Idiopathic CD4+ lymphocytopenia explained

Synonyms:	Immunodeficiency 13
Idiopathic CD4+ lymphocytopenia
Specialty:	Immunology

Idiopathic CD4+ lymphocytopenia (ICL) is a rare medical syndrome in which the body has too few CD4⁺ T lymphocytes, which are a kind of white blood cell.^[1] ICL is sometimes characterized as "HIV-negative AIDS", though, in fact, its clinical presentation differs somewhat from that seen with HIV/AIDS.^[2] People with ICL have a weakened immune system and are susceptible to opportunistic infections, although the rate of infections is lower than in people with AIDS.^[3]

Cause

The cause of ICL, like all idiopathic conditions, is unknown. It does not appear to be caused by a transmissible agent, such as a virus.^[4] It is widely believed that there is more than one cause.^[5]

Pathophysiology

The loss of CD4+ T cells appears to be through apoptosis.^[6] The accelerated deaths of the T cells is likely driven by crosslinking T cell receptors.

Diagnosis

The mandatory criteria for diagnosis of idiopathic CD4+ lymphocytopenia include:^[7]

• Low numbers of CD4+ cells, on two or more measurements over at least six weeks:
  • CD4 cell count less than 300 cells per microliter, or
  • Less than 20% of T lymphocytes are CD4+
• Laboratory evidence of lack of HIV infection
• Absence of any alternative explanation for the CD4 lymphocytopenia

A one-time finding of low CD4+ cells is usually associated with a recent infection and resolves on its own. Alternative explanations for the low CD4 counts include conditions such as blood cancers (aleukemia), treatment with chemotherapy, immunosuppressive medications, or other medications that suppress or kill T cells, infections, and problems with blood production.^[8]

All criteria must be fulfilled for a diagnosis of ICL. In addition, if these findings are present but combined with other significant findings, such as anemia or thrombocytopenia, then other diagnoses must be considered.

Treatment

Fludarabine-based hematopoietic stem cell transplantation (HSCT) has shown to be a feasible treatment for ICL.^[9]

Prognosis

In contrast to the CD4⁺ cell depletion caused by HIV, in general, patients with idiopathic CD4 lymphocytopenia have a good prognosis.^{[10] [11] [12]} The decline in CD4⁺ T-cells in patients with ICL is generally slower than that seen in HIV-infected patients.^[2] The major risk to people with ICL is unexpected infections, including cryptococcus, atypical mycobacterial and Pneumocystis jiroveci pneumonia (PCP). The condition may also resolve on its own.^[13]

ICL sometimes precedes and may be the first signal of several blood cancers. ICL patients have developed primary effusion lymphoma,^{[14] [15]} primary leptomeningeal lymphoma, diffuse large cell lymphoma,^[16] MALT lymphoma,^[17] and Burkitt's lymphoma,^[18] among others.

ICL may indirectly trigger autoimmune diseases. It has been associated with several cases of autoimmune disease Sjögren syndrome.^[19]

Because all of the reported autoimmune diseases and lymphomas involve B cells, one hypothesis proposes that ICL's narrow T cell repertoire predisposes the immune system to B cell disorders.

Epidemiology

ICL is a very rare disease. In 1993, a total of 47 confirmed cases were reported in a survey sponsored by the Centers for Disease Control.^[20]

Notes and References

1. Walker UA, Warnatz K . Idiopathic CD4 lymphocytopenia. Curr Opin Rheumatol. 18. 4. 389–95. July 2006. 16763460. 10.1097/01.bor.0000231908.57913.2f. 20289181.
2. Luo L, Li T . Idiopathic CD4 lymphocytopenia and opportunistic infection--an update . FEMS Immunol. Med. Microbiol. . 54 . 3 . 283–9 . December 2008 . 19049641 . 10.1111/j.1574-695X.2008.00490.x .
3. Wladis EJ, Kapila R, Chu DS . Idiopathic CD4+ lymphocytopenia and Sjogren syndrome . Arch. Ophthalmol. . 123 . 7 . 1012 . July 2005 . 16009850 . 10.1001/archopht.123.7.1012-a . free .
4. http://www.online-medical-dictionary.org/T-Lymphocytopenia,+CD4+.asp?q=T-Lymphocytopenia%2C+CD4%2B Online Medical Dictionary entry on T-lymphocytopenia
5. Duncan RA, von Reyn CF, Alliegro GM, Toossi Z, Sugar AM, Levitz SM . Idiopathic CD4+ T-lymphocytopenia--four patients with opportunistic infections and no evidence of HIV infection. N. Engl. J. Med.. 328. 6. 393–8. February 1993. 8093636. 10.1056/NEJM199302113280604. free.
6. Laurence J, Mitra D, Steiner M, Lynch DH, Siegal FP, Staiano-Coico L . Apoptotic depletion of CD4+ T cells in idiopathic CD4+ T lymphocytopenia. J. Clin. Invest.. 97. 3. 672–80. February 1996. 8609222. 507103. 10.1172/JCI118464.
7. UpToDate article on "Techniques and interpretation of measurement of the CD4 cell count in HIV-infected patients", by John G. Bartlett. Accessed 30 Oct 2006.
8. Busse PJ, Cunningham-Rundles C . Primary leptomeningeal lymphoma in a patient with concomitant CD4+ lymphocytopenia. Ann. Allergy Asthma Immunol.. 88. 3. 339–42. March 2002. 11926631. 10.1016/S1081-1206(10)62019-4.
9. Hamidieh . A. A.. Pourpak . Z.. Hamdi . A.. Nabavi . M.. Ghavamzadeh . A.. Successful fludarabine-based hematopoietic stem cell transplantation in a pediatric patient with idiopathic CD4+ lymphocytopenia. 10.1111/petr.12086. Pediatric Transplantation. E109–11. 2013. 23581828. 17 . 4. 206265698.
10. Laurence J, Siegal F, Schattner E, Gelman I, Morse S . Acquired immunodeficiency without evidence of infection with human immunodeficiency virus types 1 and 2. . Lancet . 340 . 8814 . 273–4 . 1992 . 1353194 . 10.1016/0140-6736(92)92359-N. 20114472 . free .
11. Ho D, Cao Y, Zhu T, Farthing C, Wang N, Gu G, Schooley R, Daar E . Idiopathic CD4+ T-lymphocytopenia--immunodeficiency without evidence of HIV infection. . N Engl J Med . 328 . 6 . 380–5 . 1993 . 8093634 . 10.1056/NEJM199302113280602. free .
12. Spira T, Jones B, Nicholson J, Lal R, Rowe T, Mawle A, Lauter C, Shulman J, Monson R . Idiopathic CD4+ T-lymphocytopenia--an analysis of five patients with unexplained opportunistic infections. . N Engl J Med . 328 . 6 . 386–92 . 1993 . 8093635 . 10.1056/NEJM199302113280603. free .
13. Zonios DI, Falloon J, Bennett JE, etal . Idiopathic CD4+ lymphocytopenia: natural history and prognostic factors. Blood. 112. 2. 287–294. July 2008. 18456875. 10.1182/blood-2007-12-127878. 2442741.
14. Niino D, Tsukasaki K, Torii K, etal . Human herpes virus 8-negative primary effusion lymphoma with BCL6 rearrangement in a patient with idiopathic CD4 positive T-lymphocytopenia. Haematologica. 93. 1. e21–3. January 2008. 18166773. 10.3324/haematol.12085. free.
15. Richetta A, Amoruso GF, Ascoli V, etal . PEL, Kaposi's sarcoma HHV8+ and idiopathic T-lymphocitopenia CD4+. Clin Ter. 158. 2. 151–5. 2007. 17566517.
16. Campbell JK, Prince HM, Juneja SK, Seymour JF, Slavin M . Diffuse large cell lymphoma and t(8;22) (q24;q11) in a patient with idiopathic CD4+ T-lymphopenia. Leuk. Lymphoma. 41. 3–4. 421–3. April 2001. 11378556. 10.3109/10428190109057998. 23366810.
17. Longo F, Hébuterne X, Michiels JF, Maniere A, Caroli-Bosc FX, Rampal P . [Multifocal MALT lymphoma and acute cytomegalovirus gastritis revealing CD4 lymphopenia without HIV infection]. fr. Gastroenterol. Clin. Biol.. 23. 1. 132–6. January 1999. 10219614.
18. Shimano S, Murata N, Tsuchiya J . [Idiopathic CD4+ T-lymphocytopenia terminating in Burkitt's lymphoma]. ja. Rinsho Ketsueki. 38. 7. 599–603. July 1997. 9267164.
19. Mandl T, Bredberg A, Jacobsson LT, Manthorpe R, Henriksson G . CD4+ T-lymphocytopenia--a frequent finding in anti-SSA antibody seropositive patients with primary Sjögren's syndrome. J. Rheumatol.. 31. 4. 726–8. April 2004. 15088298.
20. Smith D, Neal J, Holmberg S . Unexplained opportunistic infections and CD4+ T-lymphocytopenia without HIV infection. An investigation of cases in the United States. The Centers for Disease Control Idiopathic CD4+ T-lymphocytopenia Task Force. . N Engl J Med . 328 . 6 . 373–9 . 1993 . 8093633 . 10.1056/NEJM199302113280601. free .