Hiding in plain sight: a new paradigm for "opportunistic infections".

Kosseifi et al (1) presented a case of Aspergillus esophageal ulceration occurring in a man treated with radiation and chemotherapy for tracheal carcinoma. Although the patient was recognized as immunocompromised, two diagnostic procedures were needed to make the diagnosis, and several treatment courses were undertaken before resolution of the infection was achieved. The infection persisted even with restoration of a normal leukocyte count some months after the end of the patient's cancer treatment. Such occurrences are illustrative of the need for a new paradigm in the epistemology of infectious disease.

The human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic of the 1980s and 1990s introduced a new generation of physicians to the concept of infectious disease caused by "atypical organisms" as a consequence of immunosuppression. The concept of "opportunistic infections" was not a new one, having first been introduced by Utz in 1962. (2) In the West, HIV/AIDS has assumed endemic status in most countries, and treatment of HIV/AIDS has become the province of a small cadre of specialists. On the other hand, huge increases in the number of patients with other forms of immunocompromise have made it common for practitioners in many fields of medicine to encounter patients with infectious complications of disease or therapy. For example, since 1971, the number of patients in the United States living with cancer has increased more than three-fold, from 3 million in 1971 (then 1.5% of the population) to 9.8 million in 2001 (3.5% of that years' population). (3) While some of this increase may be due to lead time bias from better screening and diagnostics. (3) much is due to improvements in chemotherapy, radiation oncology, and surgical methods with their attendant effects on host immunity. During that same time frame, advances in transplant medicine and the use of immunomodulators and biologicals in immune-mediated disease have vastly swelled the ranks of patients living longer but with impaired immunity. Such patients are common in internal medicine and its subspecialties but are increasingly seen in surgical and gynecologic practices as well. These new circumstances demand that physicians raise their "index of suspicion" and sharpen their diagnostic and treatment skills for the fight against pathogens once thought of as "atypical" or "opportunistic." A new paradigm for evaluating infectious disease has taken shape.

Practitioners need to categorize the potential for infectious disease and the differential diagnostic possibilities in each patient, while remaining cognizant of the patient's position on a continuum of immunocompromise or deficiency. The concept of a "normal immune system" may not be applicable once significant disease is present.

We now know that infections with so-called "immunomodulating viruses" such as HIV, Epstein-Barr virus, Cytomegalovirus, and hepatitis B and C not only cause primary illness but play a permissive or facilitative role for "opportunistic infections" in immunosuppressed patients. (4) The well recognized rise in the incidence of fungal infections (5) and Clostridium difficile infections (6) as well as many nosocomial pneumonias (7) in severely ill patients may be due to the increasingly recognized phenomenon of "immunoparalysis." Immunoparalysis seems to be a naturally occurring development of relative immunodeficiency brought on by humoral and cellular responses after exposure to a severe inflammatory state. (7,8) In fact, such a deficiency has even been cited as a prelude to Aspergillus infection. (8)

In short, there is no such thing as an "opportunistic infection." No common virulence factor unites the organisms known to cause such disease. There is no "opportunism" gene. (2) Rather, there are organisms capable of causing human disease whose innate pathogenicity is not changed one iota by human illness. The enemy at the gate simply gains access when the gate is weakened by disease or drug. It is time to abandon the term "opportunistic infection" and replace it with "immunocompromise-dependent infection." (2) Such a designation clarifies that these infections are not rare illnesses restricted to esoteric corners of medical practice, but rather, relatively common infections in a previously rare but now routinely encountered organism-the immunocompromised host.

References

1. Kosseifi SG, Dittus K, Nassour DN, et al. Actinomycosis esophagitis in a patient with persistent dysphagia. South Med J 2005;98 662-664.

2. Frenkel JK, Armstrong D. Immunocompromise-dependent infection rather that opportunistic infection. Int J Inf Dis 2001;5:175-176.

3. Rowland J, Mariotto A, Aziz N, et al. Cancer survivorship--United States, 1971-2001. MMWR 2004;53:526-529.

4. Rubin RH. Gastrointestinal infectioius disease complications following transplantation and their differentiation from immunosuppressant-induced gastrointestinal toxicities. Clin Transplantation. 2001;15 (Suppl 4):11-22.

5. Singh N. Trends in the epidemiology of opportunistic fungal infections: predisposing factors and the impact of antimicrobial use practices. Clin Inf Diseases 2001;33:1692-1696.

6. Frost F, Craun GF, Calderon RL. Increasing hospitalization and death possibley due to Clostridiuni difficile diarrheal disease. Emerging Inf Diseases 1998;4:619-625.

7. Stephan F, Yang K, Tankovic J, et al. Impairment of polymorphonuclear neutrophil functions precedes nosocomial infections in critically ill patients. Crit Care Med 2002;30:315-322.

8. Hartemink KJ, Paul MA, Spijkstra JJ, et al. Immunoparalysis as a cause for invasive Aspergillosis? Int Care Med 2003;29:2068-2071.

Ronald A. Leo, MD

From the Digestive Health Center of Louisiana and Baton Rouge General Health Systems, Baton Rouge, LA.

Reprint requests to Ronald A. Leo, MD, Digestive Health Center of Louisiana, 9103 Jefferson Highway, Baton Rouge, LA 70809. Email: [e-mail]

Accepted May 9, 2005.