PACIFIC OAKS

RESEARCH HISTORY

A Crisis (From the Morbidity and Mortality Weekly Report (MMWR) June 5,1981:)

Epidemiologic Notes and Reports

Pneumocystis Pneumonia --- Los Angeles

In the period October 1980-May 1981, 5 young men, all active homosexuals, were treated for biopsy-confirmed Pneumocystis carinii pneumonia at 3 different hospitals in Los Angeles, California. Two of the patients died. All 5 patients had laboratory-confirmed previous or current cytomegalovirus (CMV) infection and candidal mucosal infection. Case reports of these patients follow.

Patient 1: A previously healthy 33-year-old man developed P. carinii pneumonia and oral mucosal candidiasis in March 1981 after a 2-month history of fever associated with elevated liver enzymes, leukopenia, and CMV viruria. The serum complement-fixation CMV titer in October 1980 was 256; in May 1981 it was 32.* The patient's condition deteriorated despite courses of treatment with trimethoprim-sulfamethoxazole (TMP/SMX), pentamidine, and acyclovir. He died May 3, and postmortem examination showed residual P. carinii and CMV pneumonia, but no evidence of neoplasia.

Patient 2: A previously healthy 30-year-old man developed p. carinii pneumonia in April 1981 after a 5-month history of fever each day and of elevated liver-function tests, CMV viruria, and documented seroconversion to CMV, i.e., an acute-phase titer of 16 and a convalescent-phase titer of 28* in anticomplement immunofluorescence tests. Other features of his illness included leukopenia and mucosal candidiasis. His pneumonia responded to a course of intravenous TMP/.SMX, but, as of the latest reports, he continues to have a fever each day.

Patient 3: A 30-year-old man was well until January 1981 when he developed esophageal and oral candidiasis that responded to Amphotericin B treatment. He was hospitalized in February 1981 for P. carinii pneumonia that responded to TMP/SMX. His esophageal candidiasis recurred after the pneumonia was diagnosed, and he was again given Amphotericin B. The CMV complement-fixation titer in March 1981 was 8. Material from an esophageal biopsy was positive for CMV.

Patient 4: A 29-year-old man developed P. carinii pneumonia in February 1981. He had had Hodgkins disease 3 years earlier, but had been successfully treated with radiation therapy alone. He did not improve after being given intravenous TMP/SMX and corticosteroids and died in March. Postmortem examination showed no evidence of Hodgkins disease, but P. carinii and CMV were found in lung tissue.

Patient 5: A previously healthy 36-year-old man with clinically diagnosed CMV infection in September 1980 was seen in April 1981 because of a 4-month history of fever, dyspnea, and cough. On admission he was found to have P. carinii pneumonia, oral candidiasis, and CMV retinitis. A complement-fixation CMV titer in April 1981 was 128. The patient has been treated with 2 short courses of TMP/SMX that have been limited because of a sulfa-induced neutropenia. He is being treated for candidiasis with topical nystatin.

The diagnosis of Pneumocystis pneumonia was confirmed for all 5 patients antemortem by closed or open lung biopsy. The patients did not know each other and had no known common contacts or knowledge of sexual partners who had had similar illnesses. Two of the 5 reported having frequent homosexual contacts with various partners. All 5 reported using inhalant drugs, and 1 reported parenteral drug abuse. Three patients had profoundly depressed in vitro proliferative responses to mitogens and antigens. Lymphocyte studies were not performed on the other 2 patients.

Reported by MS Gottlieb, MD, HM Schanker, MD, PT Fan, MD, A Saxon, MD, JD Weisman, DO, Div of Clinical Immunology-Allergy; Dept of Medicine, UCLA School of Medicine; I Pozalski, MD, Cedars-Mt. Sinai Hospital, Los Angeles; Field services Div, Epidemiology Program Office, CDC.

Editorial Note: Pneumocystis pneumonia in the United States is almost exclusively limited to severely immunosuppressed patients (1). The occurrence of pneumocystosis in these 5 previously healthy individuals without a clinically apparent underlying immunodeficiency is unusual. The fact that these patients were all homosexuals suggests an association between some aspect of a homosexual lifestyle or disease acquired through sexual contact and Pneumocystis pneumonia in this population. All 5 patients described in this report had laboratory-confirmed CMV disease or virus shedding within 5 months of the diagnosis of Pneumocystis pneumonia. CMV infection has been shown to induce transient abnormalities of in vitro cellular-immune function in otherwise healthy human hosts (2,3). Although all 3 patients tested had abnormal cellular-immune function, no definitive conclusion regarding the role of CMV infection in these 5 cases can be reached because of the lack of published data on cellular-immune function in healthy homosexual males with and without CMV antibody. In 1 report, 7 (3.6%) of 194 patients with pneumocystosis also had CMV infection' 40 (21%) of the same group had at least 1 other major concurrent infection (1). A high prevalence of CMV infections among homosexual males was recently reported: 179 (94%) had CMV viruria; rates for 101 controls of similar age who were reported to be exclusively heterosexual were 54% for seropositivity and zero fro viruria (4). In another study of 64 males, 4 (6.3%) had positive tests for CMV in semen, but none had CMV recovered from urine. Two of the 4 reported recent homosexual contacts. These findings suggest not only that virus shedding may be more readily detected in seminal fluid than urine, but also that seminal fluid may be an important vehicle of CMV transmission (5).

All the above observations suggest the possibility of a cellular-immune dysfunction related to a common exposure that predisposes individuals to opportunistic infections such as pneumocystosis and candidiasis. Although the role of CMV infection in the pathogenesis of pneumocystosis remains unknown, the possibility of P. carinii infection must be carefully considered in a differential diagnosis for previously healthy homosexual males with dyspnea and pneumonia.

A Calling

In the book Your Money or Your Life written by Joe Dominguez and Vicki Robin, it is written that there are three types of employment: a job, a career and a calling. A job is a place where, according to this definition, someone collects a paycheck. There is little incentive beyond the pay that keeps someone in this daily tedium, and to this person, when a better opportunity arises, they will pursue it. To someone on a career track, the job is a means to an end: they will stay only so long as their talents are recognized and their promotion is assured. This person is on a mission to succeed and they will pursue that in whatever direction their ambition leads them.

To a person who is employed in a calling, the work itself is its own reward. The pay raises, promotions, and recognition are secondary, if relevant to this person at all. To this person, they have found their purpose and their life is devoted to this effort.

One such place that employs people with a calling is Pacific Oaks Medical Group (POMG) and its research department, Pacific Oaks Research. POMG was founded in the early 1980s in direct response to the AIDS crisis. The team then consisted of a group of a number of young, talented and ambitious physicians. Some of them have passed on and others are no longer with us, but their memory and legacy inspires us still. Anthony Scarsella, MD, one of the founders of Pacific Oaks Medical Group and its President, joined in the fight to overcome what a diagnosis of AIDS then meant: a certain death.

Working long hours, Pacific Oaks Research, and our team of dedicated professionals in collaboration and affiliation with academia, industry and the private sector helped develop some of the earliest treatments for HIV infection. These included: AZT (zidovudine), 3TC (lamivudine), d4t (stauvidine), saquinavir, efavirenz, abacavir sulfate, amprenavir, lopinavir, ritonavir, and many, many others.

A Breakthrough

Across town at Consolidated Laboratory Services (CLS), and in parallel with Pacific Oaks Medical Group, we helped validate the first HIV-1 RNA Polymerase Chain Reaction tests developed by F. Hofmann-LaRoche (and others). We leaned how to quantify or count the amount of HIV-1 viral RNA (the "viral load" as it was termed).

On November 22, 1993 we enrolled the first subject in Merck & Co's Protocol MK006-00 (indinivar sulfate) – an HIV protease inhibitor (PI). This protocol included the PI in combination with AZT and 3TC - two nucleoside analogue reverse transcriptase inhibitors or "NRTIs".

Then something astonishing happened. We learned then, that an HIV protease inhibitor in combination with two NRTIs could drive a person's HIV-1 RNA viral load below the limits of detection. A breakthrough at last! (The first of what would painstakingly become many). We learned that if you drove a person's viral load to levels that couldn't be detected in their blood, then some amazing things would start to happen: their immune system would strengthen, their bodies would heal. We watched as people who were clinically deteriorating and nearing death would seemingly and miraculously recover. We witnessed health and vitality restored.

More importantly: we had hope for the first time in a long time.

A Commitment

Today, though our core research continues to be HIV, we are as diverse as the population of Los Angeles itself. Our staff is diverse: bilingual, young, not so young, intergenerational and everything in between. This has proven to be a strength that has allowed us to be resilient and prosperous and to remain vital despite some challenging economic realities. What began in response to a frightening and devastating illness, and would lead to scientific breakthroughs that gave us the strength to carry on, has today become a tribute to the bravery and struggle of those who are no longer with us. We now work to improve the lives of our patients who are as diverse as the world itself. Our studies include hypertension, diabetes, lipid disorders, other infectious diseases (influenza, hepatitis C) and many others.

Though the people and the studies have changed, one thing remains the same: our commitment. We commit ourselves daily to improve the lives and health of the patients we serve, and we do our best to advance science to make human life better.

And that will never change.

References

1. Walzer PD, Perl DP, Krogstad DJ, Rawson G, Schultz MG. Pneumocystis carinii pneumonia in the United States. Epidemiologic, diagnostic, and clinical features. Ann Intern Med 1974;80:83-93.
2. Rinaldo CR, Jr, Black PH, Hirsh MS. Interaction of cytomegalovirus with leukocytes from patients with mononucleosis due to cytomegalovirus. J Infect Dis 1977;136:667-78.
3. Rinaldo CR, Jr, Carney WP, Richter BS, Black PH, Hirsh MS. Mechanisms of immunosuppression in cytomegaloviral mononucleosis. J Infect Dis 1980;141:488-95.
4. Drew WL, Mintz L, Miner RC, Sands M, Ketterer B. Prevalence of cytomegalovirus infection in homosexual men. J Infect Dis 1981;143:188-92.
5. Lang DJ, Kummer JF. Cytomegalovirus in semen: observations in selected populations,. J Infect Dis 1975; 132:472-3.





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