1ID 1992; 166 (October)
Table 1. Peripheral blood mononuclear cell response to Borrelia burgdorferi.
Controls
EM
(n = II)
(n = 3)
Arthritis (n .", 8)
703 ± III 157-1354
302 ± 148 68-569
485 ± 75 165-838
3408 ± 1013 1159-11.409
1524 ± 792 104-2781
13,252 ± 8609* 200-71,809
6.2 ± 2.0 1.6-19.6 2
4.9 ± 2.8 1.5-10.3 I
22.0 ± 13.8* 1.2-117 4
NOTE. Proliferation data are [3H]thymidine incorporation (cpm): results indicate optimal response to 105 , 106 , or 107 spirochetes/ml., SI = stimulation index (cpm stimulated cells/cpm medium-treated cells). * Not significantly different from controls (P > .05).
mean + 2 SO of control responses. A stimulation index (SI) of ~3 was observed in 2 of 3 patients with EM and 7 of 8 with arthritis but also in 4 of 11 controls. More pronounced proliferation with an SI of> 10 [4] was demonstrated in 2 of 11 controls
Thalidomide in Painful AIDS-Associated Proctitis Colleagues-The recent communication by Law et al. [1] suggests an independent association between proctitis and infection with the human immunodeficiency virus (HIV) in homosexual men. Their study emphasizes the importance ofcareful and thorough investigation of proctitis in this patient group to exclude a treatable sexually transmitted or opportunistic infection. While it appears that histologic evidence of rectal inflammation may not always be accompanied by local symptoms [1], this condition may occasionally be associated with severe disability [2]. When an infectious cause for proctitis cannot be established or when empiric antimicrobial therapy is unsuccessful, ongoing symptoms may require the use of antiinflammatory agents such as sulfasalazine or steroids. We report our experience with two patients with AIDS and painful rectal inflammatory disease who failed to respond to multiple empiric therapies, specific antiviral agents, and steroids. In both cases, treatment with thalidomide resulted in rapid symptomatic relief.
Informed consent was obtained from the patients. and approval was obtained from the hospital ethics committee and the State and Federal Health Departments. Reprints or correspondence: Dr. Anthony M. Allworth, Department of Infectious Diseases. Royal Brisbane Hospital. Herston, Queensland 4029, Australia. The Journal of Infectious Diseases 1992;166:939-40 © 1992 by The University of Chicago. All rights reserved. 0022-1899/92/6604-0046$01.00
and in 1 of 3 patients with acute and 4 of 8 with late infection. Of the 4 seronegative patients with chronic arthritis, cells from only 1 showed an SI of> 10. Together, these results suggest that in vitro reactivity ofPBMC to B. burgdorftri (SI > 10 [4]) is a test of limited diagnostic usefulness.
Fran R. Wallach and Henry W. Murray Division ofInfectious Diseases. Cornell University Medical College. New York. New York
References I. de Souza MS. Fikrig E. Smith AL. Flavell RA, Barthold SW. Nonspecific proliferative responses of murine lymphocytes to Borrelia burgdorferi antigens. J Infect Dis 1992;165:471-8. 2. Dattwyler RJ. Volkman DJ. Luft BJ. Halperin JJ, Thomas J. Golightly ME. Seronegative Lyme disease: dissociation ofspecific T- and B-Iymphocyte response to Borrelia burgdorferi. N Engl J Med 1988; 319:144-6. 3. Zoschke DC, Skemp AA, Defosse DL. Lymphoproliferative responses to Borrelia burgdorferi in Lyme disease. Ann Intern Med 1991; 114:2859. 4. Dressler F, Yoshinari NH. Steere AC. The T-cell proliferative assay in the diagnosis of Lyme disease. Ann Intern Med 1991;115:533-9. 5. Murray HW, Hillman JK, Rubin BY, et al. Patients at risk for AIDS-related opportunistic infections: clinical manifestations and impaired gamma interferon production. N Engl J Med 1985;313: 1504--10.
Patient 1. a 36-year-old HIV antibody-positive homosexual man with a history of systemic cryptococcosis presented in May 1989 with intermittent diarrhea, tenesmus, and perianal pain. The CD4 lymphocyte count at this time was 0.29 X 109/L (normal range. 0.77-1.31), and medications included zidovudine and fluconazole. Initial sigmoidoscopy showed rectal inflammation and ulceration to 15 em. and rectal biopsies showed only nonspecific proctitis. No bacterial, fungal, or viral pathogens were isolated from rectal tissue or feces. Specific cultures for Neisseria gonorrhoeae, immunofluoresence studies for Chlamydia organisms, and serology for syphilis were all negative. The rectal symptoms continued despite treatment with steroid enemas and an empiric 3-week course of parenteral followed by oral acyclovir. Subsequent trials of doxycycline and o-salazine were also ineffective. Intractable perianal pain required highdose narcotics and admissions for epidural analgesia. Repeat sigmoidoscopy in July 1989 revealed persistent rectal ulceration and inflammation. Rectal biopsies showed nonspecific inflammation and occasional cytomegalovirus (CMV) inclusions in endothelial cells. Over the next 3 months the patient was treated sequentially with high-dose steroids, ganciclovir (complicated by pancytopenia and sepsis), and foscarnet (complicated by thrombocytopenia), without benefit. In November 1989. thalidomide (300 mg/day orally) was started. Dramatic and sustained improvement in rectal symptoms occurred within 3 days. Thalidomide was continued for a further 3 weeks until a generalized urticarial rash developed and the drug was ceased. Minor rectal symptoms persisted over the next month until the patient died of a rapidly developing encephalopathy.
Downloaded from http://jid.oxfordjournals.org/ at University of Bath Library & Learning Centre on July 16, 2015
Medium Mean ±SE Range Spirochetes Mean ± SE Range SI Mean ± SE Range No. with SI >10
939
Correspondence
940
Correspondence
target for HIV infection [8], the information presented by Law et at. [1] supports a possible role for direct retroviral infection of the mucosa or local modification of the inflammatory response in cases of nonspecific AIDS-associated proctitis. Our limited experience suggests that thalidomide may be of benefit in the treatment of painful HIV-associated inflammatory disease of the rectum. The mechanism of action of thalidomide in this condition is uncertain. The drug may have an immunomodulating effect, as seen in cases of graft-versus-host disease [9]. Alternatively, the relief of rectal pain in our patients may have been due to a reduction in sacral nociceptive input, similar to the action of thalidomide in painful lepromatous neuritis [10]. We believe that further controlled studies of thalidomide in selected HI V-infected patients with refractory inflammatory disease of the gastrointestinal tract are warranted.
Paul R. Georghiou* and Anthony M. Allworth Department ofInfectious Diseases. Royal Brisbane Hospital. Brisbane. Australia
* Present affiliation: Department of Medicine (Infectious Diseases Section). Baylor College of Medicine, Houston. References
I. Law CLH. Qassim M, Cunningham AL. Mulhall B. Grierson JM. Nonspecific proctitis: association with human immunodeficiency virus infection in homosexual men. J Infect Dis 1992; 165: 150-4. 2. Beck DE. Jaso RG. Zajac RA. Proctologic management of the HIVpositive patient. South Med J 1990;83:900-3. 3. Jenkins JS. Powell RJ. Allen BR. Littlewood SM. Maurice POL. Smith NJ. Thalidomide in severe orogenital ulceration. Lancet 1984; 2: 1424-6. 4. Youle M. Clarbour J. Farthing C, et al. Treatment of resistant aphthous ulceration with thalidomide in patients positive for HIV antibody. BMJ 1989;298:432. 5. Georghiou PRo Kemp RJ. HIV-associated oesophageal ulcers treated with thalidomide. Med J Aust 1990; 149:382-3. 6. Rabeneck L, Popovic M. Gartner S. et al. Acute HIV infection presenting with painful swallowing and esophageal ulcers. JAMA 1990;263:2318-22. 7. Bach MC, Valenti AJ. Howell DA, Smith TJ. Odynophagia from aphthous ulcers of the pharynx and esophagus in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1988; 109:338-9. 8. Nelson JA, Wiley CA, Reynolds-Kohler C, Reese CEo Margaretten W. Levy JA. Human immunodeficiency virus detected in bowel epithelium from patients with gastrointestinal symptoms. Lancet 1988; I:259-62. 9. Heney 0, Bailey Cc, Lewis IJ. Thalidomide in the treatment of graftversus-host disease. Biomed Pharmacother 1990;44: 199-204. 10. Barnhill RL. McDougall AC, Thalidomide: use and possible mode of action in reactional lepromatous leprosy and in various other conditions. J Am Acad Dermatol 1982;7:317-23.
Downloaded from http://jid.oxfordjournals.org/ at University of Bath Library & Learning Centre on July 16, 2015
Patient 2, a 31-year-old HIV antibody-positive homosexual man with a history of recurrent perianal herpes simplex virus infection, presented in July 1989 with anal pain, rectal bleeding, and mucus discharge unresponsive to high-dose oral acyclovir. Sigmoidoscopic examination was normal, and a rectal biopsy showed only nonspecific inflammation. Studies for N. gonorrhoeae, Chlamydia species, and herpes simplex virus and serologic studies for syphilis were negative. However, CMV was isolated from rectal tissue after prolonged culture. Zidovudine was commenced, but the patient was admitted 10 days later with vomiting and diarrhea. Fecal microscopy and culture demonstrated both Cryptosporidium oocysts and Campylobacterjejuni. A 10-day course of erythromycin and symptomatic treatment controlled the diarrhea, but perianal symptoms continued. The patient was readmitted 3 weeks later with fever and central abdominal pain, which responded rapidly to ganciclovir. However, the perianal and coccygeal pain continued unabated, and further rectal biopsies showed persisting inflammatory changes. By November 1989, the anorectal symptoms required high doses of narcotics, with transcutaneous nerve stimulation and epidural analgesia providing only temporary relief. Thalidomide (300 mg/day orally) was commenced. Within 5 days there was significant improvement in the rectal symptoms, with continued resolution over the next 2 weeks. The onset of nausea and abdominal pain prompted dose reduction, then cessation of thalidomide. The abdominal symptoms persisted and responded to a further course of ganciclovir. In late December 1989, the anal pain recurred and again responded rapidly to treatment with oral thalidomide, 300 mg/day reducing to 100 mg/day. In midJanuary 1990, symptoms ofa peripheral neuropathy developed. Nerve conduction studies were normal, but thalidomide was ceased. The neuropathic symptoms subsequently responded to the reinstitution of zidovudine. Thalidomide has been shown to have a beneficial effect in cases of orogenital ulceration of the Behcet type [3]. More recently, this drug has been found useful in HIV-positive patients with painful refractory aphthous ulceration of the oropharynx and esophagus [4, 5]. Studies of this condition have noted retrovirus-type inclusions in biopsy specimens [6], and HIV-l has been cultured from affected esophageal tissue [6]. In addition, there are reports describing a response of these lesions to steroids [7]. These findings suggest that mucosal inflammation and ulceration may be caused by an immune-mediated mechanism, perhaps resulting from HIV infection of mucosal cells. The precise cause of the perianal symptoms .in our two patients is unclear. CMV was seen in a rectal biopsy of patient 1 and was cultured from rectal tissue from patient 2. However, symptoms continued in both despite the use of specific agents directed at CMV. As the bowel mucosa is now known to be a
1ID 1992; 166 (October)
Table 1. Peripheral blood mononuclear cell response to Borrelia burgdorferi.
Controls
EM
(n = II)
(n = 3)
Arthritis (n .", 8)
703 ± III 157-1354
302 ± 148 68-569
485 ± 75 165-838
3408 ± 1013 1159-11.409
1524 ± 792 104-2781
13,252 ± 8609* 200-71,809
6.2 ± 2.0 1.6-19.6 2
4.9 ± 2.8 1.5-10.3 I
22.0 ± 13.8* 1.2-117 4
NOTE. Proliferation data are [3H]thymidine incorporation (cpm): results indicate optimal response to 105 , 106 , or 107 spirochetes/ml., SI = stimulation index (cpm stimulated cells/cpm medium-treated cells). * Not significantly different from controls (P > .05).
mean + 2 SO of control responses. A stimulation index (SI) of ~3 was observed in 2 of 3 patients with EM and 7 of 8 with arthritis but also in 4 of 11 controls. More pronounced proliferation with an SI of> 10 [4] was demonstrated in 2 of 11 controls
Thalidomide in Painful AIDS-Associated Proctitis Colleagues-The recent communication by Law et al. [1] suggests an independent association between proctitis and infection with the human immunodeficiency virus (HIV) in homosexual men. Their study emphasizes the importance ofcareful and thorough investigation of proctitis in this patient group to exclude a treatable sexually transmitted or opportunistic infection. While it appears that histologic evidence of rectal inflammation may not always be accompanied by local symptoms [1], this condition may occasionally be associated with severe disability [2]. When an infectious cause for proctitis cannot be established or when empiric antimicrobial therapy is unsuccessful, ongoing symptoms may require the use of antiinflammatory agents such as sulfasalazine or steroids. We report our experience with two patients with AIDS and painful rectal inflammatory disease who failed to respond to multiple empiric therapies, specific antiviral agents, and steroids. In both cases, treatment with thalidomide resulted in rapid symptomatic relief.
Informed consent was obtained from the patients. and approval was obtained from the hospital ethics committee and the State and Federal Health Departments. Reprints or correspondence: Dr. Anthony M. Allworth, Department of Infectious Diseases. Royal Brisbane Hospital. Herston, Queensland 4029, Australia. The Journal of Infectious Diseases 1992;166:939-40 © 1992 by The University of Chicago. All rights reserved. 0022-1899/92/6604-0046$01.00
and in 1 of 3 patients with acute and 4 of 8 with late infection. Of the 4 seronegative patients with chronic arthritis, cells from only 1 showed an SI of> 10. Together, these results suggest that in vitro reactivity ofPBMC to B. burgdorftri (SI > 10 [4]) is a test of limited diagnostic usefulness.
Fran R. Wallach and Henry W. Murray Division ofInfectious Diseases. Cornell University Medical College. New York. New York
References I. de Souza MS. Fikrig E. Smith AL. Flavell RA, Barthold SW. Nonspecific proliferative responses of murine lymphocytes to Borrelia burgdorferi antigens. J Infect Dis 1992;165:471-8. 2. Dattwyler RJ. Volkman DJ. Luft BJ. Halperin JJ, Thomas J. Golightly ME. Seronegative Lyme disease: dissociation ofspecific T- and B-Iymphocyte response to Borrelia burgdorferi. N Engl J Med 1988; 319:144-6. 3. Zoschke DC, Skemp AA, Defosse DL. Lymphoproliferative responses to Borrelia burgdorferi in Lyme disease. Ann Intern Med 1991; 114:2859. 4. Dressler F, Yoshinari NH. Steere AC. The T-cell proliferative assay in the diagnosis of Lyme disease. Ann Intern Med 1991;115:533-9. 5. Murray HW, Hillman JK, Rubin BY, et al. Patients at risk for AIDS-related opportunistic infections: clinical manifestations and impaired gamma interferon production. N Engl J Med 1985;313: 1504--10.
Patient 1. a 36-year-old HIV antibody-positive homosexual man with a history of systemic cryptococcosis presented in May 1989 with intermittent diarrhea, tenesmus, and perianal pain. The CD4 lymphocyte count at this time was 0.29 X 109/L (normal range. 0.77-1.31), and medications included zidovudine and fluconazole. Initial sigmoidoscopy showed rectal inflammation and ulceration to 15 em. and rectal biopsies showed only nonspecific proctitis. No bacterial, fungal, or viral pathogens were isolated from rectal tissue or feces. Specific cultures for Neisseria gonorrhoeae, immunofluoresence studies for Chlamydia organisms, and serology for syphilis were all negative. The rectal symptoms continued despite treatment with steroid enemas and an empiric 3-week course of parenteral followed by oral acyclovir. Subsequent trials of doxycycline and o-salazine were also ineffective. Intractable perianal pain required highdose narcotics and admissions for epidural analgesia. Repeat sigmoidoscopy in July 1989 revealed persistent rectal ulceration and inflammation. Rectal biopsies showed nonspecific inflammation and occasional cytomegalovirus (CMV) inclusions in endothelial cells. Over the next 3 months the patient was treated sequentially with high-dose steroids, ganciclovir (complicated by pancytopenia and sepsis), and foscarnet (complicated by thrombocytopenia), without benefit. In November 1989. thalidomide (300 mg/day orally) was started. Dramatic and sustained improvement in rectal symptoms occurred within 3 days. Thalidomide was continued for a further 3 weeks until a generalized urticarial rash developed and the drug was ceased. Minor rectal symptoms persisted over the next month until the patient died of a rapidly developing encephalopathy.
Downloaded from http://jid.oxfordjournals.org/ at University of Bath Library & Learning Centre on July 16, 2015
Medium Mean ±SE Range Spirochetes Mean ± SE Range SI Mean ± SE Range No. with SI >10
939
Correspondence
940
Correspondence
target for HIV infection [8], the information presented by Law et at. [1] supports a possible role for direct retroviral infection of the mucosa or local modification of the inflammatory response in cases of nonspecific AIDS-associated proctitis. Our limited experience suggests that thalidomide may be of benefit in the treatment of painful HIV-associated inflammatory disease of the rectum. The mechanism of action of thalidomide in this condition is uncertain. The drug may have an immunomodulating effect, as seen in cases of graft-versus-host disease [9]. Alternatively, the relief of rectal pain in our patients may have been due to a reduction in sacral nociceptive input, similar to the action of thalidomide in painful lepromatous neuritis [10]. We believe that further controlled studies of thalidomide in selected HI V-infected patients with refractory inflammatory disease of the gastrointestinal tract are warranted.
Paul R. Georghiou* and Anthony M. Allworth Department ofInfectious Diseases. Royal Brisbane Hospital. Brisbane. Australia
* Present affiliation: Department of Medicine (Infectious Diseases Section). Baylor College of Medicine, Houston. References
I. Law CLH. Qassim M, Cunningham AL. Mulhall B. Grierson JM. Nonspecific proctitis: association with human immunodeficiency virus infection in homosexual men. J Infect Dis 1992; 165: 150-4. 2. Beck DE. Jaso RG. Zajac RA. Proctologic management of the HIVpositive patient. South Med J 1990;83:900-3. 3. Jenkins JS. Powell RJ. Allen BR. Littlewood SM. Maurice POL. Smith NJ. Thalidomide in severe orogenital ulceration. Lancet 1984; 2: 1424-6. 4. Youle M. Clarbour J. Farthing C, et al. Treatment of resistant aphthous ulceration with thalidomide in patients positive for HIV antibody. BMJ 1989;298:432. 5. Georghiou PRo Kemp RJ. HIV-associated oesophageal ulcers treated with thalidomide. Med J Aust 1990; 149:382-3. 6. Rabeneck L, Popovic M. Gartner S. et al. Acute HIV infection presenting with painful swallowing and esophageal ulcers. JAMA 1990;263:2318-22. 7. Bach MC, Valenti AJ. Howell DA, Smith TJ. Odynophagia from aphthous ulcers of the pharynx and esophagus in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1988; 109:338-9. 8. Nelson JA, Wiley CA, Reynolds-Kohler C, Reese CEo Margaretten W. Levy JA. Human immunodeficiency virus detected in bowel epithelium from patients with gastrointestinal symptoms. Lancet 1988; I:259-62. 9. Heney 0, Bailey Cc, Lewis IJ. Thalidomide in the treatment of graftversus-host disease. Biomed Pharmacother 1990;44: 199-204. 10. Barnhill RL. McDougall AC, Thalidomide: use and possible mode of action in reactional lepromatous leprosy and in various other conditions. J Am Acad Dermatol 1982;7:317-23.
Downloaded from http://jid.oxfordjournals.org/ at University of Bath Library & Learning Centre on July 16, 2015
Patient 2, a 31-year-old HIV antibody-positive homosexual man with a history of recurrent perianal herpes simplex virus infection, presented in July 1989 with anal pain, rectal bleeding, and mucus discharge unresponsive to high-dose oral acyclovir. Sigmoidoscopic examination was normal, and a rectal biopsy showed only nonspecific inflammation. Studies for N. gonorrhoeae, Chlamydia species, and herpes simplex virus and serologic studies for syphilis were negative. However, CMV was isolated from rectal tissue after prolonged culture. Zidovudine was commenced, but the patient was admitted 10 days later with vomiting and diarrhea. Fecal microscopy and culture demonstrated both Cryptosporidium oocysts and Campylobacterjejuni. A 10-day course of erythromycin and symptomatic treatment controlled the diarrhea, but perianal symptoms continued. The patient was readmitted 3 weeks later with fever and central abdominal pain, which responded rapidly to ganciclovir. However, the perianal and coccygeal pain continued unabated, and further rectal biopsies showed persisting inflammatory changes. By November 1989, the anorectal symptoms required high doses of narcotics, with transcutaneous nerve stimulation and epidural analgesia providing only temporary relief. Thalidomide (300 mg/day orally) was commenced. Within 5 days there was significant improvement in the rectal symptoms, with continued resolution over the next 2 weeks. The onset of nausea and abdominal pain prompted dose reduction, then cessation of thalidomide. The abdominal symptoms persisted and responded to a further course of ganciclovir. In late December 1989, the anal pain recurred and again responded rapidly to treatment with oral thalidomide, 300 mg/day reducing to 100 mg/day. In midJanuary 1990, symptoms ofa peripheral neuropathy developed. Nerve conduction studies were normal, but thalidomide was ceased. The neuropathic symptoms subsequently responded to the reinstitution of zidovudine. Thalidomide has been shown to have a beneficial effect in cases of orogenital ulceration of the Behcet type [3]. More recently, this drug has been found useful in HIV-positive patients with painful refractory aphthous ulceration of the oropharynx and esophagus [4, 5]. Studies of this condition have noted retrovirus-type inclusions in biopsy specimens [6], and HIV-l has been cultured from affected esophageal tissue [6]. In addition, there are reports describing a response of these lesions to steroids [7]. These findings suggest that mucosal inflammation and ulceration may be caused by an immune-mediated mechanism, perhaps resulting from HIV infection of mucosal cells. The precise cause of the perianal symptoms .in our two patients is unclear. CMV was seen in a rectal biopsy of patient 1 and was cultured from rectal tissue from patient 2. However, symptoms continued in both despite the use of specific agents directed at CMV. As the bowel mucosa is now known to be a
1ID 1992; 166 (October)
