Treatment Issues, Vol 11, No 1; January 1997
Lillian Delmonte, D.Sc.

In a recently concluded study (presented at the Forty-third Annual Meeting of the Academy of Psychosomatic Medicine last November), Dr. Breitbart evaluated interrelations between fatigue, psychological well-being and quality of life in 438 ambulatory adult AIDS-diagnosed volunteers recruited primarily from three private New York hospitals from the end of 1992 through early 1995. Volunteers had been HIV seropositive for an average of 4.4 years before participating in the study. The probable sources of their HIV infection were intravenous drug abuse (52.8 per cent), homosexual contact (28.3 per cent) or heterosexual contact (sixteen per cent), and blood transfusions (0.7 per cent). Patients were assessed both by self-reported description of their own condition and by clinician-rated evaluation of psychological distress, quality of life and functional ability. Seven different scales were applied to grade fatigue, physical distress, psychological distress and performance status. The presence of fatigue was determined using the PSC (AIDS-Specific Physical Symptom Checklist) item regarding persistent fatigue lasting for at least two weeks and the MSAS (Memorial Symptom Assessment Scale) item covering "lack of energy." To be classified as having fatigue, volunteers had to respond positively to the relevant questions in both scales.

Fifty-four per cent of the study participants were considered to have fatigue on the basis of this evaluation. An analysis of multiple variables found that fatigue was more prevalent in women and in respondents with a greater number of AIDS-related symptoms, particularly persistent or frequent pain. As expected, there was a strong correlation between high scores for depression in the survey and fatigue, but 58% of the 231 individuals with fatigue did not have elevated scores for depression. In those who did have depression associated with a high level of fatigue, not all the fatigue symptoms could be accounted for by psychological factors.

The investigators concluded that more structured interviews were needed to better differentiate fatigue that is a reflection of depression from fatigue arising as a direct symptom of HIV disease. It also needs to be better determined and how frequently depression results from fatigue rather than the other way around. Notably, the incidence of fatigue did not vary according to CD4 cell count, indicating that more elaborate techniques, such as viral load assays, are required to document the relationship between HIV and fatigue.

The current Sloan-Kettering data confirms a survey of HIV-related fatigue conducted by Stanford University researchers and reported at the Ninth International Conference on AIDS in 1993 (abstract no. PO-B01-0885). That study compared fatigue in 394 HIV-negative persons and 917 people with varying stages of HIV infection. In this study, 55.8%, 28.4%, 17.3%, and 5.1% of the AIDS, ARC, asymptomatic and HIV-negative participants, respectively, reported experiencing fatigue in the seven days prior to the interview. Fatigue appeared to be a treatment-related side effect in 5.4% of respondents with AIDS, 6.2% of those with ARC and 4.3% of those with asymptomatic HIV.

Causes of Fatigue

HIV/AIDS-related fatigue is multidimensional. It has no single cause, but rather a constellation of interactive causes, of which psychological distress and depression are just one aspect. Physical symptoms, drug side effects, sleep disturbances, malnutrition and wasting, AIDS dementia, hormonal insufficiency (due to low adrenal gland output, for example) and muscular weakness (HIV- or AZT-related myopathy) all contribute to fatigue. In particular, the Memorial Sloan-Kettering study noted a small, but statistically significant association between fatigue and anemia (low oxygen transport by the blood).

Anemia may affect two-thirds of people with AIDS . Its causes include:

* Disease-related anemia: Long-term disease of any type can lead to "anemia of chronic disease." Iron is poorly incorporated into red blood cell (RBC) precursors, and hemoglobin levels are low. In addition HIV or opportunistic infections (such as Mycobacterium avium and B19 parovirus) can infect and destroy the bone marrow cells that develop into RBCs. The inflammatory agent tumor necrosis factor, whose production is stimulated by HIV, MAC and other pathogens, also decreases RBC production.

* Drug-induced depression of stem cells in the bone marrow, leading to inadequate red blood cell (RBC) production. AZT, most notoriously, has this effect in persons with AIDS. (15 to 20% of PWAs treated with AZT experience anemia -- but AZT causes anemia in only a few per cent of patients with less advanced HIV infection.)

* Disease- or treatment-related kidney damage. Cells in the kidney regulate the bone marrow's production of red blood cells by secreting erythropoietin (EPO) in response to lowered oxygen levels in the blood. Damage to these cells leads to a blunting of the EPO response and anemia.

* Nutritional deficits: Cryptosporidiosis and other gastrointestinal infections can lead to malabsorption and deficiencies in folic acid and, especially, vitamin B12, which are necessary for RBC formation. Iron deficiency can arise from chronic blood loss, for example as a result of intestinal Kaposi's sarcoma or cytomegalovirus infection.

Pneumocystis carinii and cytomegalovirus and other active opportunistic conditions directly trigger fatigue. Part of this fatigue results from the increase in inflammatory cytokines as the immune system responds to the OIs, but PCP lowers oxygen levels in the blood by interfering with lung absorption, and CMV can reduce hormonal levels by infecting the adrenal glands.

Treating the Medical Causes

Dr. Breitbart stressed the importance of appropriate medical treatment and psychosocial support for reducing a patient's fatigue symptoms and improving quality of life. Addressing the medical causes of fatigue, which may be as simple as switching patients to alternative drugs, can have a rapid, positive effect A better diet and special nutritional supplementation to combat malabsorption or the special needs of those with chronic infection can be useful in combating fatigue.

Raising hemoglobin levels by administering blood transfusions, recombinant erythropoietin (brand names: Epogen or Procrit) or nutritional therapy also gives people improved energy levels and greater functional capacity. Red blood cell transfusions are a "quick fix" for treatment-associated anemia, but they do carry a small risk of immune reactions and transmission of blood-borne infections. Recombinant erythropoietin has the advantage of being free of significant side effects. It requires three weeks to elevate hemoglobin levels, though, and occasional blood transfusions may still be required.

The team at Sloan-Kettering at present is conducting a placebo-controlled, six-week study on the ability of two commercially available psychostimulants (Ritalin and Cylert) to reduce fatigue in ambulatory HIV-positive individuals. This trial is still enrolling (call Monique Kaim, Ph.D., at 212/583-3002 for more information). According to Dr. Breitbart, "Stimulants are an umbrella kind of therapy that help you deal with fatigue of any cause." They also can interfere with sleep and cause loss of appetite, though, both of which might further fatigue in the long run.

Dr. Breitbart suggested that patients should be encouraged to develop their own methods of coping with fatigue. The first steps patients can take are pacing their daily lives, altering activity/rest patterns, including frequent rest breaks, and delegating activities to others. Working out at the gym or jogging is a form of natural psychological and physical stimulation, but more moderate exercise, like walking, can be helpful, too. People have also found such meditative exercise forms as yoga, tai chi or chi gong to be very restorative even when their physical capacity is limited by disease. Massage, therapeutic touch, acupuncture and other alternative therapies that claim to restore the body's "energy balance" also may have a role to play, if only for their meditative aspects, which relieves mental tension and depression.

Psychosocial counseling and support groups can be important for helping the patient to cope with emotional stress or anxiety. Occupational therapy can be a valuable strategy for distracting patients from focusing on their disease, symptoms and emotions. Finally, antidepressant medication can be used in cases of recalcitrant depression.

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