated with a milder clinical course and a better prognosis.KEYWORDSImmune thrombocytopenia, Mycoplasma pneumoniae, rituximabINTRODUCTIONImmune thrombocytopenia (ITP) is one of the more common causes of thrombocytopenia in otherwise healthy adults. Thrombocytopenia associated with M. pneumoniae infection is a rare condition which usually has a severe course. We report the case of a young man with a clinical diagnosis of severe ITP that was associated with M. pneumoniae infection. Extra-pulmonary features of M. pneumoniae infection occur in 20–25% of cases, with the most commonly associated haematological abnormality being haemolytic anaemia due to the formation of cold agglutinin antibodies against erythrocyte I antigen[1]. Thrombocytopenia associated with M. pneumoniae is usually associated with thrombotic thrombocytopenic purpura or disseminated intravascular coagulation, but association with ITP is rare.CASE DESCRIPTIONA 24-year-old male college student was admitted to the emergency department with a 1-day history of reddish lesions on both legs (Fig. 1), a tongue haematoma following accidental bite (Fig. 2) and two small back bruises, self-induced after pinching himself. He remembered having odynophagia and serous rhinorrhoea without a cough or fever 2 weeks before admission. With a history of infectious mononucleosis at the age of 16, he had had recurrent tonsillitis ever since. He was physically very active and his medication history included protein supplements and	a	one-time-only	use	of	sildenafil.European Journalof Case Reports inInternal MedicineDOI: 10.12890/2018_000817 European Journal of Case Reports in Internal Medicine © EFIM 2018Initial evaluation revealed normal vital signs, with a body temperature of 36.7°C, blood pressure of 132/61 mmHg, pulse rate of 54 beats/min and O2 saturation of 100% on room air. He had petechial and purpuric lesions on both legs, slightly palpable hepatosplenomegaly and no identifiable	adenopathies.	The	remaining	physical	examination	was	normal.Complete blood count showed haemoglobin of 14.6 g/dl, leucocyte count of 5.7×109 cells/l and platelet count of 3×109 cells/l. Coagulation, liver	and	renal	studies	were	normal.	CRP	was	1.15	mg/dl.	A	peripheral	blood	smear	confirmed	severe	thrombocytopenia	without	abnormal	cells.	A	chest	x-ray	did	not	show	any	signs	of	pleuroparenchymal	lung	disease	and	abdominal	ultrasound	confirmed	the	presence	of	moderate	homogeneous hepatosplenomegaly.A presumptive diagnosis of ITP was made, corticoid treatment was promptly initiated and the patient was hospitalized. No platelet count response was seen following a 3-day course of methylprednisolone 1 g IV. Oral prednisolone 1 mg/kg/day and a 3-day course of intravenous immunoglobulin (IVIG) 1 g/kg was therefore initiated with an increase in platelet count to 48×109 cells/l the day after. However, on the very next day, the platelet count dropped once again to 2×109 cells/l. A second 3-day course of methylprednisolone 1 g IV in association with 4 more days of IVIG 1 g/kg was given with no platelet response. The patient remained clinically stable until the 11th day of hospitalization when he presented with epistaxis (Fig. 3), gingival haemorrhage, vascular puncture site haematoma (Fig. 4) and new petechiae on the face and trunk. Prednisolone dosage was increased to 1.5 mg/kg/day and the anti-CD20 monoclonal antibody rituximab 375 mg/m2 IV was also initiated. Bone marrow examination revealed normal cellularity with megakaryocytic hyperplasia but no cell abnormalities, compatible with the diagnosis of ITP. A thoraco-abdomino-pelvic CT scan did not show any lymphadenopathies or lesions suggestive of a neoplastic process.Serological testing for EBV, CMV, HCV, HBV, HIV, HSV and parvovirus B19 was negative for acute infection. A urea breath test for Helicobacter pylori was negative. Assays for ANA, dsDNA, rheumatoid factor, anticardiolipin, lupus anticoagulant and anti-beta-2 glycoprotein were also negative. Antiplatelet antibodies were positive and a positive M. pneumoniae IgM titre was found. ITP secondary to M. pneumoniae infection was assumed, and clarithromycin 500 mg twice a day was added to the treatment regimen.By the 14th day of hospitalization the platelet count was still 4×109 cells/l and the patient presented with gross haematuria. As a consequence, two pools of platelets were given and he was transferred to the intermediate care unit for closer observation. He became hypertensive (blood pressure of 170/90 mmHg), anaemic (with haemoglobin dropping to 8.9 g/dl) and developed a constant headache and occasional haemolacria (Fig. 5). A cranial CT scan excluded any haemorrhagic lesions.Six days after the second dose of rituximab (on the 24th day of hospitalization), the platelet count slowly started to rise to 21×109 cells/l.Figure 1. Reddish lesions on both legs suggestive of petechiae and purpura of the inferior limbsFigure 2. Tongue haematomaEuropean Journalof Case Reports inInternal MedicineDOI: 10.12890/2018_000817 European Journal of Case Reports in Internal Medicine © EFIM 2018Given the subsequent resolution of haematuria and other haemorrhagic dyscrasia, the dose of oral prednisolone was reduced to 1 mg/kg/day and the patient was transferred back to the medicine ward, where he completed treatment with rituximab.From the 25th day of hospitalization onwards, the platelet count gradually increased, as did haemoglobin values. The patient was discharged on the 28th day after admission with a platelet count of 229×109 cells/l and no signs of blood dyscrasia. He returned for 2-week follow-up asymptomatic and with a platelet count of 273×109 cells/l, slowly tapering oral prednisolone as advised upon discharge.DISCUSSIONHaematological abnormalities associated with Mycoplasma infection are widely described, but association with ITP is rarely reported[2].We	identified	10	similar	case	reports	in	a	literature	research.	Table 1 summarizes the clinical features and outcomes of those cases. Most patients (7 out of 10) were male and the mean age was 18 years (ranging from 7 months to 64 years). The most common clinical presentation was respiratory infection (cough, fever and dyspnoea) and mild haemorrhagic manifestations (petechiae, purpura and epistaxis). Two patients presented with more severe forms of haemorrhage (haemoptysis, haematuria and haematochezia), while three patients did not have any haemorrhagic symptoms at all. The mean platelet count on admission was 11×103 cells/l. Apart from one patient, all subjects underwent corticosteroid therapy. In three of them IGIV therapy was given as well. Empiric antimicrobial therapy was administered to eight patients, targeting atypical bacteria, in most cases through macrolide usage. Interestingly, none of the patients required rituximab. The mean time required for platelets to rise above 150×103 cells/l was 21 days. In most cases evidence for Mycoplasma infection came from	a	complement	fixation	test,	cold	agglutinin	test	or	IgM	titre.	Two	patients	experienced	intracranial	haemorrhage	and	died.	Although	incompletely	 understood,	 the	 pathogenesis	 of	 ITP	 is	 thought	 to	 involve	 the	 formation	 of	 specific	 autoantibodies	 against	 platelet	 cell	membrane glycoproteins, more commonly GPIIb/IIIa [3]. In up to 60% of patients, M. pneumoniae infection manifests itself only by odynophagia and rhinorrhoea, as in our patient.Several physiopathological mechanisms have been described to explain the production of antiplatelet antibodies following Mycoplasma infection, such as molecular mimicry, the development of immune complexes that may cause platelet aggregation, serotonin release, and clearance of platelets [4] and even direct binding of Mycoplasma to the platelets, generating a complex that is then recognized as foreign by the immune system.Secondary ITP associated with M. pneumoniae infection appears to have a more severe clinical course and, to some extent, to be a refractory disease, as evidenced by the referenced cases and our own.About	66%	of	patients	with	ITP	respond	to	steroid	therapy	after	1–2	weeks.	Our	patient	was	found	to	be	corticosteroid	resistant	which	first	led to the need to initiate IGIV therapy and later, given the poor clinical response, to second-line therapy with rituximab.Figure 3. Epistaxis Figure 4. Vascular puncture site haematoma Figure 5. HaemolacriaEuropean Journalof Case Reports inInternal MedicineDOI: 10.12890/2018_000817 European Journal of Case Reports in Internal Medicine © EFIM 2018Rituximab is a monoclonal antibody directed against the B cell surface protein CD20. Response to this therapy can occur within a week but may take up to 2 months. In this case our patient had a partial response on day 14 and a complete response after 15 days of rituximab therapy.Specific	anti-Mycoplasma therapy was initiated but, in our case, had no apparent effect on the clinical course or outcome, so given the very few	cases	described,	we	cannot	evaluate	the	benefit	of	this	particular	therapy.CONCLUSIONConsidering the clinical features described above, ITP secondary to M. pneumoniae infection appears to be associated with a more severe and	refractory	clinical	course.	 It	remains	unclear	whether	specific	anti-Mycoplasma antibiotic therapy is associated with a milder clinical course and a better prognosis.Case Age (yrs) Sex Clinical Presentation Platelets on admission (×103 cells/l)MycoplasmatestingComplications Treatment Time to platelets >150 (×103 cells/l)Current case 24, Male Petechiae and purpura, odynophagia and serous rhinorrhoea 2 weeks previously3 IgM 29.9 Epistaxis, gingival haemorrhage, haematuria, haemolacria, anaemia andheadacheMethylprednisolone, IVIG, prednisolone, rituximab, clarithromicin28 daysTsai et al.[5] 0,7,  Female Cough, fever, dyspnoea (pneumonia) and petechiae14 Complement fixation test 1:4;cold agglutinin 1:128None Prednisolone, minocycline14 daysMiller et al.[6] 44, Male Cough, fever (pneumonia), haematuria7 Complement fixation test 1:4 to 1:32; cold agglutinin 1:128Brain stem haemorrhage, death on day 14Erythromycin, cefotaxime, amikacin, methylprednisoloneNeverVeenhoven et al.[7] 17, Male Cough, fever, dyspnoea (pneumonia) and petechiae25 Complement fixation test 1:64; IgM+cold agglutinin 32–256None Prednisolone, erythromycin3 monthsBeattie[8] 4, Male Cough, fever (pneumonia) 4 IgM 80–320 Purpura, epistaxis and haematuriaIGIV Not mentioned, 42×103 cells/l on day 5Pugliese et al.[9] 7, Male Sinusitis, fever <18 ELISA 1.01; cold agglutinin 1:64Headache, vomiting, diarrhoeaCeftriaxone,erythromycin, prednisone14 daysIsoyama et al.[10] 8, Male Rhinorrhoea, cough, epistaxis, petechiae and haematoma of the skin2 ELISA 4 to >1.5; 3 positive culturesEpistaxis, haematuria and haematocheziaPrednisone, IVIG 14 daysVenkatesan et al. [11] 21, Male Cough, fever (pneumonia), purpura, haemoptysis, haematuria and haematochezia6 Complement fixation test 1:8000; total anti-mycoplasma 1:5120Intracranialhaemorrhage; death on day 2Cefotaxime, methylprednisolone, erythromycinNeverScimeca and James-Herry[12]7, Male Otitis media, fever 5 Mycoplasma pneumoniae titre and antibodyPetechiae Amoxicillin, erythromycin, prednisone1 weekOkoli et al.[13] 64, Female Cough, dyspnoea, epistaxis, purpura and bruising3 IgM+cold agglutinin None Moxifloxacin, dexamethasone 40 mg3 monthsAviner et al.[14] 7, Female Cough, fever (pneumonia), petechiae and purpura2 IgM+total anti-mycoplasma 1:64Haemoptysis IVIG, prednisolone, clarithromycin2 monthsTable 1. Clinical features and outcomes of Mycoplasma infection-associated immune thrombocytopeniaEuropean Journalof Case Reports inInternal MedicineDOI: 10.12890/2018_000817 European Journal of Case Reports in Internal Medicine © EFIM 2018REFERENCES1. Waites KB, Talkington DF. Mycoplasma pneumoniae and its role as a human pathogen. Clin Microbiol Rev 2004;17:697–728.2. Kottayam R, Rozenberg G, Cohn RJ. Unusual haematologic manifestations of Mycoplasma pneumoniae infection. J Paediatr Child Health 2007;43:80–82.3. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med 2002;346:995–1008.4. Biberfeld G, Norberg R. Circulating immune complexes in Mycoplasma pneumoniae infection. J Immunol 1974;112:413–415.5. Tsai YM, Lee PP, Liu CH. A case of primary atypical pneumonia complicated with severe thrombocytopenia. Taiwan Yi Xue Hui Za Zhi 1985;84:742–746.6. Miller SN, Ringler RP, Lipshutz MD. Thrombocytopenia and fatal intracerebral hemorrhage associated with Mycoplasma pneumonia pneumonia. N Y State J Med 1986; 86:605–607.7. Veenhoven WA, Smithuis RH, Kerst AJ. Thrombocytopenia associated with Mycoplasma pneumoniae infection. Neth J Med 1990; 37:75–76.8. Beattie RM. Mycoplasma and thrombocytopenia. Arch Dis Child 1993; 68:250.9. Pugliese A, Levchuck S, Cunha BA. Mycoplasma pneumoniae induced thrombocytopenia. Heart Lung 1993; 22:373–375.10. Isoyama K, Yamada K. Previous Mycoplasma pneumoniae infection causing severe thrombocytopenic purpura. Am J Hematol 1994; 47:252–253.11. Venkatesan P, Patel V, Collingham KE, Ellis CJ. Fatal thrombocytopenia associated with Mycoplasma pneumoniae infection. J Infect 1996; 33:115–117.12. Scimeca PG, James-Herry AG. Severe, acute thrombocytopenia complicating Mycoplasma infection. Pediatr Hematol Oncol 1994; 11:557–559.13. Okoli K, Gupta A, Irani F, Kasmani R. Immune thrombocytopenia associated with Mycoplasma pneumonia infection: a case report and review of literature. Blood Coagul Fibrinolysis 2009;20: 595-814. Aviner S, Miskin H,  London D, Horowitz S, Schlesinger M. Mycoplasma pneumonia infection: A possible trigger for immune thrombocytopenia. Indian J Hematol Blood Transfus 2011; 27:46-50.

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Immune Thrombocytopenia Associated with Mycoplasma pneumoniae Infection

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