1 Department of Intensive Care, 2 Chest Department and 3 Fertility Clinic, Erasme Hospital, French-speaking Free University of Brussels, Brussels, Belgium
4 To whom correspondence should be addressed at: Fertility Clinic, Erasme Hospital, 808 route de Lennik, 1070 Brussels, Belgium. Email: adelbaer{at}ulb.ac.be
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Abstract |
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Key words: benzyl alcohol/eosinophilic pneumonia/IVF/progesterone/sesame oil
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Introduction |
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The diagnosis can be suspected upon history, but the delay after drug intake is variable. The diagnosis is confirmed by the improvement of the symptoms following withdrawal of the suspected medication. In severe cases, corticosteroid treatment is indicated.
We report two cases of acute eosinophilic pneumonia following i.m. administration of progesterone in sesame oil (excipient) and benzylic alcohol (preservative) after IVF. Drug-induced eosinophilic pneumonia related to luteal phase support in IVF has never been reported before (see www.pneumotox.com).
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Case reports |
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The only relevant disease in her past medical history was malaria. In the context of her secondary infertility evaluation, the patient had undergone a laparoscopy 2 years before, which revealed adhesions between the right Fallopian tube and the uterus. A first IVF attempt had been cancelled because of premature ovulation. She had no known allergy and was a non-smoker. She had been living in Belgium for 5 years and had not left Europe during this time. She had three children all in good health.
On admission, the patient was in respiratory distress with a respiratory rate of 30breaths/min and a regular heart rate at 100beats/min. Examination revealed bilateral basal crackles and diminished breathing sounds.
The chest X-ray on admission showed interstitial infiltrates predominating in the periphery of both lungs (Figure 1). Arterial blood gas analysis at room air indicated a PaO2 of 66 mmHg and an oxygen saturation of 94%. Laboratory findings were as follows: white blood count: 29.5 x 103/mm3 with 47% of eosinophils representing 12.2 x 103 cells/mm3; C-reactive protein 13 mg/dl (normal <0.5 mg/dl). Cytological analysis of bronchoalveolar lavage (BAL) fluid performed in the right lower lobe the day of admission identified 8 x 106 nucleated cells/ml with 69% eosinophils, 20% macrophages, 5% lymphocytes, 4% basophils and 2% neutrophils. Cultures of BAL fluid were negative for viruses, fungi, parasites and bacteria. Haemocultures were also negative. Serological studies for parasites showed only antibodies for Plasmodium falciparum, corresponding to a known past disease. HIV serology was negative. Cultures of sputum, faeces and urine did not show pathogenic organisms.
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The first treatment she received in the emergency room was oxygen and amoxicillinclavulinic acid. As the different cultures were negative, the antibiotics were stopped and a presumptive diagnosis of eosinophilic pneumonia was made. Because of the pregnancy, progesterone administration was continued but the i.m. form was shifted to an intravaginal form, free of sesame oil or benzylic alcohol (Utrogestan Belgium).
The patient was treated with i.v. corticosteroids (120 mg of methylprednisolone per day) during 3 days followed by 64 mg of oral methylprednisolone with decreasing doses during 3 weeks.
The clinical evolution was quickly favourable, but 5 days after admission the blood eosinophil count in remained very high at 15 000/mm3. A bone marrow aspirate was then performed and showed 41% of mature eosinophils and a normal population of lymphocytes. Peripheral lymphocyte profile was normal, excluding a myeloproliferative disease.
Pulmonary function tests (PFT) on day 5 revealed a pure restrictive defect, with a total lung capacity of 3.05 l (59.8% of predicted), a vital capacity (VC) of 2.12 l (60.9% of predicted) and a reduced CO diffusion capacity (TLCO) (60.3% of predicted). On day 9, PFT showed nearly normal volumes, but the TLCO remained low (66.9% of predicted). A chest X-ray on day 10 showed a clear regression of the bilateral interstitial infiltrates (Figure 2).
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Three months after discharge, a blood analysis showed a normal count of white blood cells (6.3 x 103/mm3) with 3.5% eosinophils. The patient was at that time in the fourth month of her pregnancy. The pregnancy progressed uneventfully and the patient delivered a healthy girl at term.
Patient 2
A 38 year old woman was admitted because of fever, cough and dyspnoea. The patient had undergone a first IVF treatment because of her husband's tetraplegia-associated anejaculation. Ovarian stimulation for IVF had been performed by a desensitizing protocol using a short-acting GnRH agonist preparation together with urinary gonadotrophins. Three embryos obtained by ICSI following surgical sperm retrieval by testicular sperm extraction had been transferred 3 weeks before admission. A pregnancy test was positive 2 weeks later. As luteal support, the patient received daily i.m. injections of 100 mg of progesterone in sesame oil and benzylic alcohol. From the embryo transfer onwards, the patient was also treated with daily s.c. injections of 40 mg of enoxaparin because of protein S deficiency.
The patient had been pregnant twice in a previous relationship (one spontaneous abortion and one delivery at term). She was a non-smoker and had no known allergy.
Cough and dyspnoea had started 2 weeks after the embryo transfer. During the third week, the patient developed fever, worsening of her respiratory distress and prurit on the injection site of progesterone.
On physical examination, the temperature was 38°C, the heart rate regular at 120/min and the respiratory rate 36/min. Pulmonary examination revealed basal crackles. Cardiac, abdominal and neurological examination were normal. The chest X-ray showed bilateral interstitial infiltrates. Arterial blood gas analysis at room air indicated a PaO2 of 57 mmHg. Laboratory findings showed a white blood cell count of 22.5 x 103/mm3, with 4.9% of eosinophils representing 1105 cells/mm3. The C-reactive protein was observed at 18 mg/dl (normal <0.5 mg/dl). Her total IgE level was normal. Pulmonary embolism was excluded by a ventilationperfusion isotopic lung scan and deep vein thrombosis by Doppler ultrasound. Echocardiography was normal. BAL could not be performed because of severe hypoxaemia. Cultures of sputum, faeces and urine and haemocultures did not show pathogenic organisms. The autoimmune screening (ANCA, antinuclear antibodies) and viral serologies were normal (influenza, para-influenza, chlamydia pneumoniae, mycoplasma, adenovirus and legionella).
The first treatment she received in the emergency room was oxygen, amoxicillinclavulinic acid and clarithromycin. Antibiotics were stopped as cultures were negative for bacteria. As her ventilation conditions worsened, the patient was transferred into the intensive care unit where she was administered a continuous positive airway pressure (CPAP) with a FiO2 of 80% and a positive end expiratory pressure (PEEP) at 8 cm of water to maintain a PaO2 at 50 mmHg. On the third day of hospitalization, erythema appeared on her left buttock (site of progesterone injection). A drug-induced eosinophilic pneumonia was suspected. The i.m. form of progesterone was shifted to an intravaginal form. Corticosteroids were added (methylprednisolone 2 mg/kg) during 1 day followed by decreasing doses during 4 weeks.
Respiratory function rapidly improved, the absolute number of eosinophils decreased, the chest X-ray showed a regression of the infiltrates and the patient was discharged with oral methylprednisolone.
The test for specific IgE against sesame using the RAST was negative, as was the LTT against sesame oil and against progesterone. The pregnancy progressed uneventfully and the patient delivered a healthy girl at term.
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Discussion |
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To the best of our knowledge, we report for the first time in two patients, a severe systemic allergic reaction to i.m. administration of progesterone. For both patients, it was the first exposure to luteal phase support. The patients had no known allergies and the respiratory symptoms developed around 3 weeks after starting the i.m. injections of progesterone.
Acute and chronic eosinophilic pneumonia may be idiopathic or be related to various causes such as parasitic infections (Löffler syndrome) and drug-induced toxicity (Allen and Davis, 1994). Less frequent causes of pulmonary eosinophilia are the ChurgStrauss syndrome (a vasculitis usually associated with antineutrophil cytoplasm antibodies) and allergic bronchopulmonary aspergillosis. The clinical and radiological patterns of these diseases are, however, different from those of acute eosinophilic pneumonia.
Eosinophilic pneumonia of parasitic origin should be excluded by stool smears and serological methods (Toxocara, Fasciola, Trichinella, Strongyloïdes etc.). Many medications, including common antibiotics, are liable to cause eosinophilic pneumonia (an updated list is available on the pneumotox website: www.pneumotox.com). The disease can also be induced by inhalation of illicit drugs (cocaïne, crack).
Specific allergic factors associated with the disease can be diagnosed using skin tests and lymphoblastic transforming tests (LTT). Skin tests assess immediate type hypersensitivity and LLT tests evaluate the proliferation and activation of lymphocytes put in contact with the allergen. The intradermal test and the lymphoblastic transforming tests to the solution from the progesterone ampoule were both positive for the first patient when the whole preparation was tested. The research for specific IgE against sesame using the radio-allergo-sorbent was negative. The fact that the two patients developed similar symptoms using the same preparation of i.m. progesterone and that they both recovered when shifting to a vaginal form (with peanut oil as excipient) is highly suggestive of an allergic reaction to a constituent of the preparation used rather than to progesterone itself. Based on the tests performed, we cannot draw firm conclusions about the nature of the allergen which can be either sesame oil or benzyl alcohol. Hypersensitivity reactions to sesame oil and to benzyl alcohol have been previously reported but have never presented as eosinophilic pneumonia (Grant et al., 1982; Shmunes et al., 1984
; Kanny et al., 1996
).
Other i.m. preparations of progesterone are available at least in some countries, including the USA, that use other vehicles such as peanut oil. Vaginal preparations usually also use peanut oil as excipient. Hypersensitivity reactions to peanut oil have been described, mainly in relation to food allergy and reactions to meals in subjects allergic to peanuts (O'B Hourihane et al., 1997). To the best of our knowledge, peanut oil has not been implicated in allergic reactions as part of a progesterone preparation for luteal support.
Nevertheless, acute eosinophilic pneumonia can be induced by i.m. administration of progesterone. The condition can be life-threatening if the diagnosis is not rapidly suspected. For the second patient, respiratory support in the intensive care unit was required for 1 week. Clinicians should be aware that the condition can develop after several weeks of exposure to the allergen.
The need for luteal phase support is clearly established in IVF cycles with GnRH agonist protocols, and progesterone is the generally recommended compound, as it is associated with a lower incidence of ovarian hyperstimulation syndrome. However, there is no definitive consensus regarding the optimal route of administration of progesterone nor concerning the duration of the treatment. Recent studies have indeed suggested that luteal phase support beyond the pregnancy test might not be needed (Tryde Schmidt et al., 2001). These two cases show that the use of i.m. progesterone can be associated with a severe morbidity in young, otherwise healthy, patients. The severity of the symptoms is an additional argument for the use of vaginal progesterone as luteal phase support in IVF.
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Submitted on July 24, 2003; accepted on April 16, 2004.
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