Leukemoid reaction due to Clostridium difficile infection in acquired immunodeficiency syndrome: two case reports and a review of the literature.

Abstract: The clinical presentation of colitis associated with Clostridium difficile infection in immunosuppressed patients with acquired immunodeficiency syndrome (AIDS) has not been completely characterized. Previous reports suggest that these patients present with low blood leukocyte counts, consistent with the impaired myelopoiesis that can occur with human immunodeficiency virus (HIV) infection. In contrast, we describe the cases of two patients with colitis associated with C difficile infection who developed intense leukemoid reactions despite being in advanced stages of AIDS. To the best of our knowledge, these are the first described cases of leukemoid reaction associated with C difficile or other bacterial infection in AIDS patients. We review the literature on C difficile colitis in patients infected with HIV and suggest that severe C difficile infection should be considered in such patients presenting with leukemoid reaction and diarrhea.

Key Words: acquired immunodeficiency syndrome, Clostridium difficile, leukemoid reaction, pseudomembranous colitis

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Clostridium difficile infection is the leading cause of nosocomial diarrhea in the United States. It can manifest a wide spectrum of clinical presentations, from simple, asymptomatic carriage in the large bowel, to symptomatic diarrhea, to pseudomembranous colitis and fulminant colitis. (1,2) Clinical features of colitis associated with severe C difficile infection in immunocompetent patients include megacolon, leukocytosis (including leukemoid reactions), and hypoalbuminemia. (1-5) The clinical course of C difficile colitis in patients with acquired immunodeficiency syndrome (AIDS) is not yet completely characterized. Patients infected with the human immunodeficiency virus (HIV) may have decreased granulocytic responses to infections, owing to impaired myelopoiesis. (6,7) In fact, several published reports suggest that patients with AIDS and C difficile colitis have lower leukocyte counts than do patients without HIV infection. (8,9) In contrast to these reports, we describe two cases of patients with C difficile colitis who, despite immunosuppression, developed intense leukemoid reactions.

Case Reports

Patient 1

A 25-year-old black female with AIDS (CD4 count 1 mo before admission, 6 cells/m[m.sup.3]) was admitted for diagnostic workup and treatment of diarrhea. She complained of 2 weeks of diffuse abdominal pain relieved by bowel movements; watery diarrhea (6-7 times/d); and nausea and vomiting. Her medications were acyclovir, azithromycin, clindamycin, and primaquine. Her medical history included prior Pneumocystis carinii pneumonia, genital herpes, ophthalmic zoster, and allergy to sulfonamides. Her white blood cell count was 20.4 X [10.sup.9]/L. C difficile toxin was present in her stools, with no ova, parasites, acid-fast organisms, or Cryptosporidium antigen detected. A limited sigmoidoscopy revealed pseudomembranous colitis in the rectosigmoid area, with biopsy showing an acute inflammatory exudate. Therapy was changed from clindamycin and primaquine to atovaquone, and treatment with metronidazole was started. Her symptoms resolved, and she was discharged on hospital day 7. At discharge she was taking oral metronidazole, and the leukocyte count had decreased to 9.7 X [10.sup.9]/L.

Nine days after discharge, she returned to the hospital with extreme fatigue; recurrent nausea and vomiting; diffuse, colicky abdominal pain; and watery diarrhea for which she was taking loperamide hydrochloride. She denied fever, melena, and hematemesis.

Physical examination showed that her temperature was 37.2[degrees]C; blood pressure, 55/40 mm Hg; heart rate, 154 beats/min; and respiratory rate, 32 breaths/min. She was obtunded, with arterial oxygen saturation of 90%. Oral plaques consistent with candidiasis were present, along with bilateral crackles in the lung fields. Heart examination revealed no abnormalities. The abdomen was distended, without shifting dullness, but with diffuse rebound tenderness and decreased bowel sounds. There were no masses or organomegaly; rectal examination revealed trace amounts of greenish guaiac-positive stools. Her pulse was weak and rapid.

Her initial leukocyte count was 88.3 X [10.sup.9]/L, with 61% neutrophils, 22% bands, 3% metamyelocytes, 3% myelocytes, 10% lymphocytes, and 1% monocytes, with no blasts detected. Hemoglobin level was 10.8 g/dL, and platelet count was 495 X [10.sup.9]/L. Serum chemistry values were as follows: sodium, 138 mmol/L; potassium, 6.6 mmol/L; chloride, 99 mmol/L; bicarbonate, 9 mmol/L; blood urea nitrogen, 45 mg/dL (normal, 10-20 mg/dL); creatinine, 3.8 mg/dL; alkaline phosphatase, 182 U/L (normal, 38-126 U/L); aspartate aminotransferase, 105 U/L (normal, 15-46 U/L); alanine aminotransferase, 33 U/L (normal, 7-56 U/L); amylase, 211 U/L (normal, 30-110 U/L); total bilirubin, 0.4 mg/dL (normal, 0.2-1.3 mg/dL); total protein, 2.8 g/dL; albumin, 1.2 g/dL. No abnormalities were seen on chest radiograph, and abdominal films revealed no evidence of free air, obstruction, or ileus.

The reappearance of symptoms consistent with severe colitis suggested recurrent colitis associated with C difficile infection, possibly exacerbated by treatment with self-prescribed loperamide hydrochloride. She was admitted to the intensive care unit for treatment of severe C difficile colitis and received intravenous metronidazole; in view of severe cardiovascular, renal, and respiratory failure, her treatment also included vancomycin, piperacillin/tazobactam, atovaquone, and azithromycin. Multiple cultures and smears of blood, urine, tracheal aspirates, and stools failed to reveal another bacterial, fungal, or viral etiology. Acute respiratory distress syndrome, requiring mechanical ventilation, and disseminated intravascular coagulation ensued. Her white blood cell count increased to levels as high as 120 X [10.sup.9]/L (Table 1). The patient died on the third day of treatment after refractory multiple-organ failure. A request for autopsy was refused.

Patient 2

A 54-year-old black male with AIDS and a CD4 count of 89 cells/m[m.sup.3] 4 months prior to admission presented with acute-onset, diffuse abdominal pain of 4 days' duration. He also had watery diarrhea (10 times/d), odynophagia, fatigue, dizziness, and palpitations. His medical history included a perforated duodenal ulcer 2 years before, caused by duodenal tuberculosis (treated for 12 mo and without recurrence), oral candidiasis, and two episodes of pseudomembranous colitis requiring hospitalization within the past year. Medications included lamivudine, zidovudine, nelfinavir, and sulfamethoxazole-trimethoprim.

At admission, his temperature was 36.4[degrees]C; arterial blood pressure, 132/91 mm Hg; respiratory rate, 16 breaths/min; and heart rate, 108 beats/min. Physical examination revealed bitemporal wasting, dry oral mucosa, and no thrush. Breath sounds were decreased in the lung bases, and scattered bilateral crackles were noted. Heart examination showed no abnormality. The abdomen was soft, mildly distended, and diffusely tender, with faint bowel sounds. The neurologic and musculoskeletal examinations were unremarkable.

Blood tests revealed a leukocyte count of 40.9 X [10.sup.9]/L, with 92% neutrophils, 4% lymphocytes, and 4% monocytes, with no blasts detected; his hemoglobin level was 16.2 g/dL; and his platelet count was 585 X [10.sup.9]/L. Serum chemistry laboratory values were as follows: sodium, 132 mmol/L; potassium, 4.9 mmol/L; bicarbonate, 17 mmol/L; chloride, 105 mmol/L; blood urea nitrogen, 77 mg/dL; creatinine, 1.4 mg/dL; albumin, 1.9 g/dL. Initial stool analysis showed occult blood and many leukocytes, but no ova, parasites, acid-fast organisms, or Cryptosporidium antigen were detected. Serial blood cultures were negative for microorganisms. Chest radiograph showed no abnormalities, and abdominal films showed numerous air-fluid levels with nondilated bowel loops. Abdominal computed tomography revealed pancolitis, with predominant involvement of the rectosigmoid area and without free air or fluid in the peritoneal cavity. Pseudomembranous colitis was suspected and confirmed by detection of C difficile toxin in the stool.

Oral metronidazole therapy was started, resulting in improvement of the patient's gastrointestinal symptoms, a gradual decrease in the leukocyte count, and stools becoming negative for the presence of C difficile toxin by day 4 (Table 1). On the 33rd day of hospitalization, however, the patient experienced a sudden relapse of colitis; C difficile toxin was again detected; and extreme leukocytosis recurred, with white blood cell counts as high as 43.5 X [10.sup.9]/L. Despite treatment, the patient died as a result of fulminant abdominal sepsis on day 36.

Discussion

C difficile is a spore-forming, Gram-positive, anaerobic bacillus that causes disease via toxin-mediated damage to the colonic epithelium. The disruption of normal colonic bacteria such as Bacteroides by antibiotic therapy (most commonly ampicillin, amoxicillin, cephalosporins, and clindamycin) or, rarely, chemotherapy allows for colonization by C difficile if the patient is exposed to spores. Reservoirs of infection in hospitals and long-term care facilities have allowed this enteric pathogen to become the single most important cause of nosocomial diarrhea. (10)

Spectrum of Disease and Prognostic Factors

Although costly and disabling, symptomatic C difficile infection usually presents as mild colitis that is easily controlled with treatment; however, a small subset of patients develops severe, toxic colitis, with dehydration, colonic ischemia, shock, and even death. In a retrospective case-control study of patients with severe C difficile colitis, Rubin et al (5) found that there was a significant association with advanced age, comorbid conditions (malignancy, chronic obstructive pulmonary disease, and renal insufficiency), and medications (clindamycin, antiperistaltics, and immunosuppressants). Prognostic signs and symptoms in this and other series included mental status decline, peritoneal signs, hypoalbuminemia, radiographic indexes of severity such as colonic intramural gas and leukocytosis. (4,5) In fact, C difficile infection has been occasionally associated with leukemoid reactions in patients without HIV infection. (2-4)

Colitis Associated with Clostridium difficile and HIV

In patients with AIDS and low CD4 counts, antibiotic prophylaxis against opportunistic infections is now the standard of care, resulting in increased risk of C difficile colitis. Besides immunodeficiency, other potential risk factors for C difficile infection in HIV-positive patients are more frequent hospitalizations or visits to health care facilities that are colonized by spores of the organism.

Immunosuppression associated with HIV infection would, in principle, predict a poor prognosis. Published reports are contradictory in this regard, however, with at least two studies (11,12) reporting more severe disease in HIV-infected patients with C difficile colitis, whereas others showed neither a more virulent course nor a diminished response to therapy (8,9) (Table 2). The relapse rate after treatment varies from 9.4 to 28% in HIV-positive patients, which is comparable with the rates observed in patients without HIV infection (13) (Table 2). Therefore, the prognosis of C difficile colitis in patients with AIDS is still unknown.

Granulocytic Response in AIDS

Patients with AIDS have impaired myelopoiesis and defective granulocytic response to infection. (6,7) In fact, neutropenia can occur in as many as 35 to 75% of patients with AIDS. Multiple pathologic mechanisms have been implicated, including bone marrow infection by HIV and opportunistic pathogens, low levels of granulocyte colony-stimulating factor (G-CSF), the presence of serum myeloinhibitory factors, and abnormal cytokine microenvironment in the bone marrow. (6,7) Overall, there appears to be significant impairment of the proliferative capacity of granulocyte-macrophage progenitor cells from these patients as compared with controls. Consistent with this notion, a lack of leukocytosis (and even leukopenia) has been a notable finding in all previously reported case series comparing HIV-infected patients with controls not infected with HIV. (8,9,11-13) Therefore, the leukemoid reactions in these two reported cases, both of whom had extremely advanced AIDS, represent a significant and novel finding.

Leukemoid Reactions in AIDS Patients

We performed a literature search using the MEDLINE database and, to the best of our knowledge, these are the first two cases described of any leukemoid reaction in patients with AIDS. The uniqueness of this finding is reinforced by previous studies of C difficile infection in AIDS patients in which a relative absence of leukocytosis was reported (Table 2); in two case-control series, the patients with AIDS showed significantly lower leukocyte counts than control patients without HIV infection. (8,9) In these and other studies of C difficile infection in AIDS patients, no leukemoid reactions were described (Table 2), and patients had good outcomes. Therefore, the two cases we describe illustrate a novel aspect of the presentation of C difficile colitis in AIDS patients and demonstrate that, in contrast to previous data in the literature, patients with advanced AIDS can develop leukemoid reactions similar to those seen in immunocompetent patients. The biologic mechanism by which C difficile toxins might overcome the cytokine abnormalities related to impaired myelopoiesis in AIDS is unknown but merits further study.

The pathophysiology of leukemoid reaction due to C difficile colitis might also involve colonic mucosal damage and invasion of the bloodstream by enteric bacteria. Colonic perforation (or microperforation), with activation of the systemic inflammatory response system, may also have contributed to the marked leukocytosis. It should be noted, however, that neither patient had free air on radiographic studies of the abdomen. Also, the patient in Case 2 had a leukemoid reaction at the time of his initial presentation to the hospital, which then resolved, with early clinical improvement. This leukemoid reaction preceded his multi-organ decompensation by several days (Table 1). Similarly, in Case 1, the patient had a high leukocyte count initially (20.4 X [10.sup.9]/L), almost 10 days before the critical phase of her illness. These observations would argue against frank perforation with bacterial peritonitis being the mechanism of the leukemoid reaction. Mucosal damage with enteric bacteremia, microperforation, or a mechanism specific to C difficile were more likely pathways in our patients.

The absence of previous reports of leukemoid reactions in patients with AIDS in association with any bacterial infection is noteworthy. Although definitive conclusions cannot be made, a hypothesis should be postulated that, in patients with advanced AIDS and diarrhea, leukemoid reactions might be diagnostic clues to C difficile infection. In indirect support of this hypothesis, it is noteworthy that Bulusu et al (16) found that an elevated white blood cell count increases the diagnostic likelihood of C difficile colitis in hospitalized patients with diarrhea. Despite the rarity in the literature of leukemoid reactions associated with AIDS, our hypothesis should be validated in studies specifically designed to detect how often leukemoid reactions are observed in association with C difficile versus other infections.

The patients we describe had poor outcomes, as reflected by clinical relapse, sepsis, and death. Although the literature is contradictory on this point, HIV-positive patients may be at increased risk for this syndrome, as well as for relapse and poor outcome due to impaired host response. Thus, as illustrated by the two cases described here, patients with AIDS should be promptly evaluated with cytotoxin assays and treated for this potentially lethal infection.

Conclusion

In contrast to previous data in the literature, we describe patients with AIDS capable of developing leukemoid reactions, despite advanced immunodeficiency. The two cases we describe were seen in association with C difficile infection, and we propose that severe infection with this organism should be particularly suspected if leukemoid reactions are observed in patients with AIDS who have signs and symptoms of colitis.

The man who says it cannot be done should not interrupt the man doing
it.
--Chinese proverb

Table 1. Clinical course of white blood cell count and detection of
Clostridium difficile toxin (a)

                       White blood cell count X [10.sup.9]/L
Hospital day           Patient 1          Patient 2

2 mo before admission      6.8               3.0
Day 1                     88.3              40.9 (+)
Day 2                     93.8              40.7 (+)
Day 3                    123.9              44.1
Day 4                                       31.4 (-)
Day 5                                       23.3
Day 6                                       17.2
Day 7                                       13.5
Day 11                                      10.1
Day 18                                       4.4 (-)
Day 31                                       6.4
Day 33                                      21.1 (+)
Day 35                                      43.5
Day 36                                      27.9 (+)

(a) (+). positive for C difficile toxin in stool; (-), negative for C
difficile toxin in stool.

Table 2. Studies of Clostridium difficile colitis in patients infected
with human immunodeficiency virus (a)

                           No. of      WBC range [+ or -] SD
                         HIV-positive  in HIV-positive
Series (ref. no.)         patients         patients

Harrison and Bartlett,       26                 --
  1991 (15)
Cappell and Philogene,        7        6,040 [+ or -] 4,820
  1993 (12)
Cozart et al, 1993 (8)       17        3,931 [+ or -] 2,906
Lu et al, 1994 (9)           32        5,910 [+ or -] 3,900
Tumbarello et al,            31                 --
  1995 (11)
Barbut et al, 1997 (13)      34          200 to 11,000 (neutrophils)
Willingham et al,            24                 --
  1998 (14)

                            Mean CD4
Series (ref. no.)        count [+ or -] SD    Study design

Harrison and Bartlett,           --           Case series,
  1991 (15)                                     retrospective
Cappell and Philogene,     92 [+ or -] 126    Case series
  1993 (12)
Cozart et al, 1993 (8)           --           Case-control,
                                                retrospective
Lu et al, 1994 (9)               --           Control,
                                                prospective
Tumbarello et al,          49 [+ or -] 5      Case-control,
  1995 (11)                                     prospective
Barbut et al, 1997 (13)    15 (range, 1-463)  Case-control,
                                                retrospective
Willingham et al,        <150                 Case-control,
  1998 (14)                                     prospective

                          Response to treatment
Series (ref. no.)             and prognosis

Harrison and Bartlett,     3 relapses; increased mortality
  1991 (15)                  (7 of 26 patients died)
Cappell and Philogene,   100% response, but 2 of 7
  1993 (12)                relapsed; severe symptoms
Cozart et al, 1993 (8)    88% response; similar to
                            control
Lu et al, 1994 (9)        59% response; similar to
                            control; similar symptoms;
                            9.4% relapsed
Tumbarello et al,          9.7% relapse; more severe
  1995 (11)                  symptoms in HIV+ patients
Barbut et al, 1997 (13)   28% relapsed
Willingham et al,        Higher mortality rate (42%)
  1998 (14)                compared with other causes

(a) WBC is expressed as total white blood cells/m[m.sup.3]. HIV, human
immunodeficiency virus; WBC, white blood cell count.

Accepted June 4, 2002.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9704-0388

References

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7. Perkocha LA, Rodgers GM. Hematologic aspects of human immunodeficiency virus infection: Laboratory and clinical considerations. Am J Hematol 1988;29:94-105.

8. Cozart JC, Kalangi SS, Clench MH, Taylor DR, Borucki MJ, Pollard RB, et al. Clostridium difficile diarrhea in patients with AIDS versus non-AIDS controls: Methods of treatment and clinical response to treatment. J Clin Gastroenterol 1993;16:192-194.

9. Lu SS, Schwartz JM, Simon DM, Brandt LJ. Clostridium difficile-associated diarrhea in patients with HIV positivity and AIDS: A prospective controlled study. Am J Gastroenterol 1994;89:1226-1229.

10. Kelly CP, Pothoulakis C, LaMont JT. Clostridium difficile colitis. N Engl J Med 1994;330:257-262.

11. Tumbarello M, Tacconelli E, Leone F, Cauda R, Ortona L. Clostridium difficile-associated diarrhea in patients with human immunodeficiency virus infection: A case-control study. Eur J Gastroenterol Hepatol 1995;7:259-263.

12. Cappell MS, Philogene C. Clostridium difficile infection is a treatable cause of diarrhea in patients with advanced human immunodeficiency virus infection: A study of seven consecutive patients admitted from 1986 to 1992 to a university teaching hospital. Am J Gastroenterol 1993;88:891-897.

13. Barbut F, Meynard JL, Guiguet M, Avesani V, Bochet MV, Meyohas MC, et al. Clostridium difficile-associated diarrhea in HIV-infected patients: Epidemiology and risk factors. J Acquir Immune Defic Syndr Hum Retrovirol 1997;16:176-181.

14. Willingham FF, Ticona Chavez E, Taylor DN, Bowen AB, Crane AR, Gottlieb AL, et al. Diarrhea and Clostridium difficile infection in Latin American patients with AIDS: Working Group on AIDS in Peru. Clin Infect Dis 1998;27:487-493.

15. Harrison KS, Bartlett JG. Clostridium difficile diarrhea in AIDS patients, in Program and Abstracts of the Thirty-First Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, American Society for Microbiology, 1991 (Abstract 190).

16. Bulusu M, Narayan S, Shetler K, Triadafilopoulos G. Leukocytosis as a harbinger and surrogate marker of Clostridium difficile infection in hospitalized patients with diarrhea. Am J Gastroenterol 2000;95:3137-3141.

RELATED ARTICLE: Key Points

* Clinical features of severe Clostridium difficile colitis include megacolon, hypoalbuminemia, and leukocytosis.

* Patients with acquired immunodeficiency syndrome have impaired granulocytic responses to bacterial infection.

* Leukemoid reactions have not previously been described in patients testing positive for the human immunodeficiency virus (HIV).

* Leukemoid reactions in HIV-positive patients with signs of colitis may indicate severe C difficile infection.

Frederico G. S. De Toledo, MD, and Stephen N. Symes, MD

From the Departments of Internal Medicine and Infectious Disease and Clinical Immunology, University of Miami, Jackson Memorial Medical Center, Miami, FL.

Reprint requests to Stephen N. Symes, MD, Department of Infectious Disease and Clinical Immunology, University of Miami, 1400 NW 10th Avenue, Suite 813C, Miami, FL 33136. Email: [e-mail]