From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: VA Summary 8/7/92
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Archive-Number: 5899
Organization: UCLA, Computer Science Department
Date: Fri, 14 Aug 92 16:35:58 PDT

This AIDS Information Newsletter was obtained from the HIV/AIDS Info
BBS (714) 248-2836.  It is the best source of AIDS Info available.
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                        AIDS NEWS SERVICE
                   Michael Howe, MSLS, Editor
                     AIDS Information Center
                VA Medical Center, San Francisco
                     (415) 221-4810 ext 3305
                         August 7, 1992 
   IS THERE ANOTHER AGENT THAT CAUSES LOW CD4 COUNTS AND AIDS? 
     HIV-1 and -2 are known causes of low CD4 counts and AIDS.  We have 
identified 6 percent with persistently low CD4 (<250) who are repeatedly 
HIV-seronegative.  Five are male and one is female.  Ages range from 35 
to 70 years.  The clinical presentations include 1 Pneumocystis carinii 
pneumonia, 1 Cryptococcal meningitis, cryptococcoma and localized Herpes 
zoster infection, 1 disseminated Molluscum contagiosum, 1 oral and 
vaginal candidiasis, 1 Kaposi's  sarcoma post renal transplantation, and 
1 with multiple atypical mycobacterial pneumonias and idiopathic 
pulmonary fibrosis.  Three have a history of blood transfusions (2 after 
the initiation of HIV screening); one of these also had a renal 
transplant.  One has a history of intravenous drug use.  One is a health 
care worker.  Peripheral blood lymphocytes from them were tested by 
Western blot, viral culture and PCR for evidence of HIV infection.  All 
of these tests were negative.  Serology for HTLV-1 and -2 was also 
negative.  CD4 lymphocyte counts ranged from 43 to 246 with percentages 
ranging from 4 to 18.  CD4/CD8 ratios ranged from 0.08 to 0.40.  Several 
persons have had their low counts for several years.  Preliminary data 
on 4 of these persons indicate that there is an elevated ratio of memory 
to naive CD4 lymphocytes when compared to  HIV-infected person with 
comparable CD4 lymphocyte counts.  This is similar to what is observed 
in persons with HTLV-1 and -2 infection.  In summary, we have identified 
6 persons with low CD4 counts without evidence of HIV infection with 
clinical manifestations of opportunistic infections or tumors of varying  
severity.  This suggests that HIV may not be the only infectious cause 
of immunosuppression in man.  (Proceedings from the Keystone Symposia on 
Molecular and Cellular Biology, March 27-April 4, 1992 [Abstract Q3477]. 
Thomas J. Spira and Bonnnie M. Jones, Division of HIV/AIDS, National 
Center for Infectious Diseases, Centers for Disease Control. Journal of 
Cellular Biochemistry 1992;Suppl 16E:56). 
          HIV SERONEGATIVE PERSONS WITH LOW CD4 COUNTS  
     CDC is aware of a small number of persons with low CD4 counts and 
AIDS-like illnesses who are not infected with either HIV-1 or HIV-2.  
The cause of these illnesses is not known at this time. CDC is aware 
that several laboratories are investigating the possibility that a 
previously unidentified virus may be causing this condition. However, 
this information has not yet been confirmed, and other possible causes 
are being explored.  If a new virus is discovered to be the cause of 
these AIDS-like illnesses, it should be possible to quickly develop a 
blood test for this virus. 
     CDC is reviewing AIDS case report forms to determine if any cases 
such as these were reported as cases of AIDS.  To date, none have been 
found.  Thus, this occurrence appears to be rare.  CDC continues to 
recommend that persons who believe they may have been exposed to HIV 
should seek counseling and testing. (U.S. Department Of Health and Human 
Services Public Health Service, Centers for Disease Control, July 20, 
1992). 
             U.S. AGENCY PUBLISHES ITS FIRST REPORT
              ON FIVE AIDS-LIKE, NEGATIVE-HIV CASES 
     The Centers for Disease Control published its first formal report 
of five cases of people with an AIDS-like syndrome but show no 
detectable sign of HIV infection (see below).  The CDC had promised the 
report after Jeffrey Laurence of Cornell Medical School revealed five 
such cases at the international AIDS  conference in Amsterdam last week.  
The CDC's report describes five different cases of people with weakened 
immune systems, including a 70-year-old married man with no risk factors 
for HIV who developed pneumonia, and a 58-year-old woman who had several 
blood transfusions and developed pneumonia and gynecological infections.  
The woman tested positive for HIV, which is now believed to be false 
positive, though she and other patients subsequently tested HIV-negative 
by other more definitive methods, said the CDC.  The agency has 
requested that doctors submit any similar case-reports and dispatched 
surveillance teams to New York City for follow-up.  Dr. Laurence has 
indicated that now he knows of about 40 such cases. The report of the 
five AIDS-like cases by Dr. Laurence will be published in Lancet.  It 
will also  mention that two of them showed signs of reverse 
transcriptase, which is vital to the  replication of HIV. (Wall Street 
Journal (07/31/92), P. B3  (Chase, Marilyn). 
       UNEXPLAINED CD4+ T-LYMPHOCYTE DEPLETION IN PERSONS
         WITHOUT EVIDENT HIV INFECTION -- UNITED STATES  
Epidemiologic Notes and Reports: MMWR, 1992 July 31;41(30):543-5.  
     Since 1989, 21 persons with unexplained CD4+ T-lymphocyte 
depletion, but without evident human immunodeficiency virus (HIV) 
infection, have been described (1-12). These reports included persons 
who have resided in the United States and six other countries and who 
sought medical care for conditions often associated with immune 
deficiency. Some of these cases were also described at the VIII 
International Conference on AIDS/III STD World Congress in Amsterdam. In 
addition, CDC has received reports of five persons from three states who 
have had persistently low CD4+ T-cell levels but who have had no 
evidence of HIV infection or underlying disease processes or therapies 
known to be associated with T-cell depletion. In some of these five 
patients, opportunistic infections were diagnosed that frequently occur 
in persons with acquired immunodeficiency syndrome (AIDS). This report 
describes preliminary clinical and laboratory findings from an ongoing 
investigation by CDC of these five patients.*  Patient 1  
     In March 1991, a 70-year-old man developed Pneumocystis carinii 
pneumonia that was successfully treated with trimethoprim-
sulfamethoxazole. Although serology for HIV antibody was negative, his 
CD4 count was 50 cells/uL. After this hospitalization, he developed a 
fungal infection of the groin that was treated with oral ketoconazole 
and topical antifungal medications. In April 1992, transitional cell 
carcinoma of the bladder, grade II, was diagnosed. As of July 1992, he 
was asymptomatic.  
     His family history and personal history were negative for 
immunodeficiency disease and for recurrent or unusual infections. His 
wife, who has remained healthy, is HIV seronegative and has a normal CD4 
count. He did not report sexual contact with men or injecting-drug use. 
In 1987, he received 3 units of whole blood for a bleeding duodenal 
ulcer; follow-up investigation in 1992  indicated that all three blood 
donors were HIV type 1 (HIV-1) and HIV type 2 (HIV-2) seronegative, had 
normal CD4 counts, and were in good health.  
Patient 2  
     In October 1984, a 38-year-old male health-care worker developed 
cryptococcal meningitis that was treated with a full course of 
amphotericin B and 5-fluorocytosine. In January 1985, he had an episode 
of localized herpes zoster. In July 1985, symptoms of meningitis 
recurred. A cryptococcoma was excised from his brain, and he was treated 
with another course of antifungal therapy. Since this hospitalization, 
he has been in generally good health  except for a nonspecific skin rash 
that resolved, mild hypertension, and a grand mal seizure for which he 
takes phenytoin. In December 1987 and December 1988, his CD4 counts were 
152 and 84 cells/uL, respectively. An enzyme immunoassay (EIA) test for 
HIV antibody was negative in April 1989. As of July 1992, he was 
asymptomatic.  
     There was no family history or personal history of immunodeficiency 
or unusual infections. He did not report sexual contact with men or 
injecting-drug use. He had not received blood transfusions, did not 
perform invasive procedures, and had no known parenteral or mucous 
membrane exposure to blood. He reported his spouse was in good health.  
Patient 3  
     In October 1989, a 58-year-old woman developed acute cholecystitis 
and underwent cholecystectomy. She had a prolonged postoperative course 
complicated by nosocomial pneumonia of undetermined etiology and vaginal 
candidiasis and recovered with antibiotic therapy. An HIV EIA test was 
reported as positive during this hospitalization. In December 1989, 
although HIV serology by EIA was negative, a single p24 band on Western 
blot was observed; her CD4 count was 86 cells/uL. She remained 
asymptomatic; when reevaluated in January 1991, HIV serology was 
negative on two occasions, but her CD4 count remained low (103 
cells/uL). As of July 1992, she was asymptomatic.  
     She had received multiple transfusions for hemorrhage during 
pregnancy during the 1950s and for menorrhagia in the late 1970s and 
early 1980s. There was no family history of immunodeficiency or unusual 
infections. She did not report injecting-drug use. She reported her 
spouse was in good health.   
Patient 4  
     In November 1986, a 45-year-old man received treatment for 
disseminated molluscum contagiosum. In April 1989, a lung biopsy was 
performed for evaluation of a mass on chest radiograph. The lesion was 
consistent with a plaque secondary to asbestosis, although the man had 
no known history of asbestos exposure. In February and August 1989, HIV 
EIA serologies were negative; however, CD4 counts were 96 and 68 
cells/uL, respectively. As of July 1992, he was asymptomatic. 
     His family and personal history were negative for immunodeficiency 
or for recurrent or unusual infections. He did not report sexual contact 
with men or injecting-drug use; he had not received blood transfusions. 
His spouse was in good health and had a normal CD4 count.  
Patient 5  
     In December 1983, a 70-year-old woman was hospitalized with 
disseminated cutaneous herpes zoster. In December 1988, she developed 
fever, cough, and pleurisy. On evaluation, mediastinal lymphadenopathy 
was found, and histoplasmosis was diagnosed by open lung biopsy. She was 
treated with amphotericin B and ketoconazole with resolution of both 
symptoms and lymphadenopathy. Although HIV serology was negative during 
this hospitalization, a CD4 count was 275 cells/uL. In February 1989, 
the count was 499 cells/uL.  
     In April 1991, she developed fever and cough, and a pulmonary 
infiltrate was indicated on chest radiograph; her CD4 count at that time 
was 199 cells/uL. Although her symptoms responded to ciprofloxacin, 
sputum cultures subsequently grew Mycobacterium avium-intracellulare 
(MAI). In September 1991, her pulmonary symptoms recurred, and a new 
pulmonary infiltrate was present on chest radiograph; MAI was again 
cultured from bronchial washings. Her symptoms resolved during treatment 
with ciprofloxacin, rifampin, and ethambutol. In January 1992, 
epigastric pain prompted a gastrointestinal evaluation and detection of 
an ulcerated mass lesion in the stomach. Histoplasmosis was found on 
biopsy, and Helicobacter pylori was cultured from the lesion. 
Fluconazole  therapy was initiated with good response. As of July 1992, 
she was  asymptomatic.  
     She had been in excellent health with no family history or personal 
history of immunodeficiency or unusual infections. She did not report 
injecting-drug use and had not received a transfusion. Her spouse died 
in 1984 with atherosclerotic cardiovascular disease and carcinoma of the 
kidney.  
Laboratory Findings  
     Blood samples from each of the five patients have been tested at 
CDC, and low CD4 counts (less than 300 cells/uL) and negative HIV-1 and 
HIV-2 serologies (by EIA and Western blot) have been confirmed. 
Cocultures of peripheral blood mononuclear cells (PBMC) from patients 1-
4 with normal PBMC and/or lymphoid cell lines were negative for 
cytopathicity, syncytia, and the generation of reverse transcriptase 
activity as measured by standard methods. Human T-cell lymphotropic 
virus (HTLV)-I and HTLV-II serologies were negative. Neither HIV-1- nor 
HIV-2-related DNA sequences were detected in blood of patients 1-4 by 
polymerase chain reaction (PCR). Results of studies of specimens from 
patient 5 are pending.  
REPORTED BY: Div of HIV/AIDS, National Center for Infectious Diseases, 
CDC.  
EDITORIAL NOTE: The clinical conditions of the patients described in 
this report vary considerably; however, these cases share three 
features: 1) persistently low CD4+ T-cell levels; 2) no evidence of HIV 
infection by serology, culture, or PCR analysis; and 3) infections that 
prompted physicians to consider HIV infection.   
     Review of available data on the 26 case-patients (including the 
five described in this report and 21 reported elsewhere) (1-12) does not 
indicate an epidemiologic linkage among the cases. Cases of unexplained 
CD4+ T-cell depletion have been reported from Australia (1), Denmark 
(2), England (3,4), France (5-7), Germany (8), Spain (9), and the United 
States (10-12). Of the 26  case-patients, five had received transfusions 
before onset of illness, five were homosexual men, and the remaining 16 
had no known risk factors for HIV infection. In this report, follow-up 
investigation of the blood donors for patient 1 found that they were 
HIV-seronegative, immunologically normal, and in good health. Two 
additional cases reported to CDC have been excluded because  CD4+ T-cell 
depletion may have been related to chemotherapy.  
     Although infections with HIV-1 or HIV-2 have been associated with 
immunodeficiency of the type described in these patients, no evidence 
for infection with either virus has been documented. The cause of CD4+ 
T-lymphocyte depletion in the patients described in this report and in 
other reports is unknown; moreover, it is unknown whether these cases 
represent a single syndrome. However, there are at least two possible 
hypotheses to explain this  abnormality. Persistent CD4+ T-cell 
depletion may occur in some patients as a response to certain infections 
or other exposures. Transient CD4+ T-cell depletion has been reported 
following some infections; whether this persists in some patients is 
unknown (13,14). Therefore, one possibility is that some or all of these 
case reports of unexplained CD4+ T-lymphocyte depletion are part  of 
background occurrence that may only now be recognized because of the 
increased availability of T-cell phenotyping. A second possibility is 
that some of these cases may represent a different syndrome of 
immunodeficiency associated with CD4+ T-cell depletion. 
     Two of the recent preliminary reports of CD4+ T-cell depletion in 
patients who were HIV-1 and HIV-2 seronegative have suggested the 
presence of a retrovirus (11,12). The relation of these reports to the 
immunodeficiency detected in patients described in this and other 
reports is not known.  
     CDC and the National Institutes of Health (NIH) are collaborating 
with physicians, scientists, and public health officials to identify 
other cases and investigate this problem. NIH will assist in the 
characterization of the clinical, immunologic, and virologic features by 
collaborating with investigators and working through its network of 
grantees and contractors to collect, process, and distribute specimens 
and reference materials. CDC, in  collaboration with NIH, will convene a 
meeting of investigators and public health officials in mid-August to 
discuss these cases and epidemiologic and laboratory investigations in 
progress.  
     Additional CDC epidemiologic and laboratory investigations 
regarding these cases are in progress. Health-care providers are 
requested to report to CDC through the AIDS surveillance section of 
their local or state health department patients who have 1) CD4+ T-
lymphocyte depletion (absolute CD4+ T-cell level less than 300 cells/uL 
or less than 20% on more than one determination), 2) no serologic 
evidence of HIV infection, and 3) no defined immunodeficiency or therapy 
associated with T-cell depletion. Although no cases have been reported 
in children, HIV-negative  pediatric cases with unexplained depletion of 
CD4 cells (as defined by age-adjusted normal CD4 counts) should also be 
reported.  
     Additional information on case reporting is available from the  
Surveillance Branch, Division of HIV/AIDS, National Center for 
Infectious Diseases, CDC (telephone (404) 639-2981). Reports of these 
cases will assist CDC and other public health agencies in developing a 
more precise case definition to examine this problem and providing a 
resource for investigators who are conducting etiologic studies. General 
inquiries about the cases described here as well as on HIV and AIDS 
should be directed to the CDC National AIDS Hotline, (800) 342-2437.  
REFERENCES  
      1. Gatenby PA. Reduced CD4+ T-cells and candidiasis in absence of 
HIV infection. Lancet 1989;1:1027-8. 
      2. Hansen ER, Lisby S, Baadsgaard O, Ho VC, de Villiers EM, 
Vejlsgaard GL. Abnormal function of CD4+ helper/inducer T lymphocytes in 
a patient with widespread human papillomavirus type 3-related infection. 
Arch Dermatol 1990;126:1604-8. 
      3. Pankhurst C, Peakman M. Reduced CD4+ T-cells and severe oral  
candidiasis in absence of HIV infection. Lancet 1989;1:672. 
      4. Jowitt SN, Love EM, Liu Yin JA, Pumphrey RSH. CD4 
lymphocytopenia without HIV infection in patient with cryptococcal 
infection. Lancet 1991;337:500-1. 
      5. Cozon G, Greenland T, Revillard JP. Profound CD4+ 
lymphocytopenia in the absence of HIV infection in a patient with 
visceral leishmaniasis. N Engl J Med 1990;322:132. 
      6. Seligmann M, Aractingi S, Oksenhendler E, Rabian C, Ferchal F, 
Gonnot G. CD4+ lymphocytopenia without HIV in patient with cryptococcal 
disease. Lancet 1991;337:57-8. 
      7. Gautier V, Chanez P, Vendrell JP, et al. Unexplained CD4-
positive T-cell deficiency in non-HIV patients presenting as a 
Pneumocystis carinii pneumonia. Clin Exp Allergy 1991;21:63-6. 
      8. Daus H, Schwarze G, Radtke H. Reduced CD4+ count, infections, 
and immune thrombocytopenia without HIV infection. Lancet 1989;2:559-60. 
      9. Castro A, Pedreira J, Soriano V, et al. Kaposi's sarcoma and  
disseminated tuberculosis in HIV-negative individual. Lancet 
1992;339:868. 
      10. Daar ES, Moudgil T, Ho DD. Persistently low T-helper (CD4+)  
lymphocyte counts in HIV-negative asymptomatic men. Western Society of 
Clinical Investigation meeting, February 1990.  11. Gupta S, Ribak CE, 
Gollapudi S, Kim CH, Salahuddin SZ. Detection of a human intracisternal 
retroviral particle associated with CD4+ T-cell deficiency. Proc Natl 
Acad Sci USA (in press). 
      12. Laurence J, Siegal FP, Schattner E, Gelman IH, Morse S. 
Acquired immune deficiency without evidence of infection with human 
immunodeficiency virus types 1 and 2. Lancet 1992 (in press). 
      13. Scalzini A, Castelnuovo F, Puoti M, Cristini G. A case of  
cryptococcal meningoencephalitis and focal cerebral vasculitis with 
transient immunodeficiency. Acta Neurol (Napoli) 1990;12:301-4.  14. 
Lehmann PF, Gibbons J, Senitzer D, Ribner BS, Freimer EH. T lymphocyte 
abnormalities in disseminated histoplasmosis. Am J Med 1983;75:790-4.  
               MEETING CALLED ON AIDS-LIKE ILLNESS 
     The Centers for Disease Control will hold a meeting in August of 
the country's leading AIDS experts to address the discovery of the 
syndrome that resembles AIDS but shows no sign of HIV infection, 
announced officials on July 30.  Though the CDC has known about five 
cases since 1989, it did not investigate them because officials did not 
consider the syndrome prevalent or a threat, said James Curran, CDC's 
deputy director for AIDS.  A total of 21 more cases were revealed at the 
8th International AIDS Conference held in Amsterdam last week.  "It is 
important to determine whether some or all of these cases might be 
caused by an infectious agent and, if so, determine how that agent is  
transmitted and prevented," Curran said.  There has been no date  set by 
the CDC for the meeting.  Curran stressed that it is too early to label 
the disease as a type of AIDS, even though it depletes the immune system 
in much the same way that AIDS does. The 26 patients known to have the 
condition all have very low numbers of CD4 cells.  Yet they have all 
tested HIV-negative, and 16 have  no known risk factors for HIV 
infection.  Blood transfusions had been received by five and another 
five were homosexual men. (Washington Post (07/31/92), P. A5). 
               DOUBTS EXPRESSED ON NEW AIDS VIRUS 
     Two leading researchers have expressed skepticism over the recent 
report of a new virus leading to AIDS-like symptoms.  The controversial 
report will be published in this month's Proceedings of the National 
Academy of Sciences and was submitted by Dr. Sudhir Gupta of the 
University of California--Irvine.  The report has prompted public fear 
that a possible fatal virus may be transmitted  by humans and through 
the nation's blood supply.  Dr. Ludwik Gross, a member of the National 
Academy of Sciences from New York, sponsored Dr. Gupta's report in the 
science academy's proceedings, and now says he wished he had never done 
so. Due to the publicity of the report, Dr. Gross said he "wanted to 
brake the scare" and stop "unwarranted conclusions" that yielded public 
fear that an  AIDS-like virus was running rampant.  He said that "too 
much has been made of the finding" and that he doubted the condition 
discussed in the report had any relation to AIDS.  At the international 
AIDS conference in Amsterdam last month, scientists from Europe and the 
U.S. told of a few dozen cases of an AIDS-like conditions in individuals 
who had no detectable signs of HIV.  Dr.  Luc Montagnier, the French co-
discoverer of HIV, said that he was also doubtful of the report. (New 
York Times (08/02/92), P. 7).