CLINICAL ASPECTS

PULMONARY ASPERGILLOSIS, THE QUIET AND SEVERE COMPLICATION OF IMMUNOSUPPRESSIVE THERAPY IN PEMPHIGUS VULGARIS

MARIA ROTARU1, FLORINA POPA2, MIOARA MUNTEANU3, MIHAELA STANCIU4

1,2,4“Lucian Blaga” University of Sibiu, 3Respiratory Hospital of Sibiu

Keywords: pemphigus Abstract: Of the autoimmune bullous diseases, pemphigus vulgaris is the most severe, requiring long- vulgaris, pulmonary term immunosuppressive therapy and high doses. Although the disease can be controlled with therapy, aspergillosis, severe complications can occur secondary to the immunosuppressive therapy. Pulmonary aspergillosis complication, is a severe form of lung injury caused by Aspergillus spores that can appear on immunosuppressive immunosupresiv status with life-threatening risk if not diagnosed and treated in time. We present a case of a patient with therapy pemphigus vulgaris found in immunosuppressive therapy with systemic corticosteroids and azathioprine, who was diagnosed and treated for a severe form of pulmonary aspergillosis, occurred 4 months after the treatment of the underlying disease.

Cuvinte cheie: Rezumat: Dintre bolile buloase autoimune, pemfigusul vulgar este forma cea mai severă, necesitând pemfigus vulgar, tratament imunosupresiv de lungă durată şi în doze mari. Chiar dacă boala poate fi controlată aspergiloză pulmonară, terapeutic, pot apărea complicaţii severe secundare tratamentului imunosupresiv. Aspergiloza complicaţii, tratament pulmonară este o formă severă de afectare pulmonară produsă de sporii de Aspergillus ce poate apărea imunosupresiv pe fond imunosupresiv, cu risc vital dacă nu este diagnosticată şi tratată în timp util. Se prezintă cazul unui pacient cu pemfigus vulgar aflat în tratament imunosupresiv cu corticoterapie sistemică şi azatioprină care a fost diagnosticat şi tratat pentru o formă severă de aspergiloză pulmonară, apărută la 4 luni de la instituirea tratamentului bolii de bază.

INTRODUCTION CLINICAL CASE Pemphigus vulgaris, also called malignant pemphigus We report the case of a patient, 40 years old, from a because of the evolution’s severity, is the most serious and most rural area, who has been admitted to our clinic with a recent common of autoimmune bullous dermatoses.(1,2,3,) In the onset (of 2 months) of vesiculobullous lesions on the chest. The etiopathogenesis of the disease, the responsibility goes to IgG lesions had ulcerated and were covered with yellow-brown autoantibodies that act on target antigens, desmoglein 3, adherent crusts with expansion to the posterior thorax, upper desmoglein 1. limbs and the face. The Nikolsky phenomenon was positive in Aspergillosis is characterized by an invasion of blood the periphery of the lesions. In the mouth, on the jugal mucosa, vessels by hyphae, almost always limited to the lung tissue he presented multiple ulcerative lesions with irregular borders developed in immunosuppressed patients (5), with the (figure no. 1). occurrence of thrombosis, necrosis and hemorrhagic infarction. Massive inhalation of Aspergillus spores by healthy people may Figure no. 1. Post bullous ulceration of the posterior torax lead to diffuse, self-limited, acute pneumonia. All common species of Aspergillus that cause disease in humans are ubiquitous in the environment, growing on decaying vegetables. Inhalation of Aspergillus spores is extremely common, but aspergillosis is rare. Pulmonary aspergillosis is a possible complication of immunosuppressive therapy and it can cause complications such as allergic bronchopulmonary aspergillosis, chronic necrotizing pulmonary aspergillosis, bronchiectasis, respiratory failure, pulmonary fibrosis in severe cases (15,16,17), pulmonary aspergilloma and invasive aspergillosis. Other manifestations of the aspergillosis are sinusitis, endophthalmitis, encephalitis, Aspergillus endocarditis, The histopathological exam revealed intraepidermal, abscesses in the myocardium, kidney, liver, spleen, soft tissue intramalpighian bullae, with normal appearance of the dermo- and bone.(13,14) epidermal junction; dermis with pericapilar reduced Pemphigus vulgaris, due to long-term lymphocytic inflammatory infiltrate (figure no. 2). Direct immunosuppressive therapy, can be grafted by bacterial, viral or immunofluorescence examination was positive for IgG, C3 with fungal infection episodes, with varying degrees of severity intraepidermal rete pattern. The corroboration of the clinical, depending on the precocity of the diagnosis and the treatment histopathological and immunofluorescence (direct/indirect) and according to the ability of individual defence. established the diagnosis of pemphigus vulgaris.

1Corresponding author: Maria Rotaru, B-dul. Corneliu Coposu, Nr. 2-4, Sibiu, România, E-mail: [email protected], Tel: +40269 215050 Article received on 10.09.2014 and accepted for publication on 03.11.2014 ACTA MEDICA TRANSILVANICA December 2014;2(4):262-264

AMT, v. II, no. 4, 2014, p. 262 CLINICAL ASPECTS

Chest radiography showed no evidence of pleural and The appearance of a chest X-Ray, together with pulmonary changes at the moment of establishing a pemphigus pneumology and infectious disease consultations, raised the vulgaris diagnosis. suspicion of tuberculosis or staphylococcal pneumonia. Pulmonary tuberculosis was excluded for the following reasons: Figure no. 2. a, b. Intraepidermic bullae negative intradermal reaction to tuberculin, the sputum exam isolated pneumococci and Aspergillus, with negative cultures for Koch bacillus. Pneumococcal pneumonia was excluded because of the lack of typical radiologic appearance (“crumb” image), emphasizing the lack of Staphylococcus by Gram stain and by culture. Pulmonary aspergillosis was confirmed by isolation in culture of Aspergillus. Based on examination and pneumology advice, we established the following diagnosis: pneumococcal pneumonia and pulmonary aspergillosis. We agreed on a systemic treatment with antibiotics A systemic immunosuppressive treatment was and antifungals (Fluconazole initially 300 mg / day for a month, initiated with corticosteroids (methylprednisolone 1.2 mg / kg) then itraconazole 200 mg / day for 3 months). This resulted in a with a decrease of the dose depending on the clinical and complete remission of the pulmonary symptoms and the biological response. We performed azathioprine therapy (100 recovery of weight deficit. The complications of the long- term mg / day) and administered short courses of antibiotic glucocorticoid therapy that occurred in our patient were: type II (Cefuroxime 2 g / day), antifungal (Fluconazole 150 mg / day), insulinonecesitant diabetes, hypercoagulable syndrome, accompanied by a complementary therapy of topical drying, cortisone myopathy, diffuse osteoporosis with compaction of antiseptic and epithelising treatment. This led to a favourable T10 vertebral body, iatrogenic Cushing syndrome, stage II, evolution of the disease. After 6 weeks of initiating hypertension, pyoderma-like lesions, pharyngitis with corticosteroid therapy, the patient developed a staphylococcal Enterobacter (figure no. 5,a,b). infection of the left index, left knee and pharyngitis with Figure no. 5. a. Postlesional hiperpigmentation; b. Enterobacter –for which he followed systemic antibiotic and Cushingoid face topical treatment. Approximately 4 months after the diagnosis had been established and immunosuppressive therapy was initiated, the patient was admitted to the clinic again. He presented weight loss (about 20 kg in 3 months), and a dry cough, accompanied by a stabbing sensation in the left hemitorax. Stetacustic slightly decreased the vesicular murmur in the pulmonary bases. Relatively quickly afterwards, he developed a productive cough, initially with mucous sputum, then bloody and with a decreased vesicular murmur of the lungs in the left hemitorax, multiple foci of crackles in the apex and bases bilaterally. A chest x-ray revealed discrete inhomogeneous DISCUSSIONS nodular opacities in the right subclavian area, the left parahilar Differential diagnosis was made with: area and the left lung base. Heart with stage I left ventricular a) Staphylococcal pneumonia, which shows an hypertrophy, degree I. The costo-diaphragmatic sinuses were insidious onset, fever, malaise, cyanosis, dyspnea, chest pain, free of content (figure no. 3). CT of the chest revealed multiple cough with mucopurulent/ hemoptoic expectoration. The bilateral pulmonary nodular and macronodular masses, most of radiologic appearance showed: opaque multiple foci within them them hollow (the largest SRL). The upper lobe of the left lung showed areas of hypertransparency, “crumb” aspect, with presented a condensation. Tissue mass with central necrosis pleural damage. Examination of sputum by Gram stain and lower left lobe. Low pericarditis (figure no. 4). culture revealed Staphiloccocus (7,8), unlike in our case where Figure no. 3. Inhomogeneous nodular opacities Pneumococcus and Aspergillus were isolated. b) Primary pulmonary tuberculosis is usually located in the middle and lower lung fields. The lesion is usually peripheric and is associated with hilar or paratracheal lymphadenopathy. In most cases the lesion heals spontaneously and may be evidenced later as a small calcified nodule (lesion of Ghon). An examination of the sputum highlights acid- alcolo- resistant bacilli. The intradermal reaction to tuberculin has limited value in the diagnosis of active tuberculosis, due to its low sensitivity and specificity. False-negative reactions are Figure no. 4. Nodular hollow bilateral pulmonary masses common in immunosuppressed patients and those with aggressive tuberculosis.(9) c) Nocardia pneumonia is typically subacute. Immunosuppressed patients may have a more acute onset with cough with small amounts of thick, purulent, odourless sputum. Fever, anorexia, weight loss are common; dyspnea, pleural pain and hemoptysis are less common. Radiographic appearance is variable. Infiltrates vary in size and have generally moderate or high densities. Nodules and formation of cavities are

common.(6) AMT, v. II, no. 4, 2014, p. 263 CLINICAL ASPECTS

d) Eosinophilic pneumonia belongs to the group of 4. Braun-Falco O, Plewing G.W olff HH, Burgdorf WHC- eosinophilic syndrome of intrinsec origin. It is characterized by Dermatology, II-Edition, Springler-Verlag; 2000. cough for at least 2 months, sputum eosinophils greater than 3%, 5. Bennett JE. Aspergiloza, Harrison’s Principles of Internal and no evidence of airway obstruction. Eosinophils can often be Medicine Ed. XIV; 2008. p. 1278-79. observed in the bronchoalveolar lavage fluid. Radiologically, 6. Filice GA. Nocardioza, Harrison’s Principles of Internal peripheral alveolar infiltrates, which can be migratory, can be Medicine Ed. XIV; 167:1090-91. observed and in a quarter of cases the appearance of pulmonary 7. Gherasim L. Medicina Interna Vol.1. Bolile aparatului edema.(10,11) respirator si locomotor; Ed. Medicala Bucuresti; 1995. It is known that the treatment of pemphigus vulgaris 8. Harrison’s Principles of internal medicine. 12-th ed. W. can lead to complications related to corticosteroids and Branwald, I. Fanci, ed. McGraw-Hill; 1991. immunosuppressive therapy.(12) 9. Raviglione MC, O’Brien RJ. Tuberculosis, Harrison’s The treatment of aspergillosis can cause complications Principles of Internal Medicine Ed. XIV; 171: 1109-21. secondary to the antifungal therapy.(11) 10. http://emedicine.medscape.com. Pulmonary Eosinophilia- Evolution of both pemphigus vulgaris and pulmonary Author: J. J Saukkonen, MD; Chief Editor: Z.Mosenifar, MD. aspergillosis is severe in the absence of treatment with exitus, 11. Gonlugur U, Gonlugur TE. Eosinophilic bronchitis without but in the era of corticosteroid and immunosuppressant the asthma. Int Arch Allergy Immunol 2008;147(1):1-5. pemphigus complications are related to the therapy, more than [Medline]. to the actual disease; pulmonary aspergillosis is evolving 12. Diaconu C. Justin-Dumitru, Coman OA, Benea V. Tratat de favourably with antifungal therapy.(1,2,3,5) Pemphigus vulgaris terapeutica dermato-venerologica; Editura “Viata medicala shows lasting remissions, the permanent cures beeing romaneasca”, Bucuresti 2002;79-89;229-236. questionable: in most cases, pemphigus patients become 13. http://emedicine.medscape.com. Aspergillosis -Author: Eloise corticodependent for life. The healing prognosis for aspergillosis M Harman, MD; Chief Editor: Zab Mosenifar, MD. is good in immunocompetent patients.(1,2,3,5) 14. Salez F, Brichet A, Desurmont S, Grosbois JM, Wallaert B, In medical literature, there exists an example of a case Tonnel AB. Effects of itraconazole therapy in allergic where a patient under polichimioterapic treatment for bronchopulmonary aspergillosis. Chest Dec pemphigus vulgaris developed pulmonary aspergillosis and 1999;116(6):1665-8. cerebral abscess and was diagnosed post-mortem.(18) In 1995, a 15. Patterson TF. Aspergillus species. In: Mandell GL, Bennett JE, group of Japanese dermatologists have reported the case of a 71- Dolin R, eds. Principles and Practice of Infectious Diseases. year old patient with pemphigus vulgaris who had been 7th ed. Philadelphia, Pa: Elsevier Churchill Livingstone; administered a treatment with steroids for seven months. He 2009:chap 258. developed pulmonary invasive aspergillosis during therapy, with 16. Stevens DA. Aspergillosis. In: Goldman L, Ausiello D, eds. rapid progression to death, despite early diagnosis and Cecil Medicine. 23rd ed. Philadelphia, Pa: Saunders Elsevier; treatment.(19) 2007: chap 360. The studies of M.S. Lionakis in 2003 and those of 17. Walsh TJ, Anaissie EJ, Denning DW et al. Treatment of D.P. Kontoyiannis in 2011 on glucocorticoids and invasive aspergillosis: clinical practice guidelines of the Infections fungal infections have shown that in vitro glucocoticoids can Diseases Society of America. Clin Infect Dis 2008;46(3):327- increase growth rate for Aspergillus flavus and Aspergillus 60. fumigatus 67. A clinical study on respiratory function in patients 18. Sima D, Tietz HJ, Reisshauer H, Buchholtz I, Schulze P et all.- with pemphigus vulgar showed that in the patients with Invasive metastasing pulmonary aspergillosis under pemphigus there was a slight reduction of CO diffusion polychemotherapy. Mycoses. 1994 Nov-Dec; 37(11-12):421- capacity, with patients often developing respiratory tract 5. infections that could be life-threatening.(20,21) 19. Niki Y, Yoshida K, Tamada S, Miyashita N, Hashiguchi K et Medical literature reports more frequent cases of all- A case report of invasive pulmonary aspergillosis which pulmonary nocardiosis secondary to immunosuppressive therapy could not be saved in spite of making an early diagnosis. of pemphigus.(22) Kansenshogaku Zasshi 1995 Nov; 69(11):1307-11. The particularity of our case consisted in the rapid 20. Lionakis MS, Kontoyiannis DP. Glucocorticoids and invasive development of a severe form of pulmonary aspergillosis, fungal infections. The Lancet 2003;29:1828-38. relatively shortly after the initiation of the immunosuppressive 21. Apalla Z, Chloros D, Argyropoulou P, Georgopoulos D, treatment (after 4 months), followed by infectious complications Patakas D et al. Respiratory function in patients with (pharyngitis with Enterobacter, staphiloccocal infections) due to pemphigus vulgaris - a small clinical study; J Dermatol Case the high dose of corticosteroid therapy and secondary Rep 2011;1:01-04. immunosuppression. This demonstrated the increased 22. Mari B, Montón C, Mariscal D, et al. Pulmonary Nocardiosis: susceptibility to infection of the patient, who also developed Clinical Experience in Ten cases; Respiration 2001;68:382- other complications after the systemic corticosteroid therapy. 388. Establishing a prompt diagnosis of pulmonary aspergillosis and setting a specific therapy has led to the healing of the patient’s lung infection, with a good performance and successful control of the bullous disease.

REFERENCES 1. Pătrascu V. Boli dermatologice si infectii sexual-transmisibile; Editia aII-a; Editura SITECH, Craiova; 2012. p. 264-270. 2. Bolognia. Dermatology, 2nd ed; Elsevier; 2008. 3. Bernard P, Aubin F, Barbaud A, Carsuzaa F, Dupin N.- Dermatoses bulleuses auto-imunes-Ann Dermatol Venerol 2005;132:7S91-7S97. AMT, v. II, no. 4, 2014, p. 264