SEARCH

SEARCH BY CITATION

Keywords:

  • Cytomegalovirus;
  • Immune thrombocytopenic purpura;
  • thrombocytopenia

Summary

  1. Top of page
  2. Summary
  3. Case reports
  4. Discussion
  5. Acknowledgements
  6. Author contribution
  7. References

Immune thrombocytopenic purpura (ITP) is characterized by decreased platelet numbers secondary to platelet destruction and reduced platelet production. Even if the ITP persists, it typically responds to ‘ITP-specific’ therapies, such as intravenous immunoglobulin, steroids, intravenous anti-D, and splenectomy. Several reports, including our previous study, have implicated cytomegalovirus (CMV) in the pathogenesis of infrequent cases of ITP that were not severe in nature. A recent study from China suggested that CMV is the aetiology of some cases of acute ITP of childhood and may require different treatment. We report two adult and two paediatric patients with refractory, severe, symptomatic thrombocytopenia, who were diagnosed with ITP and found to have active CMV infection. Their presentations included fever, transaminitis, neutropenia, and atypical lymphocytosis, but in particular, treatment-refractory, severe ITP. Treatment with steroids appeared to worsen the CMV-ITP. All four cases showed improvement in platelet counts within two weeks of starting ganciclovir and cytogam and tapering steroids. Based on the four patients described here, we believe that, in certain cases, CMV infection will result in symptomatic, severe, refractory ITP, which may be indistinguishable from typical ITP. Eradication of CMV with antiviral therapy improved the ITP in these cases.

Immune thrombocytopenic purpura (ITP) is a common cause of acquired thrombocytopenia. It is generally believed to be caused by auto-anti-platelet antibodies that are thought to not only destroy platelets peripherally, but also to damage megakaryocytes and/or inhibit platelet production in the marrow (Bussel et al, 2006;Xiao et al, 2006). The aetiology of ITP is not known in most instances and a highly sensitive and specific test for its diagnosis has yet to be developed.

ITP in childhood has been estimated to be post-infectious in approximately two thirds of instances. Many different agents have been implicated in the aetiology of this form of ITP, including not only cytomegalovirus (CMV), but also varicella, rubella, mumps, Epstein-Barr virus, and parvovirus B19, among others (Chanarin & Walford, 1973; Fiala & Kattlove, 1973;Ip & Corner, 1973; Harris et al, 1975; Muntendam, 1975; Dor et al, 1977; Sahud & Bachelor, 1978; Shimm et al, 1980; Aguado et al, 1984; Anton et al, 1985; Amitai & Granit, 1986; Landonio et al, 1992; Wright, 1992; Eisenberg & Kaplan, 1993; Murray et al, 1994; Mizutani et al, 1995; Von Spronsen & Breed, 1996; Wright et al, 1996; Arruda et al, 1997; Miyahara et al, 1997; Swanobori et al, 1997; Gasbarrini et al, 1998; Gural et al, 1998; Lopez et al, 1998; Heegaard et al, 1999; Sakata et al, 1999; Aboulafia et al, 2000; Crapnell et al, 2000; Garcia-Suarez et al, 2000; Hida et al, 2000; Hsiao, 2000; Emilia et al, 2001; Scaradavou, 2002; Yenicesu et al, 2002; Ichiche et al, 2003; Aktepe et al, 2004; Alliot & Barrios, 2005; Jackson et al, 2005; Li et al, 2005; Nomura et al, 2005; Rajan et al, 2005; Asahi et al, 2006; Cooper & Bussel, 2006; Sayan et al, 2006; Suvajdzic et al, 2006). These infections trigger an autoimmune process against platelets, even though the infections themselves are transient and seemingly neither atypical or severe in nature. However, in the past several years, cases of apparently idiopathic ITP have been found to be secondary to an unsuspected, persistent infection. Optimal management of the ITP in these cases, secondary to human immunodeficiency virus (HIV), H. Pylori or hepatitis C infection, often requires recognition and treatment of the underlying infection.

CMV has been reported to both cause and perpetuate ITP (Chanarin & Walford, 1973; Fiala & Kattlove, 1973; Ip & Corner, 1973; Harris et al, 1975; Muntendam, 1975; Dor et al, 1977; Sahud & Bachelor, 1978; Shimm et al, 1980; Aguado et al, 1984; Anton et al, 1985; Wright, 1992; Eisenberg & Kaplan, 1993; Mizutani et al, 1995; Von Spronsen & Breed, 1996; Arruda et al, 1997; Miyahara et al, 1997; Swanobori et al, 1997; Gural et al, 1998; Lopez et al, 1998; Sakata et al, 1999; Crapnell et al, 2000; Ichiche et al, 2003; Alliot & Barrios, 2005; Nomura et al, 2005). These cases and their treatments are summarized in Tables I and II, respectively. The majority of the small number of previously described cases were newly diagnosed, acute ITP in adults that, nonetheless, appeared to be susceptible to standard treatments. Our previous study found that only three out of 28 paediatric patients (11%) and three out of 80 adult patients (4%) presenting to Cornell University Weill Medical Centre for the management of thrombocytopenia were positive for CMV in the urine by shell vial assay. None of the viruric cases were linked to refractory disease and none had their CMV treated (Levy & Bussel, 2004).

Table I.   Findings in reported cases of CMV-related ITP*.
Clinical Features/Laboratory FindingsReference
  1. ITP, idiopathic thrombocytopenic purpura; CMV, cytomegalovirus; PCR, polymerase chain réaction; ICH, intracerebral haemorrhage.

  2. *References Muntendam, 1975; Dor et al, 1977; Aguado et al, 1984; Lopez et al, 1998; and Anton et al, 1985 were not included in the table because the articles were unavailable in English.

Paediatrics patients ≤18 years oldMizutani et al (1995); Fiala and Kattlove (1973); Sakata et al (1999)
Adult patientsAlliot and Barrios (2005); Ichiche et al (2003); Von Spronsen and Breed (1996); Sahud and Bachelor (1978); Wright (1992); Arruda et al (1997); Gural et al (1998); Swanobori et al (1997); Chanarin and Walford (1973); Harris et al (1975); Ip and Corner (1973); Eisenberg and Kaplan (1993); Miyahara et al (1997); Nomura et al (2005); Shimm et al (1980)
Increase in platelet count as CMV PCR normalizesAlliot and Barrios (2005); Arruda et al (1997); Harris et al (1975)
Steroids result in worsening ITP/no benefitAlliot and Barrios (2005); Sahud and Bachelor (1978); Arruda et al (1997); Gural et al (1998); Harris et al (1975); Fiala and Kattlove (1973)
Nadir platelet count ≤5 × 109/lIchiche et al (2003); Von Spronsen and Breed (1996); Wright (1992);Gural et al (1998); Chanarin and Walford (1973); Nomura et al (2005); Fiala and Kattlove (1973)
TransaminitisVon Spronsen and Breed (1996); Sahud and Bachelor (1978); Wright (1992); Mizutani et al (1995); Gural et al (1998); Swanobori et al (1997); Eisenberg and Kaplan (1993); Miyahara et al (1997)
Improvement in platelet count with ganciclovir/cytogamVon Spronsen and Breed (1996); Arruda et al (1997)
Need for splenectomySahud and Bachelor (1978); Gural et al (1998); Fiala and Kattlove (1973)
Presence of ICHGural et al (1998)
Bone marrow with megakaryocytic hyperplasiaAlliot and Barrios (2005); Sahud and Bachelor (1978); Mizutani et al (1995); Arruda et al (1997); Gural et al (1998); Swanobori et al (1997); Chanarin and Walford (1973); Harris et al (1975); Fiala and Kattlove (1973); Sakata et al (1999)
History of, or presented with CMV-like illness: myalgia, fever, headache, malaise, throat painIchiche et al (2003); Von Spronsen and Breed (1996); Arruda et al (1997); Gural et al (1998); Swanobori et al (1997); Chanarin and Walford (1973); Harris et al (1975); Ip and Corner (1973); Eisenberg and Kaplan (1993); Miyahara et al (1997); Nomura et al (2005); Shimm et al (1980); Fiala and Kattlove (1973)
Severity of bleeding worse than others with ITP with similar degree of thrombocytopeniaGural et al (1998); Eisenberg and Kaplan (1993)
Episodes of neutropeniaMizutani et al (1995)
Atypical lymphocytes on peripheral smearIchiche et al (2003); Von Spronsen and Breed (1996); Sahud and Bachelor (1978); Wright (1992); Arruda et al (1997); Gural et al (1998); Swanobori et al (1997); Chanarin and Walford (1973); Ip and Corner (1973); Eisenberg and Kaplan (1993); Miyahara et al (1997); Shimm et al (1980); Fiala and Kattlove (1973)

In the current study, four patients with treatment unresponsive, clinically severe cases of ITP were discovered to have active CMV infection. Two of the patients had an intracranial haemorrhage and one died secondary to complications of ITP. These cases, as well as their treatments, are summarized in Tables III and IV, and Fig 1. Their treatment of CMV combined with discontinuation of immunosuppression, in particular prednisone, lead to marked increases in the platelet counts within 1–2 weeks. Although the ITP did not go completely into remission in the four cases, it improved markedly and became amenable to management with conventional agents.

Table III.   Diagnostic and other clinical features in the four cases of CMV-related ITP in this study.
Clinical features/Laboratory findingsCase 1Case 2Case 3Case 4
  1. ITP, idiopathic thrombocytopenic purpura; CMV, cytomegalovirus; PCR, polymerase chain réaction; ICH, intracerebral haemorrhage; HIV, human immunodeficiency virus.

Increase in platelet number as CMV PCR normalizes++++
Steroids result in worsening ITP/ no benefit++++
Nadir platelet count (×109/l)2251
Transaminitis++++
Immunodeficiency present
Improvement in platelet count with ganciclovir/cytogam++++
Need for splenectomy++
Presence of ICH++
Bone marrow characteristicsMegakaryocytic hyperplasiaNo significant megakaryocytic hyperplasiaNo significant megakaryocytic hyperplasiaMegakaryocytic hyperplasia
Presented with CMV like illness-myalgia, fever, headache, malaise, throat pain+
Severity of bleeding worse than others with ITP with similar degree of thrombocytopenia++++
HIV testing negative++++
Episodes of intermittent neutropenia+
Atypical lymphocytes on smear+
Table IV.   Proposed guidelines for treatment of CMV-related ITP.
Initiate Treatment of CMV:
 Cytogam (100–200 mg/kg) 1–3 times/week
 Ganciclovir (5 mg/kg) 2 times/day
If patient experiences myelosupression from ganciclovir, switch to foscarnet or cidofavir
Once CMV PCR becomes undetectable for approximately 2 weeks, wean ganciclovir to daily and then cytogam
Reduce immunosuppressive agents, including steroids, as rapidly as feasible
Further discontinuation of therapy depends upon the clinical setting and the platelet response
If platelet-specific treatment is required while awaiting a response to anti-CMV therapy, use IVIG to avoid immunosuppression (the first indication of improvement may be an improved response to IVIG)
image

Figure 1.  Relationship of platelet count to CMV titres and anti-CMV treatment. (A) Case 1 was found to be thrombocytopenic with an elevated CMV PCR. Standard therapies for ITP did not cause an increase in her platelet count until anti-CMV therapy and a thrombopoietic agent were initiated. (B) Case 2 had no clinical or laboratory response to standard agents (IVIG) prior to the eradication of the active CMV infection. After the CMV load by PCR was <200 DNA copies/ml, the patient showed some response to standard agents even though it was not durable. In this case, eradication of CMV was not curative but it was an essential first step in allowing the patient to respond to standard therapies, such as splenectomy and IVIG. (C) The temporal association of suppression of CMV and rising platelet counts is illustrated for Case 3. In April 2004, the patient experienced an asthma attack and needed steroids, which resulted in presumed CMV reactivation and worsening of the platelet count. The ITP exacerbation required ganciclovir IV BID. Ganciclovir was continued for two months post the first non-detectable CMV PCR. (D) Case 4 was initially treated with high dose steroids without a significant rise in platelet counts. Once he was started on anti-CMV therapy and the CMV PCR became undetectable, his platelet count began to rise and remained stable despite simultaneously rapidly tapering the steroids.

Download figure to PowerPoint

Case reports

  1. Top of page
  2. Summary
  3. Case reports
  4. Discussion
  5. Acknowledgements
  6. Author contribution
  7. References

Case one

A 3-year-old female was well until 4 months of age, when she developed fever. An evaluation revealed thrombocytopenia, with a platelet count of 76 × 109/l and elevated liver enzymes. An infectious disease work-up was significant for a CMV DNA polymerase chain reaction (PCR) of 200 copies, for which she was started on ganciclovir. A bone marrow biopsy revealed megakaryocytic hyperplasia, consistent with ITP. Metabolic and genetic work-ups were negative. An immunological work-up, which included immunoglobulin levels, T cell and B cell function, antibody levels to pneumococcus, and Toll-Like Receptors (TLR) 2, 7, and 9, was also found to be normal. She had a poor response to several courses of intravenous immunoglobulin (IVIG) and intravenous (IV) anti-D. Her platelet count responded well initially to steroids, but a subsequent course of high-dose solumedrol (30 mg/kg/day) did not increase her platelet count.

She was placed on combination of IV anti-D, IVIG, IV solumedrol, and vincristine with no response. She was started on azathioprine, which resulted in pancytopenia and a febrile illness, forcing its discontinuation. A trial of rituximab lead to serum sickness and forced its discontinuation after two infusions, without any platelet response, and without effect on her B cell count and immunoglobulin levels (she received multiple plasma and IVIG infusions during this period). She started requiring daily platelet transfusions and every other day red cell transfusions for gastrointestinal bleeding. Her hospital course was complicated by a basal ganglia haemorrhage, transfusion-related acute lung injury (TRALI) from continuous platelet transfusions, and acute respiratory distress syndrome requiring ventilation. Although she did not fully recover from her lung and brain injuries, she remained stable and was discharged after several months.

She also experienced episodes of intermittent neutropenia and anaemia, believed to be induced by the treatments for her ITP and also by prolonged ganciclovir. She suffered from chronic CMV infection for which she received cytogam twice weekly and initially ganciclovir IV daily, until its eventual discontinuation secondary to myelosuppression. After several months of good platelet counts on the combination of anti-CMV therapy and an experimental thrombopoietic agent, and PCRs that were undetectable for CMV, discontinuation of the cytogam resulted in the platelet count again dropping to less than 10 × 109/l. During this hospitalization, she experienced a second intracranial haemorrhage, gram positive bacteraemia, and respiratory failure, secondary to a combination of pulmonary haemorrhage and TRALI, which resulted in multiple failed extubations. Due to her very young age, history of bacterial and viral infections, and intracranial bleeds, she was not considered a candidate for splenectomy. She expired from respiratory failure at almost 3 years of age after having received foscarnet and cidofavir and with her CMV PCR under good control.

An essential component of her response to ITP treatment, including a thrombopoietic agent, was the suppression of CMV (Fig 1A). In this case, CMV infection was one part of a complicated disease process.

Case two

A 9-year-old male was admitted with acute onset of epistaxis associated with a platelet count of 2 × 109/l, fever, and mild transaminitis. Physical examination revealed diffuse petechiae, bruising, and epistaxis leading to anaemia. A bone marrow biopsy showed a mild increase in megakaryocytes. The platelet count increased to 30 × 109/l in response to IVIG, but decreased to <10 × 109/l on the following day. Prednisone was started at 2 mg/kg/day without effect on the platelet count. A work-up of the fever and transaminitis revealed acute CMV infection with a viral titre of 7748 DNA copies/ml of blood. Anti-CMV therapy was started with cytogam every other day for three doses and twice daily IV ganciclovir. The CMV viral load decreased to <200 DNA copies/ml of blood within 12 d of starting the therapy, but the patient continued to have difficulty in managing his thrombocytopenia and epistaxis. He was given high-dose solumedrol therapy with a peak platelet count of 42 × 109/l, but rapidly returned to a platelet count <10 × 109/l after the therapy was stopped. Daily IV ganciclovir was continued and the CMV viral load remained below the level of detection. His platelet count stabilized at around 20–40 × 109/l on IVIG every two weeks. Although the thrombocytopenia persisted, the patient now responded to standard ITP agents. His platelet count normalized on IVIG every two weeks and daily ganciclovir with an undetectable CMV viral load. Ganciclovir, however, was discontinued after two months secondary to transaminitis; he once again experienced refractory thrombocytopenia and epistaxis, despite a negative CMV viral load. Splenectomy was then performed; his platelet count normalized and he currently remains asymptomatic three months after surgery with the antiviral and other medications for his ITP discontinued. Figure 1B illustrates how the addition of anti-CMV treatment was critical to the response to IVIG in this patient, even if that response was transient.

Case three

A 50-year-old male with a history of asthma, controlled with albuterol and pulse prednisone as needed for exacerbations, and chronic ITP presented acutely with a platelet count of 5 × 109/l, multiple bleeding symptoms, atypical lymphocytes on smear, and a mild transaminitis. He was initially refractory to treatment with steroids, IVIG, and rituximab administered separately and was then resistant to a combination IVIG, IV methylprednisolone, IV anti-D, and IV vincristine, with a peak platelet count of 18 × 109/l (Boruchov et al, 2007). At the time of transfer, his platelet count remained <10 × 109/l and he had multiple cutaneous ecchymoses, petechiae, and oral wet purpura. He received additional IVIG, danazol, azathioprine, and anti-thymocyte globulin without platelet response. Testing for H. Pylori was negative; a urine culture was sent for CMV which, when positive, was confirmed by a serum PCR. He was treated with twice daily IV ganciclovir and twice weekly cytogam. The CMV PCR became undetectable over 4 weeks. His platelet count increased substantially on IVIG every two weeks. He was eventually weaned off of the ganciclovir and the cytogam months after the CMV PCR became undetectable.

He experienced a reactivation of his CMV infection, with a positive PCR, 2 months later while being treated with a one week course of prednisone for an asthma exacerbation, which required an additional 4 month course of IV ganciclovir. His ITP worsened during that time and then improved again. It was managed for approximately one year with IVIG infusions every two weeks to maintain a platelet count >20 × 109/l. He now maintains stable platelet counts of approximately 50 × 109/l, has no signs/symptoms of bleeding complications and has been off of all medications for more than one year. He has not undergone splenectomy and avoids steroids and other immunosuppressive therapy.

This was the first case in which the CMV was recognized. The temporal association of response to standard ITP therapy and suppression of CMV is illustrated in Fig 1C.

Case four

A 72-year-old man with a history of asthma began experiencing recurrent episodes of epistaxis. He was found to have a platelet count of 1 × 109/l and ITP was diagnosed. He was treated with IVIG, steroids, platelets, and packed red blood cells, with a peak platelet response to 45 × 109/l. He was discharged home from the hospital on prednisone. On the day of discharge, he suffered a grand mal seizure. An magnetic resonance imaging scan demonstrated a right-sided subdural hematoma and a subarachnoid haemorrhage. Shortly after, his platelets dropped to <20 × 109/l, and he was placed on IVIG and prednisone. His peak platelet count was 71 × 109/l, but decreased rapidly. Due to fear of recurrent intracerebral haemorrhage (ICH), he underwent a splenectomy, without overall improvement in platelet counts, and was discharged home on 80 mg daily of prednisone. A serum CMV PCR was obtained secondary to transaminitis and was positive with 111 000 DNA copies/ml. Ganciclovir IV daily, valganciclovir po daily, and cytogam once a week were initiated. With this regimen and rapid steroid taper, the CMV viral load fell and became undetectable. His platelets increased substantially and he discontinued all platelet-specific therapy. Currently, his CMV viral load remains undetectable more than one year after tapering off his anti-CMV medications and his platelet count has remained >150 × 109/l. Figure 1D demonstrates the response of the platelet count to suppression of the CMV in this case; the platelet count, only maintained by 100 mg/day of prednisone after failed splenectomy, increased despite accelerated tapering of the prednisone.

Discussion

  1. Top of page
  2. Summary
  3. Case reports
  4. Discussion
  5. Acknowledgements
  6. Author contribution
  7. References

Nineteen cases of CMV-associated thrombocytopenia have been reported in the English language (Tables I and II; Alliot & Barrios, 2005; Ichiche et al, 2003; Von Spronsen & Breed, 1996; Sahud & Bachelor, 1978; Wright, 1992; Mizutani et al, 1995; Arruda et al, 1997; Gural et al, 1998; Swanobori et al, 1997; Crapnell et al, 2000; Chanarin & Walford, 1973; Harris et al, 1975; Ip & Corner, 1973; Eisenberg & Kaplan, 1993; Miyahara et al, 1997; Nomura et al, 2005; Shimm et al, 1980; Fiala & Kattlove, 1973; Sakata et al, 1999; Muntendam, 1975;Dor et al, 1977; Aguado et al, 1984; Lopez et al, 1998; Anton et al, 1985), but only two described severe, refractory cases (Eisenberg & Kaplan, 1993; Gural et al, 1998). Several important trends are evident from these 19 cases. Thirteen presented with a CMV-like illness, including symptoms of fever, myalgia, malaise, headache and sore throat. A work-up of the thrombocytopenia revealed atypical lymphocytes in 13 cases and transaminitis in 10; bone marrow aspirates revealed megakaryocytic hyperplasia in 10 cases. Steroids were the main treatment in the majority of reports; however, they proved to be of minimal or no benefit in six of the cases. Three of these six cases did not respond consistently to conventional therapy and ultimately required splenectomy. Ganciclovir was instituted in only two of these cases.

There are few reported paediatric cases of CMV-associated ITP (Fiala & Kattlove, 1973; Mizutani et al, 1995; Sakata et al, 1999). This present report describes a 3-year-old female and 9-year-old male with CMV-ITP. A recent study in China demonstrated that in 81 children with ITP at diagnosis and a mean age of 2·75 years, the majority had evidence of CMV infection. Fifty cases were myeloid CMV antigen positive with a positive rate of 61·73%, while 17 cases were blood CMV IgM positive (20·99%), and 70 cases were CMV IgG positive (86·42%). The CMV-infected patients were more likely to experience an exacerbation of ITP, be refractory, and experience chronic disease, and the authors concluded that CMV is an important risk factor for more severe, persistent childhood ITP (Ding et al, 2007).

In marked contrast to the reported cases of CMV infection in patients with ITP, the four cases described here with CMV are notable for their refractory nature. The cases proved largely unresponsive to front line ITP treatments; any responses at all were very short-lived. In these cases, as illustrated in Fig 1, it appeared that the CMV must be suppressed (or eradicated if possible) before standard therapy will be effective. For instance, in Case 2, although the thrombocytopenia was still significant after eradication of CMV, the patient was responsive to standard agents; prior to CMV treatment, he had had no response. In fact, the aggressive immunosuppression used to treat refractory ITP may exacerbate the primary CMV infection and worsen the ITP, or at least prevent it from improving. Treatment with steroids led to CMV reactivation and exacerbation/relapse of ITP in two of the patients. Given that steroids, along with other immunosuppressive therapies, may reactivate CMV, patients on immunosuppresive therapies who experience severe, refractory, thrombocytopenia should be screened with a PCR for CMV infection. Fortunately, this appears to be a relatively infrequent phenomenon. This exacerbation by steroids is similar to reports of hepatitis C-associated ITP, in which steroid treatment of the thrombocytopenia worsened the hepatitis and failed to increase the platelets (Rajan et al, 2005).

In the reported cases here, the patients presented with a transaminitis, experienced improved platelet counts once ganciclovir and cytogam were instituted and immunosuppression was reduced, and, in two of the cases, had megakaryocytic hyperplasia upon bone marrow examination. Only one patient presented with a CMV-like illness or showed atypical lymphocytes on smear, highlighting the need to have a very low threshold in suspecting CMV infection as the underlying cause of thrombocytopenia (Table V).

Table V.   Signs and symptoms that are possibly suggestive of the diagnosis of CMV-related ITP.
Transaminitis
Hepatomegaly
Fever of unknown aetiology
Atypical lymphocytes on smear
Severe symptomatic ITP with platelet counts less than 5–10 × 109/l and/or ICH
ITP unresponsive to standard therapies
ITP exacerbations with steroid or other immunosuppressive treatment

It is not clear why the four patients presented here were so vulnerable to CMV. Immunoglobulin levels, T cell and B cell function, and antibody levels to pneumoccocus, were found to be normal in each case. None of the patients were ever hypogammaglobulinemic or had any significant history of other infections either before or after their episodes of CMV ITP. The 3-year-old patient only experienced other infections after being intubated in the paediatric intensive care unit, having a central line, and receiving antibiotics for fever that may have been caused by CMV. Her PCR had been negative for at least one month at the time of her death. In her case, she appeared to have had a very complex, multi-factorial disease in which CMV was just one manifestation. Furthermore, CMV infection and hepatitis preceded the development of her ITP. The other three patients were remarkably well before, and since diagnosis and treatment of the CMV.

No specific studies of the mechanism of the underlying thrombocytopenia were performed other than carefully tracking the CMV PCR and relating platelet improvement to the decreasing PCR level in all four cases. Although the exact mechanism by which viral or bacterial agents lead to ITP is not known, several hypotheses exist (see Table VI). While molecular mimicry and chronic infection leading to immune dysregulation are possible, CMV is able to directly infect megakaryocytes and thereby decrease platelet production (Mizutani et al, 1995; Crapnell et al, 2000; Xiao et al, 2006). This seems to be the best explanation for the failure to respond to any of the conventional ITP therapies, especially as their primary effects are to block platelet destruction, not to stimulate platelet production (Psaila & Bussel, 2008). If this is the case, short-term use of thrombopoietic agents may be useful in these patients in the future. Two of the four patients suffered intracranial haemorrhages, and all four cases involved bleeding symptoms that were severe, suggesting that vasculopathy or dysfunctional platelets may compound the underlying thrombocytopenia.

Table VI.   Possible mechanisms of how viruses/bacteria cause ITP.
Molecular mimicry (Wright et al, 1996)
Immune dysregulation (Cooper & Bussel, 2006)
Induction of platelet phagocytosis (Swanobori et al, 1997)
Direct infection of megakaryocytes (Amitai & Granit, 1986; Landonio et al, 1992; Mizutani et al, 1995; Crapnell et al, 2000; Xiao et al, 2006)
Production of hematopoietic inhibitory cytokines such as interferon-γ and tumour necrosis factor-α by CMV-infected leucocytes and stromal cells of bone marrow (Miyahara et al, 1997)
Suppression of haematopoiesis of human progenitor cells (Arruda et al, 1997)
Megakaryocyte production of dysfunctional platelets
Induction of vascular disease

Treatment of the CMV requires two components: effective treatment of the CMV and discontinuation of immunosuppressive medications (see Table IV). The treatment protocol followed was arbitrary but included a combination of both IV ganciclovir and IV cytogam to optimize rapid suppression of the CMV. Simultaneous reduction of immunosuppression, with IVIG as needed to transiently support the platelet count, may be crucial during this phase. If an effect on the platelet count is seen over 2–4 weeks, tapering of the CMV-specific therapies may be instituted. Because of the potential for myelosuppression by prolonged IV ganciclovir, it is recommended to taper this first. In Case 1, long-term treatment with high-dose ganciclovir led to the eventual development of myelosuppression, forcing the use of foscarnet, despite its nephrotoxicity, and later, cidofavir. The main point of management is that when CMV is controlled by anti-viral therapies, normal treatments for ITP, such as IVIG and splenectomy, regain their effectiveness.

Several general points can be made based on these four reported cases. First, on presentation, the thrombocytopenia is essentially indistinguishable from classic ITP, characterized by decreased platelet numbers while other cell lines remain intact, and by (at best) a rather limited response to ‘ITP specific’ therapies, such as IVIG, anti-D, and steroids. Second, if there is any suspicion of CMV based on exposure to it, refractoriness or severity of the ITP, or due to similarities to the cases listed in the tables (transaminitis, atypical lymphocytes on smear, fever, etc), it is appropriate to test for CMV infection by PCR. The authors believe that PCR testing is superior to serology, given the likelihood of false positive results when using serology after a patient has received IVIG. There is no requirement for any type of a mono-like illness, which was seen in only one of the four cases. Third, if steroids appear to worsen or have no affect on the thrombocytopenia, CMV infection should be high on the differential diagnosis. Finally, in certain areas, if suited to the population epidemiology, such as possibly in parts of China, screening of all cases of de novo ITP for CMV may be appropriate so that treatment can be altered accordingly in infected cases.

Acknowledgements

  1. Top of page
  2. Summary
  3. Case reports
  4. Discussion
  5. Acknowledgements
  6. Author contribution
  7. References

The authors wish to acknowledge Amber Fitzgerald for her help in preparing the manuscript and Lynne Strassfeld for her making possible our obtaining CMV PCR results.

Author contribution

  1. Top of page
  2. Summary
  3. Case reports
  4. Discussion
  5. Acknowledgements
  6. Author contribution
  7. References

DD collected and analyzed patient data, performed literature review, and co-wrote the manuscript. AA collected and analyzed patient data for patient 2, edited the manuscript. JB managed the patients, collected and analyzed patient data and co-wrote the manuscript. The authors have no conflict of interest although JBB has received clinical research support for treatment of ITP with thrombopoietic agents and IVIG. The study was partially supported by Dana Hammond Stubgen and the Children’s Cancer and Blood Foundation.

References

  1. Top of page
  2. Summary
  3. Case reports
  4. Discussion
  5. Acknowledgements
  6. Author contribution
  7. References
  • Aboulafia, D.M., Bundow, D., Waide, S., Bennet, C. & Kerr, D. (2000) Initial observations on the efficacy of highly active antiretroviral therapy in the treatment of HIV-associated autoimmune thrombocytopenia. The American Journal of the Medical Sciences, 320, 117123.
  • Aguado, J.M., Chocarro, A., Collazos, J., Labanda, F. & De Vila Lobos, E. (1984) Purpura trombocitopenica en el adulto tras infeccion por citomegalovirus. Revista Clinica Espanola, 173, 133134.
  • Aktepe, O., Yetgin, S., Olcay, L. & Ozbek, N. (2004) Human parvovirus B19 associated with idiopathic thrombocytopenic purpura. Pediatric Hematology and Oncology, 21, 421426.
  • Alliot, C. & Barrios, M. (2005) Cytomegalovirus induced thrombocytopenia in an immunocompetent adult effectively treated with intravenous immunoglobulin: a case report and review. Hematology, 10, 277279.
  • Amitai, Y. & Granit, G. (1986) Thrombocytopenic purpura during the incubation period of rubella. Helvetica Paediatrica Acta, 41, 5557.
  • Anton, A., Oyarzabal, I.F. & Rivero, P.A. (1985) Thrombocipenia grave secundaria a citomegalovirus. Presentacion de un caso. Medicina Clinica, 85, 518.
  • Arruda, V., Rossi, C., Nogueira, E., Annicchino-Bizzacchi, J., Costa, F. & Costa, S. (1997) Cytomegalovirus infection as a cause of severe thrombocytopenia in a nonimmunosuppressed patient. Acta Haematologica, 98, 228230.
  • Asahi, A., Kuwana, M., Suzuki, H., Hibi, T., Kawakami, Y. & Ikeda, Y. (2006) Letters to the editor: effects of a helicobacter pylori eradication regimen on anti-platelet autoantibody response in infected and uninfected patients with idiopathic thrombocytopenic purpura. Haematologica, 91, 14361437.
  • Boruchov, D.M., Gururangan, S., Driscoll, M.C. & Bussel, J.B. (2007) Multi-agent induction and maintenance therapy for patients with refractory immune thrombocytopenic purpura (ITP). Blood, 110, 35263531.
  • Bussel, J.B., Kuter, D.J., George, J.N., McMillan, R., Aledort, L.M., Conklin, G.T., Lichtin, A.E., Lyons, R.M., Nieva, J., Wasser, J.S., Wiznitzer, I., Kelly, R., Chen, C.F. & Nichol, J.L. (2006) AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. New England Journal of Medicine, 19;355, 16721681.
  • Chanarin, I. & Walford, D.M. (1973) Thrombocytopenic purpura in cytomegalovirus mononucleosis. Lancet, 2, 238239.
  • Cooper, N. & Bussel, J. (2006) The pathogenesis of idiopathic immune thrombocytopenia purpura. British Journal of Haematology, 133, 364374.
  • Crapnell, K., Zanjani, E., Chaudhuri, A., Ascensao, J., Jeor, S. & Macciejewski, J. (2000) In vitro infection of megakaryocytes and their precursors by human cytomegalovirus. Blood, 95, 487492.
  • Ding, Y., Zhao, L., Mei, H., Zhang, S. & Huang, Z. (2007) Role of myeloid human cytomegalovirus infection in children’s idiopathic thrombocytopenia purpura. Pediatric Hematology and Oncology, 24, 179188.
  • Dor, J.F., Arlaud, J., Chambourlier, P. & Mongin, M. (1977) Purpura thrombopenique revelateur d’une maladie des inclusions cytomegaliques chez l’adulte. La Nouvelle presse médicale, 6, 24412442.
  • Eisenberg, M.J. & Kaplan, B. (1993) Cytomegalovirus induced thrombocytopenia in an immunocompetent adult. Western Journal of Medicine, 158, 525526.
  • Emilia, G., Longo, G., Luppi, M., Gandini, G., Morselli, M., Ferrara, L., Amarri, S., Cagossi, K. & Torelli, G. (2001) Helicobacter pylori eradication can induce platelet recovery in idiopathic thrombocytopenic purpura. Blood, 97, 812814.
  • Fiala, M. & Kattlove, H. (1973) Cytomegalovirus mononucleosis with severe thrombocytopenia. Annals of Internal Medicine, 79, 450451.
  • Garcia-Suarez, J., Burgaleta, C., Hernanz, N., Albarran, F., Tobaruela, P. & Alvarez-Mon, M. (2000) HCV-associated thrombocytopenia: clinical characteristics and platelet response after recombinant α2b-interferon therapy. British Journal of Haematology, 110, 98103.
  • Gasbarrini, A., Franceschi, F., Tartaglione, R., Landolfi, R., Pola, P. & Gasbarrini, G. (1998) Regression of autoimmune thrombocytopenia after eradication of helicobacter pylori. Lancet, 352, 878.
  • Gural, A., Gillis, S., Gafanovich, A., Israel, Z., Wolf, D., Pomeranz, S. & Ben-Yehuda, D. (1998) Massive intracranial bleeding requiring emergency splenectomy in a patient with CMV-associated thrombocytopenia. Haemostasis, 28, 250255.
  • Harris, A.I., Meyer, R.J. & Broody, E.A. (1975) Cytomegalovirus-induced thrombocytopenia and hemolysis in an adult. Annals of Internal Medicine., 83, 670671.
  • Heegaard, E.D., Rosthøj, S., Petersen, B.L., Nielsen, S., Karup Pedersen, F. & Hornsleth, A. (1999) Role of parvovirus B19 infection in childhood idiopathic thrombocytopenic purpura. Acta paediatrica, 88, 614617.
  • Hida, M., Shimamura, Y., Ueno, E. & Watanabe, J. (2000) Childhood idiopathic thrombocytopenic purpura associated with human parvovirus B19 infection. Pediatrics International, 42, 708710.
  • Hsiao, C. (2000) Epstein-Barr virus associated with immune thrombocytopenic purpura in childhood: a retrospective study. Journal of Paediatrics and Child Health, 36, 445448.
  • Ichiche, M., Fontaine, C. & Lacro, P. (2003) Severe thrombocytopenia secondary to cytomegalovirus infection in an immunocompetent adult. European Journal of Internal Medicine, 14, 5659.
  • Ip, H. & Corner, B.D. (1973) Thrombocytopenic purpura in cytomegalovirus mononulceosis. Lancet, 2, 621.
  • Jackson, S., Beck, P.L., Pineo, G.F. & Poon, M.C. (2005) Helicobacter pylori eradication: novel therapy for immune thrombocytopenic purpura? A review of the literature American Journal of Hematology, 78, 142150.
  • Landonio, G., Nosari, A., Spinelli, F., Vigorelli, R., Caggese, L. & Schlact, I. (1992) HIV-related thrombocytopenia: four different clinical subsets. Haematologica, 77, 398401.
  • Levy, A. & Bussel, J. (2004) Immune thrombocytopenic purpura: investigation of the role of cytomegalovirus infection. British Journal of Haematology, 126, 622623.
  • Li, Z., Nardi, M. & Karpatkin, S. (2005) Role of molecular mimicry to HIV-1 related immunologic thrombocytopenia. Blood, 106, 572576.
  • Lopez, V.J., Falgueras, L.L., Martin, F.S. & Muniz, G.R. (1998) Thrombocitopenia severa secundaria a infeccion por citomegalovirus en un adulto immunocompetente. Anales de medicina interna, 15, 6364.
  • Miyahara, M., Shimamoto, Y., Yamada, H., Shibata, K., Matsuzaki, M. & Ono, K. (1997) Cytomegalovirus associated myelodysplasia and thrombocytopenia in an immunocompetent adult. Annals of Hematology, 74, 99101.
  • Mizutani, K., Azuma, E., Komada, Y., Ito, M., Sakurai, M., Hironaka, T. & Hirai, K. (1995) An infantile case of cytomegalovirus induced idiopathic thrombocytopenic purpura with predominant proliferation of CD10 positive lymphoblast in bone marrow. Acta Pediatrica Japonica, 37, 7174.
  • Muntendam, H. (1975) Thrombocytopenie door cytomegalovirus infectie. Nederlands tijdschrift voor geneeskunde, 119, 1517.
  • Murray, J.C., Kelley, P.K., Hogrefe, W.R. & McClain, K.L. (1994) Childhood idiopathic thrombocytopenic purpura: association with human parvovirus B19 infection. The American Journal of Pediatric Hematology/Oncology, 16, 314319.
  • Nomura, K., Matsumoto, Y., Kotoura, Y., Shimizu, D., Kamitsuji, Y., Horiike, S. & Tamiwaki, M. (2005) Thrombocytopenia due to cytomegalovirus infection in an immunocompetent adult. Hematology, 10, 405406.
  • Psaila, B. & Bussel, J.B. (2008) Refractory immune thrombocytopenic purpura: current strategies for investigation and management. British Journal of Haematology, 143, 1626.
  • Rajan, S.K., Espina, B.M. & Liebman, H.A. (2005) Hepatitis C virus-related thrombocytopenia: clinical and laboratory characteristics compared with chronic immune thrombocytopenic purpura. British Journal of Haematology, 129, 818824.
  • Sahud, M. & Bachelor, M. (1978) Cytomegalovirus-induced thrombocytopenia. An unusual case report. Archives of Internal Medicine, 138, 15731575.
  • Sakata, H., Ikegami, K., Nagaya, K., Shirai, M. & Maruyama, S. (1999) Thrombocytopenia caused by acquired cytomegalovirus infection in children. Pediatrics International, 41, 113114.
  • Sayan, O., Erikci, A.A. & Ozturk, A. (2006) The efficacy of helicobacter pylori eradication in the treatment of idiopathic thrombocytopenic purpura – the first study in Turkey. Acta Haematologica, 116, 146149.
  • Scaradavou, A. (2002) HIV-related thrombocytopenia. Blood Reviews, 16, 7376.
  • Shimm, D., Logue, G. & Rosse, W. (1980) Recurrent thrombocytopenia following idiopathic thrombocytopenic purpura. Archives of Internal Medicine, 140, 855857.
  • Suvajdzic, N., Stankovic, B., Artiko, V., Cvejić, T, Bulat, V, Bakrac, M, Colović, M, Obradović, V. & Atkinson, H.D. (2006) Helicobacter pylori eradication can induce platelet recovery in chronic idiopathic thrombocytopenic purpura. Platelets, 17, 227230.
  • Swanobori, M., Nakagawa, Y., Inoue, Y. & Suzuki, K. (1997) Severe thrombocytopenia after cytomegalovirus infection in an immunocompetent host. Japanese Journal of Clinical Immunology, 20, 134138.
  • Von Spronsen, J.V. & Breed, W. (1996) Cytomegalovirus-induced thrombocytopenia and haemolysis in an immunocompetent adult. British Journal of Haematology, 92, 218220.
  • Wright, J. (1992) Severe thrombocytopenia secondary to asymptomatic cytomegalovirus infection in an immunocompetent host. Journal of Clinical Pathology, 45, 10371038.
  • Wright, J.F., Blanchette, V.S., Wang, H., Arya, N., Petric, M., Semple, J.W., Chia, W.K. & Freedman, J. (1996) Characterization of platelet-reactive antibodies in children with varicella-associated acute immune thrombocytopenia purpura (ITP). British Journal of Haematology, 95, 145152.
  • Xiao, Y., Lin, W., Liu, Q., Jin, R. & Fei, H. (2006) Direct infection of colony forming unit-megakaryocyte by human cytomegalovirus contributes the pathogenesis of idiopathic thrombocytopenic purpura. Journal of Huazhong University of Science and Technology, 26, 555557.
  • Yenicesu, I., Yetgin, S., Ozyurek, E. & Aslan, D. (2002) Virus associated immune thrombocytopenic purpura in childhood. Pediatric Hematology and Oncology, 19, 433437.