C A s E r E P o r T
`
`life-threatening Pneumocystis jiroveci
`pneumonia following treatment of severe
`Cushing’s syndrome
`
`J.K. Oosterhuis1, G. van den Berg3, W.E. Monteban-Kooistra2, J.J.M. Ligtenberg2, J.E. Tulleken2,
`J.H.J.M. Meertens2, J.G. Zijlstra2*
`
`1Department of Anaesthesiology, 2Intensive and Respiratory Care Unit, 3Division of Endocrinology/
`Department of Internal Medicine, Groningen University Medical Center, University of Groningen,
`Groningen, the Netherlands, *corresponding author: tel.: +31 (0)50-361 61 61, fax: +31 (0)50-361 32 16,
`e-mail: j.g.zijlstra@int.umcg.nl
`
`A b s T r A C T
`
`We describe two patients with a severe Cushing’s syndrome
`due to ectopic production of ACTH. both patients developed
`a life-threatening Pneumocystis jiroveci pneumonia (PCP)
`shortly after treatment of the hypercortisolism was started
`by means of inhibition of production of glucocorticoids and
`glucococorticoid receptor blockade. We presume that the
`restored immune response elicited the clinical symptoms
`of the opportunistic, previously subclinical Pneumocystis
`jiroveci infection. The immunocompromised state and the
`delicate glucocorticoid balance in patients with a severe
`Cushing’s syndrome necessitate a specific diagnostic and
`therapeutic approach.
`
`K E Y W o r d s
`
`Cushing’s syndrome, opportunistic infections, treatment
`
`i N T r o d U C T i o N
`
`Cushing’s syndrome is a well-known but nevertheless
`rare syndrome with an incidence of 0.7 to 2.4 per million
`population per year and a prevalence of 39.1 cases
`per million, iatrogenic cases not included.1,2 Cushing’s
`syndrome results from lengthy and inappropriate
`exposure to excessive concentrations of circulating
`free glucocorticoid. In most cases Cushing’s syndrome
`is adrenocorticotropin hormone (ACTH) dependent,
`originating either from a pituitary ACTH-secreting
`tumour (Cushing’s disease) or, less frequently, from
`nonpituitary tumours secreting ectopic ACTH. Of all
`
`patients with endogenous Cushing’s syndrome 9 to
`18% have ectopic ACTH production.3,4 We describe two
`patients with opportunistic respiratory infections due to
`extremely high cortisol levels because of ectopic ACTH
`production. In both patients the symptoms developed
`shortly after the treatment of the hypercortisolism was
`started.
`
`C A s E r E P o r T 1
`
`A 62-year-old woman presented with complaints of
`hypertension, hirsutism, oedema of the tongue, a
`moon face and visual disturbances. These complaints
`had already been present for three years but varied in
`intensity. She had lost 10 kg in weight over the last
`two months. Moreover, during the last weeks she also
`developed muscle weakness in the lower extremities.
`She was found to have hypokalaemia. She also had a
`new-onset diabetes mellitus. ACTH (296 ng/l, normal
`<46 ng/l), cortisol (1945 nmol/l, normal <800) and urine
`cortisol (51,414 nmol/24 h, normal <270 nmol/24 h) were
`markedly elevated. A pituitary adenoma was not seen with
`gadolinium-enhanced magnetic resonance imaging (MRI).
`She was referred to the Department of Endocrinology in
`our hospital under the suspicion of an ectopic ACTH-
`producing tumour. Inferior sinus petrosus sampling
`confirmed the already supposed absence of pituitary
`ACTH production. A computerised tomography (CT) scan
`of the abdomen and thorax revealed a solid mass of 1.5 cm
`in the left upper lobe of the lung. The pulmonary lesion
`showed an increased uptake on (18)F-DOPA-PET. This
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`© 2007 Van Zuiden Communications B.V. All rights reserved.
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`made a pulmonary carcinoid very likely. Spironolactone
`and mifepristone (400 mg) were started as dual receptor
`blockade, in anticipation of pulmonary surgery.
`A few days later she complained of dyspnoea. Bilateral
`infiltrates were seen on the chest X-ray. She was admitted
`to the intensive care unit because of severe hypoxia. A
`bronchial lavage was carried out but was negative for
`Pneumocystis jiroveci or other pathogens. Nevertheless,
`high-dose trimethoprim-sulphamethoxazole (3 x 1920 mg)
`was started because of the strong clinical suspicion
`of Pneumocystis jiroveci pneumonia (PCP). Dyspnoea,
`hypoxia and chest X-ray improved. She did not need
`ventilatory support and was transferred back to the ward.
`Few weeks later the patient underwent a left upper
`lobectomy. Histology indeed showed a carcinoid of the
`lung with evidence of ACTH production. Cortisone acetate
`substitution was necessary for six months following
`surgery. Afterwards endogenous cortisol production
`was sufficient, with normal suppression after repeated
`dexamethasone inhibition. She has been free of symptoms
`for one year now.
`
`C A s E r E P o r T 2
`
`A 57-year-old woman was well until January 2006, when
`she noticed malaise. Hypertension was found in May
`2006 for which she was referred to hospital. Cushing’s
`syndrome was diagnosed. She was found to have multiple
`masses in the liver and a solid mass in the tail of the
`pancreas by CT scan. Percutaneous liver biopsy revealed
`an undifferentiated non-small-cell carcinoma with some
`neuroendocrine characteristics. Laboratory examinations
`revealed marked elevations of plasma ACTH (318 ng/l,
`normal <46 ng/l), cortisol (2371 nmol/l, normal <800)
`and urine cortisol (294,306 nmol/24 h, normal <270
`nmol/24 h) and hypokalaemia. Her hypertension required
`medication. Insulin was started because of a diabetes
`mellitus de novo. She was referred to the Department of
`Endocrinology in our hospital in June 2006. A diagnosis
`of severe Cushing’s syndrome was made, due to ectopic
`ACTH production, probably from a primary endocrine
`tumour of the pancreas with liver metastases. Palliative,
`but directly life-saving bilateral adrenalectomy was
`contemplated because of the extremely high cortisol
`level. Curative surgery was impossible but the usual slow
`growth of neuroendocrine tumours made this attempt
`worthwhile.
`Symptomatic treatment was started with ketoconazole,
`shortly afterwards followed by additional dual receptor
`blockade with 400 mg mifepristone and spironolactone.
`Also trimethoprim-sulphamethoxazole prophylaxis
`(960 mg on alternate days) was started as Pneumocystis
`jiroveci pneumonia prophylaxis. Nevertheless, she became
`
`dyspnoeic two days later and was transferred to the ICU.
`Physical examination on admission showed a typical
`Cushingoid appearance with moon face, alopecia, muscle
`weakness, striae and central obesity. She was tachypnoic
`(30 breaths/min) and had a peripheral oxygen saturation
`of 80% with a 100% O2 non-rebreathing mask. She was
`haemodynamically stable. Chest X-ray revealed bilateral
`alveolo-interstitial opacities. Before further diagnostic
`procedures could be performed she had to be intubated
`and mechanically ventilated. A bronchial lavage was
`carried out, which revealed Pneumocystis jiroveci.
`Afterwards trimethoprim-sulphamethoxazole was given
`in a therapeutic dose (3 dd 1920 mg iv). Mifepristone
`was stopped and glucocorticosteroids (hydrocortisone
`400 mg/24 h) were started because of hypotension. The
`pulmonary symptoms improved.
`For better control of the cortisol levels she underwent
`the planned bilateral adrenalectomy five days later. Large
`tumours in the liver and pancreas were found during the
`laparotomy, as well as a peritonitis carcinomatosa. A biopsy
`from the peritoneum showed a neuroendocrine tumour.
`Adipositas and muscle weakness made weaning difficult
`but ultimately she could be extubated. She had a short but
`much valued time with her family before she died, probably
`due to tumour progression.
`
`d i s C U s s i o N
`
`We describe two patients with Cushing’s syndrome
`and very high cortisol levels due to an ectopic ACTH
`production. One patient had a proven PCP; the other
`patient was clinically very suspect for a PCP. Both patients
`responded well to specific PCP therapy. Opportunistic
`infections after external glucocorticoids are well known,
`but opportunistic infections in patients with endogenous
`cortisol overproduction are less common. However, as
`early as in 1952, infections and wound healing problems
`in 17 of 33 patients with Cushing’s disease, all untreated
`for their Cushing’s syndrome, were described.5 Graham
`described six patients with severe endogenous Cushing’s
`syndrome and opportunistic infections.6 He showed that
`patients with Cushing’s syndrome have the same spectrum
`of infections as patients treated with pharmacological doses
`of corticosteroids. The risk of an opportunistic infection
`in Cushing’s syndrome is related to the cortisol level.6,7
`An opportunistic infection is therefore less likely to occur
`in patients with pituitary Cushing’s disease than it is in
`patients with higher levels of cortisol overproduction from
`adrenal tumours or due to ectopic ACTH secretion. But still
`there is an increased risk, also for pituitary gland related
`Cushing’s disease.8,9 Cryptococcus neoformans, Aspergillus
`fumigatus, Nocardia spp and Pneumocystis jiroveci are the
`most frequently found pathogens.
`
`Oosterhuis, et al. PCP after treatment of Cushing’s syndrome.
`
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`3. Wajchenberg BL, Mendonca BB, Liberman B, et al. Ectopic adrenocortico-
`tropic hormone syndrome. Endocr Rev 1994;15:752-87.
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`4. Newell-Price J, Trainer P, Besser M, Grossman A. The diagnosis and
`differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s
`states. Endocr Rev 1998;19:647-72.
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`5. Plotz CM, Knowlton AI, Ragan C. The natural history of Cushing’s
`syndrome. Am J Med 1952;13:597-614.
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`6. Graham BS, Tucker WS Jr. Opportunistic infections in endogenous
`Cushing’s syndrome. Ann Intern Med 1984;101:334-8.
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`7. Sarlis NJ, Chanock SJ, Nieman LK. Cortisolemic indices predict
`severe infections in Cushing syndrome due to ectopic production of
`adrenocorticotropin. J Clin Endocrinol Metab 2000;85:42-7.
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`8. Keenan N, Dhillo WS, Williams GR, Todd JF. Unexpected shortness of
`breath in a patient with Cushing’s syndrome. Lancet 2006;367(9508):446.
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`9. Dutta P, Bhansali A, Bhat MH, Sinha SK. Cytomegalovirus infection
`in a patient with endogenous Cushing’s syndrome. Saudi Med J
`2005;26:1137-8.
`
`10. Jacobs JA, Dieleman MM, Cornelissen EI, Groen EA, Wagenaar SS, Drent M.
`Bronchoalveolar lavage fluid cytology in patients with Pneumocystis carinii
`pneumonia. Acta Cytol 2001;45:317-26.
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`11. Thomas CF Jr, Limper AH. Pneumocystis pneumonia: clinical presentation
`and diagnosis in patients with and without acquired immune deficiency
`syndrome. Semin Respir Infect 1998;13:289-95.
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`12. Sistek CJ, Wordell CJ, Hauptman SP. Adjuvant corticosteroid therapy for
`Pneumocystis carinii pneumonia in AIDS patients. Ann Pharmacother
`1992;26:1127-33.
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`13. Fischer M, Bhatnagar J, Guarner J, et al. Fatal toxic shock syndrome
`associated with Clostridium sordellii after medical abortion. N Engl J Med
`2005;353:2352-60.
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`14. Torpy DJ, Mullen N, Ilias I, Nieman LK. Association of hypertension and
`hypokalemia with Cushing’s syndrome caused by ectopic ACTH secretion:
`a series of 58 cases. Ann N Y Acad Sci 2002;970:134-44.
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`15. Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK. Cushing’s
`syndrome due to ectopic corticotropin secretion: twenty years’
`experience at the National Institutes of Health. J Clin Endocrinol Metab
`2005;90:4955-62.
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`16. Isidori AM, Kaltsas GA, Pozza C, et al. The ectopic adrenocorticotropin
`syndrome: clinical features, diagnosis, management, and long-term
`follow-up. J Clin Endocrinol Metab 2006;91:371-7.
`
`Immunocompromised hosts other than HIV patients can have
`a low Pneumocystis load explaining the negative broncoalveolar
`lavage in the first patient.10,11 Interestingly, in both patients the
`clinical symptoms occurred shortly after almost total blockade
`of cortisol activity by the use of mifepristone. This has been
`described previously. The reconstituted immune response
`might be responsible for this.8 Apparently there is a delicate
`balance between the immune system of the patient and the
`pathogen that can be disturbed by treatment. This is also
`illustrated by the treatment of severe PCP in HIV patients. In
`these patients PCP treatment is combined with glucocortico-
`steroids to avoid a life-threatening immune response.12
`Mifepristone is used to induce medical abortion. It has also
`been suggested to potentiate infections in this setting. The
`mechanism behind this might be the innate immunity.13
`This might be a complementary or alternative explanation
`for the sequence of events seen in our patients. The
`incidence of infection after mifepristone is, however, very
`low and it is a completely different population, so this is not
`very likely. Enzyme inhibitors as ketoconazole have a rapid
`onset of action but these drugs are not effective enough in
`severe Cushing’s syndrome. Mifepristone is a highly potent
`antagonist of glucocorticoid and progesterone receptors,
`especially suited for use in severe Cushing’s syndrome as
`temporary medical therapy. Indeed both patients became
`insulin independent after mifepristone therapy started.
`Titration of the mifepristone dose is difficult because the
`effect of mifepristone, as a receptor blocker, cannot be
`quantified by the cortisol level itself. Insulin dependence
`and blood pressure can both be measured for glucocorticoid
`activity. However, excess inhibition is less easily measurable
`and in case of doubt mifepristone should be stopped and
`cortisol be substituted. In addition, a mineralocorticoid
`receptor antagonist such as spironolactone is usually
`necessary to control hypokalaemia.14
`Definitive therapy is surgical extirpation of the ACTH-
`producing tumour, if feasible. Bilateral adrenalectomy
`may be a useful palliative therapy in case of metastasised
`disease.15,16 In conclusion, high endogenous glucocorticoid
`levels are immunosuppressive. Glucocorticoid receptor
`blockade by mifepristone is a powerful temporary medical
`treatment, awaiting definitive surgical therapy. However,
`this might elicit clinical symptoms of a previous subclinical
`Pneumocystis jiroveci infection justifying at least prophylactic
`and maybe even therapeutic doses of trimethoprim-
`sulphamethoxazole. Titration of the optimal level of corticoid
`activity is a clinical challenge in these critically ill patients.
`
`r E f E r E N C E s
`
`1. Lindholm J, Juul S, Jorgensen JO, et al. Incidence and late prognosis of
`Cushing’s syndrome: a population-based study. J Clin Endocrinol Metab
`2001;86:117-23.
`
`Oosterhuis, et al. PCP after treatment of Cushing’s syndrome.
`
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