BRIEF REPORT

The epidemiology of I

1mmune thrombocytopenia

WALTER F SCHLECH Ill , MD, FACP, FRCPC, CHRISTINE NESDOLY, MD, N ANCY MEAGHER, RN,

JANET TURNER, RN , D ONALDA DICKEY, RN

WF ScHLECH ill, C NESDOLY, N M EAGHER, J TuRNER, D DICKEY. The epidemiology of i mmune t hrombo­cytopenia. Can J Infect Di s 1992;3(6) :3 11-314. Th ree cases of immune U1rombocyi.openia (ITP) as-

ociated \vith human immunodeficiency vims (HlV) infe lion prompted a review of communi ty-acquired thrombocytopenia in Nova Scotia from January 1980 to D cember 1987. 1\vo hundred and seven patients meeting the case defmition of ITP were identified. The incidence of ITP rose from 2.0x 105 in 1980 LO 3.3x 105

in 1987. More cases of ITP in the sexu ally active population occurred between 1984 and 1987 than in U1c previous four years (P=0.034). All Uwee cases of known HIV-associa ted ITP were captured in the relro pee­live surveillan ce system . The study concluded that increases in community-acquired ITP in a sexua lly active population may be a surrogate marker o f the HN epidemic. even in geographic areas \vith a low scroprevalence for HN. Serological tests for HN infection hould be a routine part of the diagnostic investigation of lTP in all sexu ally active patients or those with other pol nlial r isk factors for HN infection.

K ey Words: Epidemiology. Human immunodeficiency virus. Immune thrombocytopenia

Epidemiologie de Ia thrombocytopenie immune

RESUME: Trois cas de thrombocylopenie immune associee au virus de l"immunodeficience humaine MH) ont conduit les ch erch eurs a passer en revue les cas de Lhrombocytopenie acquise en Nouvelle-Ecosse entre janvier 1980 et decembre 1987. Deux cent sept patients on t ete identifies portcurs cl"une Lhrombocyi.openie immune. L"incidence de lhrombocylopenie immune s·est elevce de 2.0 X 105 en 1980 a 3.3 X 105 en 1987. Plus de cas de th rombocytopenic immune dans Ia population active scxu ellem ent sont survenus entre 1984 ct 1987 que dans les qualre annees precedentes (p=0.034). Les trois cas de thrombocytopenic immune associee au VIH onl ele decclcs pa r un system e de con lr61c epiclemiologique retrospectif. L"etudc a onclu que !"augmentation clu nombre de cas de l hrombocylopenie immune clans une population active pourraient conslituer un indicaleur substi tul cl"une epid . m ie au VIH , mem c clans les zones geographiques ou Ia seroprevalence du VIH e t faible. Les tests serologique pour !"infection au VIH doivent faire partie integrate de Ia recherch e diagnostique clans Ia U1rombocytopenie immune chez tousles patients actifs sexuellcment OU chez ceu;-c qui presentcnt un autre faclcur cle risque a l"ega rcl de !"infection au VI H.

Dalhousie Un iversity. Faculty of Medicine. Halifax. Nova Scotia Correspondence and reprints: Dr WP Schlech Ill. Room 4089 ACC. Victoria General Hospital. 1278 Tower Road. Halifax.

Nova Scotia 83H 2Y9 Received for publication July 15. 1991. Accepted November 26. 1991

CAN J INFECT DIS VOL 3 N o 6 N OVEMBER/DECEMBER 1992 311

SCHLECH et Oi

IMMU E THROMBOCYTOPENIA (ITP) FIRST WAS REPO RTED AS A

manifesta tion of the human immunodefic iency virus (HN) epidemic in 1982 (l) and now is recognized widely as a common manifestation of acute and chronic HIV infection (2). Estimates of thrombocytopenia in human s ubjects of known HIV seropositive cohorts are as high as 10% at a single visit (3). and thrombocytopenia has been reported in all risk groups for HIV infection (3-7). However no studies of community-acquired ITP exist that would allow a direct comparison of the inciden ce of ITP in HIV infection vers us that in the general population. Three cases of HIV-related ITP diagnosed in Nova Scotia prompted a study of the incidence of ITP in that province. The hypothesis was that the incidence of ITP - a relatively uncomm on h em atological condition but a common manifestation of HIV infection - would be increasing as an epiphenomenon of the spread of HIV infection in the community .

CASE PRESENTATIONS Case 1: A 22-year-o ld heterosexual female noted easy bruising and increased menstrual bleeding during Sep­tember 1984. She was admitted in November 1984 wi th a platelet count of 13.000/ mm3 . White blood cell count was 4800/mm3 \vi.th a nom1al differential . A bone mar­row exam in ation demonstrated normal megakaryo­cytes. antinuclear antibody and anti -DNA and lupus erythematosis tests were n egative. A diagnos is of ITP was made and the patient was treated with platelet transfusions and prednisone (100 mg daily): a rapid resolution of thrombocytopenia resulted. In September 1985 a human Tcelllymphotrophic virus (H1VL)-IIl titre was positive by enzyme immunoassay and Western blot. The patient rem ained asymptomatic (Centers for Dis ­ease Control [CDC] group Ill with a CD4 coun t of 500 in July 1989. Th e patient's on ly sexual pa rtner in 1984 had hemophilia A and ha d referred h er for evaluation after finding out that h er was HTLV-lll positive. In July 1989 the partner had CDC group Ill HIV infection wiU1 a CD4 coun t of 300. Case 2: A 26-year-o ld male developed easy bruising in January 1985 and in July of that year was found to be U1rombocytopenic. He was hospita lized in September 1985 \vi.th a platelet count of 67.000/mm3 because of failure to maintain an adequate platelet count while off prednisone. Total white blood cell coun t was 13.300/ mm3 and U1e differential count was nom1al. A bone marrow aspirate revealed megakaryocytic hyperplasia. confirming the diagnosis of lTP. The patient was treated with vinblastine. and prednisone was con tinued. The thrombocytopenia resolved over sL-x m onths . An HTLV-111 titre was positive in September 1985. OU1er studies were not done . The patient had a s in <fle homosexual relationship two years prior to presentation while at­tending university in central Canada. There were no other risk factors for HIV infec tion . Case 3: A 25-year-old homosexual male developed a

312

widespread petechial rash and bleeding of the gums in April 1986. He had a positive HTLV-III antibody test, a platelet count of 8000 I mm3 and a white b lood cell count of 7600/mm3 wiU1 25% atypical lymphocytes. The pa tient was hepatitis B surface antigen-positive and had a cytomegalovirus titre of 1:256 and a herpes s implex virus titre of 1:64. Bone marrow examination showed megalmryocytic hyperplasia, CD4 count was 480. and immunoglobulin (!g) G level was 28.3 (normal 6.9 to 18 .0) . lgA 4.2 (0.9 to 4.0) and IgM 4.1 (0.6 to 3.6). A diagnosis of HTLV-III -associated ITPwas made. Treat­men t \vi.th 100 mg prednisone daily resulted in rapid resolution of thrombocytopenia. Case as certainment: Medical records at all Ha lifax hospi tals were reviewed for ICD-9 codes 287.3 (primary U1rombocytopenia), 287.4 (secondary U1rombocytopen ­ia) a nd 287.5 (U1rombocytopenia. unspecified). A diag­nosis of ITP was based on a platelet count of 120.000/ mm3 or less on two determinations wiU1 evidence of pe1;pheral destruction and no underlying ex.'planatory disease or condition s u ch as drug use. alcohol abuse. liver disease or other autoin1mune diseases. Bone ma r­row examination was performed in all cases. Immune complex determinations. antiplatelet a ntibody a nd specific platelet-bound Ig detem1inations were not rou ­tinely performed. Cases m eeting U1e case definition willi dates of diagnosis between 1980 and 1987 were ab­sti-acted for demographic information including age. sex. date of onset, county of residence, initial platelet coun t, treatinent regimen, HIV risk factors and out­come . Office records of all h ematologists in Nova Scotia were reviewed and a mailing to internists and ped­iau;cians soliciting cases of lTP was carried out. Con­sultation s wiU1 hematologists and general practitioners in U1e province s uggested U1at cases of suspected ITP would routinely be referred to practising hematologists (all located Ln Ha lifax) or internists by primary care physicia ns. a nd that review of office and hospital records of these specialists only would not significantly underestimate the number of ITP cases .

Nova Scotia census data obtained in 1980 with pop­ulation projections through 1987 were used to estab­lis h lTP incidence by yea r. No attempt was m ade to contact patients identified during the survey to deter­mine risk factors for HIV infection or to determ ine wheU1er serological evaluation for HIV would be war­ranted.

RESULTS Two hundred and seven cases of ITP were identifi ed

between January 1980 and December 1987 in Nova Scotia . Ages ranged from one montl1 to 93 years . \villi

86 cases occurring in males and 121 in females (male: female ratio 1: 1.4) . The age disti;bution of reported cases is illustrated in Figure l.

Rates of ITP per 100,000 popula tion were deter­mined in each of tl1e age groups (Ta ble 1). In U1e first

C AN J INFECT DIS V O L 3 N O 6 N OVEMBER/DEC EMBER 1992

A L L

c A s E s I 1 9 8 0 I 1 9 8 7

0 TO 9 10 TO 19 20 TO 29 30 TO 39 40 TO 49 >49

AGE GROUP IN YEARS

Figure 1) Total number (n=207) of cases of immune throm­bocytopenia in Nova Scotia by age group and seY:from I 980 to 1987. The overall pattern shows higher incidences in the groups aged zero to nine and over 49

four years of the survey (1980-83). rates were highest in the first decade of life and in patients over 49 years of age . Rates did not significantly change for these groups during the last four years of the survey (1984-87). Between 1984 and 1987, rates of!TP for the second through fourth decades of life significantly increased (P=0.034) (x2 test= 1.9 [confidence interva l l.l to 3.6]). For tl1e age group presumed to be most sexually active (ages 20 to 39) . the increase was even more striking (P=0.002) (l test= 2 .9 [confidence interval 1.4 to 6 .0]) (Figure 2). There was little change in the male:female ratio bel:\:veen the two time periods in this o·roup al­though in the 30- to 39-year-old group. U1e ratio changed from l: 1 to 0. 7:1 in favour of ma les. All three cases of knO\~m HIV-related lTP described above were in th is age group and were identified during the reu·ospec­tive surveillance. Cases were reported from Nova Scotia's 18 counties with no differences in ITP rate between counties. There were 14 deat11s. for a case fatality rate of 6.8%. No deaths were due to possibl HIV-related conditions.

DISCUSSION Before the identification of th e causative agent of

acquired immune deficiency syndrome (AJDS). surrogate markers of HIV infection -such as Pneumocystis carinii pneumonia (8) and Kaposi's sarcoma (9) - iden tified groups of patients subsequently determined to h ave HIV infection . These conditions primarily are seen in immunosuppressed hosts and reflect advanced dis­ease. The epidemiology of tuberculosis. which can occur in boili normal and immunosuppressed patients. has clearly been affected by the spread of HIV infection. with increased rates of tubercu losis occurring in hyper­endemic areas for HIV infection (10). The pres nt authors postulated lliat anollier potential marker for HIV infection in a communi ty may be an increase in

CAN J INFECT DIS VOL 3 N o 6 N OVEMBER/DECEMBER 1992

Immune thrombocytopenia and HIV infection

- 20 TO 39 MALES

- 20 TO 39 FEMALES

c 51---------­

A s 4 1---- - -------E s 3

2 '---·-

1980 1981 1982 1983 1984 1985 1986 1987

YEARS

Figure 2) Immune thrombocytopenia (ITPJ cases for the group aged 20 to 39 by year of diagnosis. Tl1e increase in ITP between 1984 and 1987 is significant (?=0.002. l testfor trend) . Num­bers did not significantly change for the groups aged zero to nine and over 49. There was a reversal in the malejemale ratio in 1985. but not in sttbsequenl years

TABLE 1 Rates of immune thrombocytopenia per 100,000 population

Age group 1980 1981 1982 1983 1984 1985 1986 1987

0 to 9 3.8 1.5 3.8 6.8 4.5 4.5 3.7 2.9

10 to 19 0.6 1.3 3.2 1.3 1.4 2.1 2.1 4.3

20 to 29 1.3 1.9 2.5 1.2 4.3* 3.7' 3.6* 4 .8*

30 to 39 0.0 1.6 0.0 0.7 3.6" 4.8* 3.3* 1.3*

40 to 49 2.4 0.0 2.3 2.2 1.1 0.0 3.1 1.0

> 49 3.4 3.4 4.8 4.8 3.8 3.3 5.1 4.2

Mean 2.0 1.9 3.0 3.1 3.3 3.5 3.7 3.3

'Rates significantly different from previous four years (P=0.002) (/test for trend= 2. 9 (confidence interva/1 .4 to 6.0)

ITP. a common and often early manifestation of HIV infection.

Previous studies of community-acquired ITP have not been reported. The province of Nova Scotia provided a unique opportunity to perform a retrospective study of ITP incidence because of the referral patterns for th is condition.

The population of Nova Scotia has been relatively stable. growing from 850,000 to 900.000 during U1e period of llie present study. Access to healtl1 care is exce llent. wiU1 regular and rapid referral to consultants for uncommon disorders. The first case of AIDS in a Nova Scotia resident was identifi ed in 1983: 72 cases have been reported to December 1990 wi.U1 a peak incidence in 1987 of 1.8 per 100.000 popu lation. The incidence a nd prevalence of HIV infection in tl1e province is un­knO\~. altl1ough mandatory reporting requirements for HIV infection a re in p lace. Cross-matching ITP files with reported AIDS cases did not produce additional cases of lTP or AIDS.

The study supports llie hypothesis fuat increases in llie lTP rate in sexually active age groups may parallel

313

ScHLECH ef Of

the spread of HN infection. Automated platelet counts were introduced before and during the survey. and although they may report artefactually low platelet counts. U1is would not account for U1e differences in rates seen be~veen age groups. In addition. all patients identified in U1e survey had clin ical findings (easy bruising or petechia) resulting in referral for diagnosis and management. The mean platelet count at onset for the patients was 13.000/mm3 . Increased availability of automated platelet counts therefore seems an unlikely bias towards increased rates in the study's last four years. The data, however. may underestimate asymp­tomatic thrombocytopenia. of which some cases may be clue to immune U1rombocytopenia associated wiU1 HN infection.

Changes in referral patterns with increased avail­ability of h ematological or internal medicine consult­ations could also account for increased recognition in U1e IaUer part of U1e survey. However, this bias would be reflected in increased rates of ITP in all age groups: clinically significant thrombocytopenia should not have been systematically under-reported in any age group in the study's first four years. Increased reporting of known HN-related !TP did not occur. and cases 1 and 2 were recognized only in retrospect after epidemiologi­cal risk factor for HN infection were ascertained. Despite U1is delayed diagnosis. all U1ree cases of !mown HN-related !TP were captured in the survey.

Rates of ITP did nol differ between counties for any study period. and disproportionate cases of AIDS have not been reported from Halif<Lx county. the major urban centre in the province with 30% of U1e total population. ( ova Scotia may be atypical in that respect. compared with other Canadian provinces. as two of the U1ree ITP cases cited in U1is report were not from Halifax county.) The authors believe thai referral patterns did nol s ig-

ACKNOWLEDGEMENTS: The authors are gmtcful lo Drs Or­mi lle Hayne. Vincenl lng, G Ross Langley and Allan Pysemany for access lo patient records for review. and to the physicians in ova Scotia who responded to the SUJ-vey . The authors also thank Daureen Stover and Janice Flynn for preparation of Lhe manuscript.

REFERENCES I. Mon·is L. Distenfeld A. Amorosi E. KarpaU'"in S.

Autoimmune thrombocytopenia in homosexual m en. Ann lntem Med 1982:96:7 14-7.

2. Ratner L. Human immunodeficiency virus-associated autoimmune thrombocytopenic purpura: A review. Am J Med 1989:86: 194-8.

3. Kaslow RA. Phair JP. Freedman HB. et al . Infection with Lhe human immunodeficiency vims: Clinical manifestations andlheir re lationship lo immune deficiency. A report of Lhe multicenter AIDS cohort study. Ann lntem Med1987:107:474-80.

4. Savona S. Nardi MA. Lennelle ET, Karpalkin S. Thrombocytopenic pL11-pura in narcotic addict Ann Intern Med 1985:102:737-41.

314

nificanUy change between 1980-83 and 1984-87. malting it likely U1at ch anges in ITP rates represent true changes in the incidence of disease in U1e communi ty.

HN infec tion in Nova Scotia has been seen piincipaJ ­ly in homosexual men (85% of reported AJDS cases) . The a uthors expected a change over time in the maJe:femaJe ratio for ITP in sexually active age groups. This change was not noted in the overall population , bul was seen in U1 e 30- to 39-year-olcl age group. in which more cases were reported in males U1an in females for U1e study's last four years. HN may be only one of several factors thai affect the overall rate of community­acquired ITP because the maJe:female ratio did not change clran1atically. It might be easier to identify U1e effect of HIV infection on rates of ITP and male:female ratio change in areas of high prevalence. The auU1ors are unaware of similar studies to s upport the con­clusion U1at ITP cases may be surrogate markers for HN transmission. alU1ough anecdotal case reports and case series show a male predominance in l-IN-positive ITP patients.

The study provided support for the oullined hypo­Ulesis but other population-based studies of ITP in areas of boU1 high and low HN prevalence are needed for confirmation. Review of ITP's clinical features in U1e chart review of patients in the sexually active age group supports the hypothesis; cases of ITP exh ibited the typical chronic. autoimmune form of ITP reported in l-IN-positive patients . Independent confirmation U1rough serological investigation of the cases would have strengU1ened the observation but would have been intrusive. However U1e authors recommend. on U1e basis of U1e study. that serological tests for I-IN infec­tion should be a routine part ofU1e diagnostic investiga­tion of ITP. particularly in age groups that are likely to be sexually active .

5. Ratnoff OD. Menitove JE. Aster RH. Lederman MM. Coincident classic hemophilia and 'idiopathic· U1rombocylopenic purpura in patients under treatment wiU1 concentrates of antihemophiliac (factor VIII) . N Eng! J Med 1983:308:439-42.

6. Saulsbu ry TJ. Boyle RJ. Wykoff RF. Howard TH. Thrombocytopen ia as lhe presenting man ifestation of human T-lympholropic virus type Ill infection in infants. J Pedialr 1986:109:30-4.

7. l<arpatkin S. Nardi MA. Hymes KB. Immunologic thrombocytopenic purpura after heterosexual transmission of human immunodeficiency virus (HIV). Ann Intern Medl988:109:190-3.

8 . Centers for Disease Control. Pneumocystis pneumonia­Los Angeles . MMWR 1981:30:250-2 .

9. Centers for Disease Control. Update on Kaposi' s sarcoma and pncumocyslis pneumonia among homosexual men -New York City and California. MMWR 1981 :30:305-8.

I 0. Centers for Disease Control. Tuberculosis- United Stales. 1985 - and the possible impact of human T -lyn1pholropic virus type 111 / lymphadenopalhy associated viru infections. MMWR 1986:35:74-6.

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