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Postgraduate Education Corner: PULMONARY AND CRITICAL CARE PEARLS |

A 69-Year-Old Woman With Respiratory Failure and Thrombocytopenia* FREE TO VIEW

Kevin Lawrence, MD; Patrick White, MD; Ramsey Hachem, MD
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*From Pulmonary and Critical Care Medicine (Drs. Lawrence and Hachem) and Internal Medicine (Dr. White), Washington University School of Medicine, St. Louis, MO.

Correspondence to: Kevin Lawrence, MD, 600 S Euclid, Campus Box 8052, St. Louis, MO 63110; e-mail: klawrenc@im.wustl.edu



Chest. 2008;133(5):1256-1259. doi:10.1378/chest.07-2601
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Published online

A 69-year-old morbidly obese woman with a history of osteoarthritis presented to a community hospital for a routine left, total knee arthroplasty. Postoperatively, diffuse diarrhea developed and was diagnosed as Clostridium difficile colitis. Despite appropriate treatment, she decompensated clinically with toxic megacolon developing requiring subtotal colectomy with ileostomy. Her postoperative course was complicated by septic shock, respiratory failure, and acute renal failure requiring renal replacement therapy. On hospital day 15, thrombocytopenia developed that was progressive and complicated by bleeding most notably at venipuncture sites, requiring RBC transfusion. Her platelet count remained severely depressed despite multiple platelet transfusions. She had been treated with broad-spectrum IV antibiotics, vasopressor support, and corticosteroids for septic shock during her hospitalization. Her hemodynamics ultimately improved allowing discontinuation of the vasopressors. Due to her refractory thrombocytopenia and multiple acute medical problems, she was transferred to our ICUs for further management on hospital day 31.

Physical Examination

The patient arrived sedated on mechanical ventilation. Vital signs were as follows: temperature, 37.5°C; heart rate, 62 beats/min; BP, 144/74 mm Hg; respiratory rate, 15 breaths/min; and oxygen saturation, 94% on fraction of inspired oxygen of 0.4. There was a right internal jugular hemodialysis catheter in place and a left internal jugular central venous catheter in place, both associated with large hematomas. Her abdomen was obese, soft, and nontender with an ileostomy site in place in the right lower quadrant. The midline abdomen incision appeared unremarkable. Lower extremities demonstrated pitting edema and extensive ecchymosis over her left knee with an incision that was clean, dry, and intact. Her skin was otherwise warm and moist with no petechiae or erythema.

Laboratory Findings

Laboratory findings included the following: WBC count, 4.8 × 103/μL; hemoglobin, 9.4 g/dL; platelet count, 12 × 103/μL; BUN concentration, 90 mg/dL; creatinine level, 2.4 mg/dL; lactate dehydrogenase level, 450 U/L; haptoglobin level, 131 mg/dL; fibrinogen level, 504 mg/dL; and a prothrombin time that was mildly prolonged but corrected with the administration of vitamin K. A peripheral blood smear was significant for one to two platelets per high-power field. Chest radiography demonstrated a small left pleural effusion and patchy bibasilar atelectasis. Records indicated that all hematologic parameters were normal prior to admission to the community hospital.

Hospital Course

The patient was admitted to our medical ICU. She was continued on treatment for C difficile colitis until a 3-week course was completed. She improved clinically except for severe persistent thrombocytopenia that did not respond to platelet transfusion. Heparin was avoided, and antibodies to platelet factor 4 were negative. HIV testing was negative as well as a direct Coombs test. Blood and urine culture results were sterile. All medications deemed unnecessary were stopped, including corticosteroids. She was continued on dialysis for nonoliguric renal failure secondary to acute tubular necrosis. She began to make progress in terms of ventilator weaning. Mild neutropenia developed on hospital day 35, and a bone marrow biopsy was planned but serology provided further information.

What is the etiology of the thrombocytopenia?
Diagnosis: active cytomegalovirus infection (blood cytomegalovirus polymerase chain reaction, 243,606 copies/mL)

Cytomegalovirus (CMV) is a common infectious pathogen that usually occurs during childhood. A latent infection then develops, characterized by anti-cytomegalovirus (IgG) antibodies. Active infection can result from reactivation or reinfection with another virus strain. Depending on the immune status of the host, active CMV infection can range from asymptomatic virus shedding to severe disease with various clinical pictures. The clinical diagnosis of active CMV infection is confounded by nonspecific signs and symptoms.

CMV is a well-recognized pathogen contributing to significant morbidity in organ transplantation, hematologic malignancy, and AIDS. It is now recognized that patients who are critically ill and not otherwise thought to be immunosuppressed are at risk for active CMV infection, with severe CMV disease developing in fraction. The exact prevalence of active CMV infection resulting from critical illness has varied in the literature, but some studies estimate the prevalence to be as high as 35%. Among those with critical illness, sepsis and length of hospital stay of > 1 week seem be the most consistent risk factors for active CMV infection. While the exact mechanism is unknown, CMV reactivation may occur due to an immunosuppression of critical illness. This is thought to be due to an imbalance in immunomodulatory mediators leading to immunodysfunction. The depression of lymphocyte function may be an important part in this entity given their key role in antiviral defense. Active CMV infection during critical illness has been associated with a longer duration of ICUs stay and a longer duration of mechanical ventilation. Mortality has also been shown to be higher in those with active CMV infection in some series. Whether CMV is a “true pathogen” or an indicator of immunosuppression during critical illness deserves further investigation.

Thrombocytopenia is a recognized complication of a variety of viral infections in immunocompetent adults. However, CMV is not one of the viruses typically implicated; several case reports are present in the medical literature linking CMV and thrombocytopenia. While the exact mechanism leading to thrombocytopenia associated with CMV infection is unknown, several theories have been proposed. CMV may exert a direct cytopathic effect on bone marrow progenitor cells leading to thrombocytopenia. Alternatively, platelet destruction that is immune mediated has also been theorized similar to other autoimmune phenomenon associated with CMV infection. Lastly, changes in accessory cells that provide growth factors for maintenance, proliferation, and differentiation may lead to bone marrow suppression. Thrombocytopenia may occur early in the course of the infection or it may be delayed, suggesting that the direct cytopathic effect of the virus or an immune-mediated mechanism may be responsible at different times in the disease course, respectively.

The exact treatment of thrombocytopenia associated with CMV infection is unknown. Treatments described have ranged from corticosteroid therapy, IV Ig infusion, antiviral therapy with ganciclovir, and splenectomy. Variable times to recovery from thrombocytopenia have been reported, and there are insufficient data to suggest a standard treatment modality. If one believes that early onset thrombocytopenia is due to a direct cytopathic effect of the virus, then antiviral therapy might be beneficial. Likewise, if the thrombocytopenia is delayed with respect to the clinical infection, then corticosteroids, IV Ig, or splenectomy could be reasoned to provide benefit. Without sufficient evidence to guide therapy, the overriding principle should be to “first, do no harm.”

Clinical Course

We began ganciclovir for the treatment of the active CMV infection with associated severe thrombocytopenia. The platelet count rapidly increased to normal (Fig 1 ). The mild neutropenia rapidly resolved as well. Serology revealed a positive test result for CMV IgG but a negative test result for CMV IgM, indicating reactivation of a latent infection. The patient was successfully weaned from the mechanical ventilator and began to make progress with physical rehabilitation. Dialysis was soon discontinued secondary to recovery of renal function. Ganciclovir was continued for 21 days then and discontinued, at which time testing demonstrated CMV DNA at a level too low to quantitate by polymerase chain reaction testing of the blood. The patient was discharged to a facility for physical rehabilitation prior to returning home.

  1. CMV infection has been described in the medical literature to be associated with severe thrombocytopenia; however, it appears to be relatively uncommon, and a high index of suspicion is needed for an accurate diagnosis.

  2. The exact mechanism leading to thrombocytopenia in the setting of CMV infection is unknown, but several theories have been proposed.

  3. The specific treatment for CMV associated thrombocytopenia is not well defined, and therapies should be addressed on an individual basis.

  4. An active CMV infection can occur during times of critical illness secondary to reactivation of a latent infection or acquisition of a new virus strain.

  5. Active CMV infection during times of critical illness is associated with worse clinical outcomes.

This work was performed at Barnes-Jewish Hospital, St. Louis, MO.

The authors have no conflicts of interest to disclose.

Figure Jump LinkFigure 1. Trend in platelet count in relation to cumulative hospital day and relevant clinical events.Grahic Jump Location
Arruda, VR, Rossi, CL, Nogueira, E, et al (1997) Cytomegalovirus infection as cause of severe thrombocytopenia in a nonimmunosuppressed patient.Acta Haematol98,228-230. [PubMed] [CrossRef]
 
Cohen, JI, Corey, GR Cytomegalovirus infection in the normal host.Medicine (Baltimore)1985;64,100-114. [PubMed]
 
Eisenberg, MJ, Kaplan, B Cytomegalovirus-induced thrombocytopenia in an immunocompetent adult.West J Med1993;158,525-526. [PubMed]
 
Gural, A, Gillis, S, Gafanovich, A, et al Massive intracranial bleeding requiring emergency splenectomy in a patient with CMV-associated thrombocytopenia.Haemostasis1998;25,250-255
 
Heininger, A, Jahn, G, Engel, C, et al Human cytomegalovirus infections in nonimmunosuppressed critically ill patients.Crit Care Med2001;29,541-547. [PubMed]
 
Jaber, S, Chanques, G, Borry, J, et al Cytomegalovirus virus infection in critically ill patients: associated factors and consequences.Chest2005;127,233-241. [PubMed]
 
Von Muller, L, Klemm, A, Weiss, M, et al Active cytomegalovirus infection in patients with septic shock.Emerg Infect Dis2006;12,1517-1522. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Trend in platelet count in relation to cumulative hospital day and relevant clinical events.Grahic Jump Location

Tables

Suggested Readings

Arruda, VR, Rossi, CL, Nogueira, E, et al (1997) Cytomegalovirus infection as cause of severe thrombocytopenia in a nonimmunosuppressed patient.Acta Haematol98,228-230. [PubMed] [CrossRef]
 
Cohen, JI, Corey, GR Cytomegalovirus infection in the normal host.Medicine (Baltimore)1985;64,100-114. [PubMed]
 
Eisenberg, MJ, Kaplan, B Cytomegalovirus-induced thrombocytopenia in an immunocompetent adult.West J Med1993;158,525-526. [PubMed]
 
Gural, A, Gillis, S, Gafanovich, A, et al Massive intracranial bleeding requiring emergency splenectomy in a patient with CMV-associated thrombocytopenia.Haemostasis1998;25,250-255
 
Heininger, A, Jahn, G, Engel, C, et al Human cytomegalovirus infections in nonimmunosuppressed critically ill patients.Crit Care Med2001;29,541-547. [PubMed]
 
Jaber, S, Chanques, G, Borry, J, et al Cytomegalovirus virus infection in critically ill patients: associated factors and consequences.Chest2005;127,233-241. [PubMed]
 
Von Muller, L, Klemm, A, Weiss, M, et al Active cytomegalovirus infection in patients with septic shock.Emerg Infect Dis2006;12,1517-1522. [PubMed]
 
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