Pneumocystis Pneumonia Tied to High Mortality in Cushing’s

Infection is more frequent in patients with cancer-related Cushing’s

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by Andrea Lobo |

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Pneumocystis pneumonia, a serious infectious complication of Cushing’s syndrome, is associated with a high mortality rate, researchers in France report.

The onset of infection tends to occur shortly after beginning therapy to reduce cortisol levels, and is more frequent in patients with cancer-related Cushing’s and/or high levels of cortisol.

In such patients, preventive therapy might be considered, although its use “remains controversial, and requires comparative studies for evidence-based medicine,” the researchers wrote.

The study, “Pneumocystis pneumonia in patients with Cushing’s syndrome: a French multicenter retrospective study,” was published in the journal Annales d’Endocrinologie.

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In most cases, Cushing’s syndrome is caused by benign tumors in the brain’s pituitary gland, a form of the syndrome called Cushing’s disease. Such tumors elicit the excessive production of adrenocorticotropic hormone (ACTH), which will lead to the overproduction of cortisol by the adrenal glands sitting atop the kidneys. In rare cases, the cause is an ACTH-producing tumor found outside the pituitary gland, a form of the condition known as ectopic Cushing’s syndrome.

Pneumocystis pneumonia is an opportunistic infection caused by the fungus Pneumocystis jirovecii. Transmission occurs via the respiratory tract, and is more frequent in patients with a weakened immune system, including those with AIDS, cancer, autoimmune, or inflammatory diseases.

Several studies reported pneumocystis pneumonia in Cushing’s patients. Those with ectopic Cushing’s are at a higher risk of experiencing complications, particularly infections, resulting in higher mortality. Some clinicians suggest that higher-risk patients should undergo preventive treatment for Pneumocystis jirovecii.

Here, a team of researchers reviewed the medical records of patients with Cushing’s and pneumocystis pneumonia in several French university hospitals and cancer centers, to characterize the disease and treatment course.

The analysis included 25 patients (12 women and 13 men) recently diagnosed with Cushing’s and pneumocystis pneumonia, who had never received anti-tumor or cortisol-lowering medications. Their mean age at diagnosis was 56.6 years.

Cushing’s was caused by a neoplastic tumor in 21 cases (84%), including carcinomas in the adrenal gland (three patients), neuroendocrine tumors (17 patients), and lung adenocarcinoma (one patient). The remaining patients had a benign cause: three had Cushing’s disease, and one had adrenal hyperplasia.

Neuroendocrine tumors are tumors that arise in organs or glands that are responsible for producing and releasing hormones. In most cases in this study, neuroendocrine tumors were found in the pancreas (six patients).

When Cushing’s was diagnosed in these patients, blood cortisol levels were very high (mean of 2,424 nanomoles per liter (nmol/L) at 8 a.m.; normal range: from 140–690 nmol/L), and urinary-free cortisol levels were more than five times above the upper normal limit in 18 of 20 patients (90%).

Hypokalemia, or low potassium levels in the bloodstream, also was present in 22 of 24 patients (91.7%), and low lymphocyte (white blood cell) counts in 15 of 18 patients (83.3%).

Using cortisol blockers

Patients initiated treatment with cortisol blockers for Cushing’s, the majority of whom (88%) received metyrapone (sold as Metopirone) alone or in combination with one or two other medications. All patients were diagnosed with pneumocystis pneumonia, with a median onset time of 5.5 days after starting treatment or upping its dose.

At pneumonia onset, 17 of 19 patients (89.5%) had low lymphocyte counts; in 68.4% of them, this reduction was severe. Eight patients (32%) received oxygen therapy and 15 (60%) were hospitalized in intensive care. Of the 25 patients analyzed, five (20%) died of pneumocystis pneumonia.

“Our study showed a large predominance of neoplastic etiologies of [Cushing’s syndrome] in patients with [pneumocystis pneumonia],” the researchers wrote, adding that “one main reason … could be higher plasma cortisol levels.”

However, other factors, including comorbidities and hypokalemia, also may be risk factors for pneumocystis pneumonia.

Seven patients (28%) with ectopic Cushing’s received preventive treatment for pneumocystis pneumonia with trimethoprim-sulfamethoxazole (160/800 mg orally, three times a week). Even so, they still ended up developing the infection. They presented very high blood cortisol levels, urinary-free cortisol levels were 10 to 100 times above the upper normal limit, and low lymphocyte counts.

Two of these patients were hospitalized for oxygen therapy, five were in intensive care, and two (28.6%) died from pneumocystis pneumonia.

In this study, patients receiving preventive treatment had lower lymphocyte counts at the time of Cushing’s diagnosis and at pneumonia onset, compared with those who did not receive preventive treatment.

“This lymphopenia [low lymphocyte count] may explain the choice to implement prophylaxis in these patients,” the researchers wrote.

“Based on our data and the literature, we would advocate systematic prophylaxis in patients with cancer-related [Cushing’s syndrome], considering the high mortality in cancer patients after [pneumocystis pneumonia],” the researchers concluded.

For benign Cushing’s patients, preventive treatment might be considered if urinary-free cortisol levels are higher than five times the upper normal limit, or if other risk factors are present. Preventive treatment should be maintained for six weeks after a patient achieves normal cortisol levels.