ORIGINAL
ARTICLE
Opportunistic infections in patients with pemphigus Yael A. Leshem, MD,a Michael Gdalevich, MD, MPH,b,c Michael Ziv, MD,d Michael David, MD,e,f Emmilia Hodak, MD,e,f and Daniel Mimouni, MDe,f Portland, Oregon; and Beer Sheva, Afula, Petach Tikva, and Tel Aviv, Israel Background: Opportunistic infections (OIs) can be defined as infections in immunosuppressed patients that are more frequent or severe because of immunosuppression. The literature on OIs in pemphigus is sparse. Objective: We assessed the incidence, risk factors, and characteristics of OIs in patients with pemphigus. Methods: This was a historical prospective study following a cohort of 172 patients with newly diagnosed pemphigus for the development of OIs. Results: Fourteen patients developed OIs at a mean of 4 months from the time of diagnosis while taking a mean dose of 0.8 mg/kg/day of prednisone, 5 in conjunction with azathioprine. The risk of developing an OI in the first year after the diagnosis of pemphigus was 9.3%, subsequently dropping to 0. Advanced age and possibly diabetes were found to be risk factors for OI development. Infectious agents included Nocardia, cytomegalovirus, Legionella, and Listeria. Two patients died within 2 months of OI diagnosis, and 2 more had neurologic impairment. Limitations: Limitations include the extraction of historical data and the cohort originating from a single geographic region. Conclusion: OIs present in a significant number of patients with pemphigus during the first year after the diagnosis of pemphigus, with potential deleterious effects. Older and possibly diabetic patients are at increased risk. Physician vigilance and patient education on limiting pathogen exposure is recommended. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2014.03.020.) Key words: corticosteroids; cytomegalovirus; legionella; listeria; nocardia; opportunistic infection; pemphigus.
P
emphigus is a group of organ-specific autoimmune mucocutaneous disorders characterized by intraepithelial blisters and erosions of the skin and mucous membranes.1 The mainstay of treatment for pemphigus is systemic corticosteroids (CS) and other immunosuppressive medications administered for prolonged periods of time, which predispose patients to infections. In a large cohort of 1209 patients with pemphigus, infections were the most common complication, observed in 19% of patients—half of which
From the Department of Dermatology,a Oregon Health and Science University, Portland; Faculty of Health Sciences,b Ben-Gurion University of the Negev, and the South District Health Office,c Ministry of Health, Beer Sheva; Department of Dermatology,d Ha’emek Medical Center, Afula; Department of Dermatology,e Beilinson Hospital, Petach Tikva; and the Sackler Faculty of Medicine,f Tel Aviv University, Tel Aviv. Funding sources: None. Conflicts of interest: None declared.
Abbreviations used: CS: OI: TMP-SMX: PCP:
corticosteroids opportunistic infection trimethoprim-sulfamethoxazole Pneumocystis jirovecii pneumonia
were skin infections.2 Another series of 155 pemphigus patients found an even higher infection rate (60%).3 The most common infections in this series were oral candidiasis, skin infections Accepted for publication March 16, 2014. Reprint requests: Yael A. Leshem, MD, Department of Dermatology, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR 97239. E-mail: [email protected]. Published online May 6, 2014. 0190-9622/$36.00 Ó 2014 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2014.03.020
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(primarily Staphylococcus aureus), and herpes The beginning of 2003 was selected as the starting simplex infections, comprising about 75% of all point for the study because the hospital’s database infectious episodes. Moreover, infections are a leadwas fully computerized in mid-2002. Third, the ing cause of mortality in pemphigus patients and computerized and hardcopy files of the cohort popwere responsible for 18% of deaths in a cohort of 835 ulation were reviewed from the date of pemphigus patients—second only to malignancies as the cause diagnosis onwards for noncutaneous OIs. of mortality in this patient population.4 Verification of the offending organism was mandaOne unique type of infectory for a diagnosis of OI. For tions in immunosuppressed additional substantiation, the CAPSULE SUMMARY patients are opportunistic Beilinson Hospital Inpatient infections (OIs), which can computer system (Ofek) was Little is known about opportunistic be defined as infections that queried for International infections (OIs) in patients with are more frequent or more Classification of Diseases, pemphigus. severe because of immuno9th revision diagnoses of We found a significant risk for OIs in the suppression.5 Different OIs pemphigus crossed with first year after pemphigus diagnosis, develop in different types the following: Listeria, increasing with advancing age and of immunosuppression. For Salmonella, Nocardia, Mycopossibly diabetes. example, Candida and bacteria, Legionella, BartoAspergillus infections are nella, cytomegalovirus Educating patients on limiting pathogen the most frequent invasive (CMV), herpes simplex exposures and acquaintance with the mycoses in patients with virus, varicella zoster virus, presentation of OIs is recommended. neutropenia.6 The OIs that Candida, cryptococcosis can be expected in and pneumocystis. These pemphigus patients are those related to impaired pathogens were selected because they are the cell-mediated immunity, which is suggested to be the OIs associated with states of impaired cellprimary immunosuppressive effect of pemphigus mediated immunity.14,15 Finally, all patient files 7 treatments. were assessed for sex, age at pemphigus diagThe current literature on OIs in pemphigus— nosis, pemphigus treatments, diabetes mellitus, excluding cutaneous infections, such as oral and prophylactic OI treatment. The course and candidiasis—consists of case reports.8-13 Although characteristics of OI cases were also extracted. OIs are seemingly rare in pemphigus patients when deducing from the dearth of literature, a constructed Statistical analysis study on this topic has not been performed. Baseline characteristics were summarized using We aimed to assess the incidence and descriptive statistics and compared using the t or characteristics of severe (noncutaneous) OIs in a ManneWhitney tests for numerical observations, the cohort of patients with pemphigus. Fisher exact test for comparison of proportions, and logistic regression for multivariable analysis. All analyses were performed with WinPepi METHODS software (version 11.39; available for download at Study design http://www.brixtonhealth.com/pepi4windows.html). This was a historical prospective study conducted P \ .05 was considered statistically significant. in the Autoimmune Bullous Disease Clinic of the Department of Dermatology in Beilinson Hospital, Rabin Medical Center, Petach Tikva, Israel. The study RESULTS cohort was established using the following protocol: The cohort included 172 patients with pemphigus first, the hospital outpatient clinic’s computerized diagnosed beginning on January 1, 2003 and database was queried for the names of all patients followed-up within the designated 10-year period who attended the Autoimmune Bullous Disease (Fig 1). The mean follow-up time of the cohort was Clinic between January 1, 2003 and December 31, 3.5 6 2.7 years. Within this group, 14 patients 2012. Second, patient files were reviewed, and only developed OIs, and all of these patients required those with a clinical, histologic, and immunofluoreshospitalization. Two patients who developed aseptic cence diagnosis of pemphigus (variants vulgaris, meningitis were excluded from the OI group foliaceus, erythematosus, or vegetans) were because an offending organism was not isolated. extracted. Patients diagnosed before January 1, OIs developed exclusively during the first year 2003 or those lacking a documented date of after pemphigus diagnosis, at an average interval of pemphigus diagnosis were excluded from the study. 4 6 3.2 months (range, 2 weeks to 11 months) from d
d
d
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Fig 1. Pemphigus patient cohort assembly.
Table I. Pemphigus cohort patient characteristics stratified by opportunistic infection development Cohort characteristics
M:F (ratio) Age at diagnosis, y 6 SD (range) Diabetes mellitus Treatment, n (%) Prednisone Azathioprine Mycophenolate mofetil Rituximab Methotrexate Intravenous immunoglobulin Dapsone Cyclophosphamide
OIs (n = 14)
No OIs (n = 158)
P value
6:8 (1:1.3) 66 6 16 (35-94) 8 (57%) pretreatment, 1; posttreatment, 7*
67:91 (1:1.4) 54 6 16 (21-94) 42 (27%) pretreatment, 20; posttreatment, 22
NS .011 .028y
14 (100) 6 (43) 0 0 0 0 0 0
157 70 22 20 8 8 3 2
(99) (44) (14) (13) (5) (5) (2) (1)
NS NS NS NS NS NS NS NS
F, Female; M, male; NS, not significant; OI, opportunistic infection. *Diabetes that developed after pemphigus treatment but before the OI. y Comparison between the presence or absence of diabetes.
diagnosis. The incidence of OIs in that first year was 8.1%, subsequently dropping to 0. This risk could be an underestimation, because 23 of the patients who did not develop an OI had \1 year of follow-up, and
may have developed an OI later. Of these patients, 9 were diagnosed during the last year of data collection (2012) and therefore could not be followed-up for a full year, and 14 were lost to
Patient no. Sex
Previous comorbidities
Age at Past onset, y treatment(s)
Pemphigus treatment complications
1
F HTN, HLD, atrial fibrillation, and fatty liver
61
CS
2
M NAD
35
CS and AZA
3
F DM type 2, HLD, €gren Sjo syndrome, and OP M NAD
60
CS
42
CS
Myopathy
4
OIs
DM, myopathy, Nocardia, and depression disseminated brain, meninges, and pulmonary Nocardia, DM, OP, acne, disseminated recurrent pulmonary and staphylococcal abscesses, HTN, hematogenous glaucoma, and Kaposi sarcoma Myopathy Nocardia, pulmonary
Cumulative Treatment onset to OI, Treatment at time prednisone Disease status dose at OIy* during OI months of OI per dayy
3
11
Prednisone 50 mg (0.7 mg/kg)
9310 mg
No lesions
19,000 mg No lesions Prednisone 40 mg (0.7 mg/kg); AZA 200 mg
Treatment for OI and outcome
Meropenem plus amikacin; mild neurologic impairment and partial rehabilitation TMP-SMX plus imipenem; full recovery
4
Prednisone 50 mg (1 mg/kg)
8200 mg
Minimal activity
TMP-SMX; full recovery
Nocardia, pulmonary
3
8970 mg
Active oral lesions
TMP-SMX; full recovery
Nocardia, shin abscess after spontaneous shin muscle rupture Nocardia, shin abscess at site of mild skin trauma
5
Prednisone 110 mg (1 mg/kg) Prednisone 50 mg (0.8 mg/kg)
8460 mg
No lesions
Debridement, TMP-SMX plus amikacin and ceftriaxone; full recovery
F Alopecia areata and hypothyroidism
66
CS
DM and OP
6
M HTN, glaucoma, BPH, and skin SCC
78
CS
NAD
7
F HTN, HLD, IHD, and PVD
74
CS and AZA
DM
Systemic CMVz
1
8
M NAD
67
CS
DM and myopathy
CMV, pulmonaryz
3
9
F Hypothyroidism
61
CS and AZA
DM
CMV, hepaticz
3
11
Prednisone 10 mg (0.1 mg/kg)
11,260 mg Minimally active disease
2850 mg Prednisone 85 mg (1.5 mg/kg); AZA 150 mg 5060 mg Prednisone 60 mg (0.75 mg/kg) CS 65 mg/d 5370 mg (1 mg/kg)
Minimal activity
TMP-SMX; recurrent Nocardia osteomyelitis after 1 y resolved with surgical drainage and TMP-SMX; full recovery Ganciclovir; death 2 months after OI of unknown causes
No lesions
Ganciclovir; complete recovery
No lesions
Ganciclovir; complete recovery
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Table II. Pemphigus patients with opportunistic infections: Characteristics and course
M Glaucoma and Alzheimer disease
94
CS and AZA
None
CMV, pulmonaryz
4
Prednisone 60 mg; AZA 50 mg
11
M S/P malignant thymoma, myasthenia gravis, bone Paget disease, and HTN F Alzheimer disease, HTN, CHF, PEG, and Parkinson disease F HLD and psoriasis
70
CS and AZA
DM
CMV,z skin and pulmonary
2
5100 mg Prednisone 45 mg (0.6 mg/kg); AZA 100 mg
Moderate activity
86
CS
NA
Legionella, pulmonary
3
Prednisone 25 mg
NA
72
CS and AZA
NAD
Legionella, pulmonary
1
57
CS
OP
Listeria meningoencephalitis
2
4960 mg Prednisone 95 mg (1.6 mg/kg); AZA 100 mg Prednisone 4375 mg 75 mg (1.2 mg/kg)
12
13
14
F HLD, fatty liver, and s/p thyroiditis
6260 mg
NA
No lesions
Ganciclovir; OI outcome unknown, death 4 years after OI of unknown causes Ganciclovir with recovery’ 9 months later, recurrent CMV pneumonitis and death because of respiratory failure Levofloxacin; full recovery, but death 6 months later because of urinary sepsis
Active disease
Levofloxacin; full recovery
Minimal activity
TMP-SMX plus meropenem; mild left-side hemiparesis
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AZA, Azathioprine; BPH, benign prostate hypertrophy; CHF, congestive heart failure; CMV, cytomegalovirus; CS, systemic corticosteroids; DM, diabetes mellitus; F, female; HLD, hyperlipidemia; HTN, hypertension; IHD, ischemic heart disease; M, male; MI, myocardial infarction; NA, not available; NAD, no appreciable disease; OP, osteoporosis; PEG, percutaneous endoscopic gastrostomy; PV, pemphigus vulgaris; PVD, peripheral vascular disease; SCC, squamous cell carcinoma; S/P, status post; TMP-SMX, trimethoprim-sulfamethoxazole. *Cumulative doses in milligrams. y Prednisone or prednisone equivalents per day. Numbers in parentheses indicate the corticosteroid treatment per day (mg/kg/day). z The diagnosis of CMV disease required compatible clinical findings and the detection of CMV using a validated method in the appropriate clinical specimen. In our institution, these include the shell vial (rapid culture) technique, CMV pp65 antigenemia, and polymerase chain reaction studies. Because pre-CMV serology was not available, differentiation of primary infections from virus reactivation could not be accomplished.
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follow-up in \1 year for unknown reasons. To address the loss to follow-up during the first year of the study, we calculated the OI incidence during that period using the person-time incidence approach; the number of incident cases was divided by the observed person-years (summation of the months under follow-up per patient within the first year, translated into years). Using this approach, the OI incidence rate in the first year after pemphigus diagnosis was 9.3 OIs per 100 patients. Patient characteristics stratified by OI development are shown in Table I. Only 1 patient in the cohort was treated prophylactically with trimethoprim-sulfamethoxazole (TMP-SMX) because of triple immunosuppression (ie, CS, azathioprine, and rituximab), and he did not develop an OI during the follow-up period. In a univariable analysis, age at diagnosis and presence of diabetes were found to be significantly associated with OI development, while sex and treatment regimens were not. The associations between diabetes and age at diagnosis with OIs were reevaluated with a multivariable model, because the possibility of confounding arose because of the association of age and diabetes. Using a logistic approach, adjusted for the influence of diabetes, the association between age at diagnosis and OI remained significant and substantial, showing an additional 4% estimate of risk difference for each year of age (odds ratio [OR], 1.042; 95% confidence interval [CI], 1.002-1.084). The adjusted association between diabetes and OI, even though it presented a strong risk estimate (OR, 2.89), was of borderline significance (P = .068 [95% CI, 0.92-9.04]). Elaboration on the OI cases is presented in Table II. All patients were diagnosed with pemphigus vulgaris except for patient 6, who was diagnosed with pemphigus foliaceus. All patients were undergoing systemic CS therapy during OI development. The mean prednisone (or equivalent) daily dosage was 59 6 27 mg or 0.8 6 0.4 mg/kg (for 2 patients without a recorded weight, 70 kg was substituted). The mean cumulative prednisone dose was 7629 6 4170 mg. Five patients received concomitant azathioprine (1 more received azathioprine previously, but it was discontinued before OI development). No patients were neutropenic at the time of OI development. HIV status was checked in patients 1, 2, 4, 5, 11, 13, and 14, and was negative in all of these cases. Ten patients had minimal to no pemphigus activity during the OI, implying that disease severity is not related to this complication. Four patients suffered severe adverse outcomes. Two patients with CMV disease died; 1 during a
relapse of CMV pneumonitis (patient 11) and another of unknown causes 2 months after hospitalization for CMV (patient 7). The 2 patients who had central nervous system (CNS) involvement (patient 1, with Nocardia; patient 14, with Listeria) remained with neurologic impairment. The cumulative prednisone dose was significantly higher in patients who developed a Nocardia compared to a CMV infection (median 9140 mg vs 5100 mg, accordingly; P \ .01). There were no significant differences in age, CS dose, or the presence of diabetes mellitus at the time of OI among the different OIs.
DISCUSSION Patients with pemphigus are expected to be at risk for developing OIs because of their immunosuppressive treatments. However, only few such cases have been reported to date,8-13 limiting our understanding of this serious complication. This contrasts with other fields of medicine that deal with immunosuppressed patients, such as transplant medicine, oncology, and HIV medicine, which offer abundant knowledge on OIs. Some concluded that because of the paucity of reports, OIs are very rare in pemphigus patients,9 but our findings argue differently. In our cohort of 172 patients with pemphigus followed-up for a mean of 3.5 years, 14 patients developed OIs, all during the first year after diagnosis. The risk of developing an OI in that first year was 9.3%, while no risk was shown later. Some OIs led to devastating outcomes. One patient died an OI-related death, another died in temporal proximity to the OI, and 2 patients remained with permanent neurologic and functional impairment. It is important to recognize these unusual infections, because dermatologists are often the primary physicians attending to these patients because of their chronic skin disease and complex immunosuppressive therapy. Our study highlights a few important findings that were not discussed previously in the literature. The patients in our cohort developed OIs at a mean of 4 months from the initiation of pemphigus treatment while taking a mean prednisone dose of 0.8 mg/kg/ day. Therefore, OIs did not develop while patients were taking maximum daily CS doses (1-2 mg/kg at treatment initiation16), but rather on lower daily doses yet after several months of cumulative CS exposure. Of note, adjuvant azathioprine in standard daily doses was administered to 5 of the patients when they developed an OI. The patients who developed OIs were significantly older than patients who did not (mean age, 66 vs 54 years). In a univariable analysis,
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diabetes mellitus was also significantly associated with OIs, but this association became less significant when adjusting for age (P = .068). However, this attenuated result could be attributed to the paucity of diabetes cases in the study and does not necessarily reflect the lack of impact of diabetes on the development of OIs. The opportunistic pathogens observed in our study include, in decreasing frequency, Nocardia, CMV, Legionella, and Listeria, which are known to cause OIs17-21 in patients with impaired cell-mediated immunity.14,15 Of interest is the unexpectedly high incidence of Nocardia cases, comparable to reported frequencies of nocardiosis in solid organ transplant patients.18 Several studies reported high-dose chronic CS treatment to be the major risk factor for nocardiosis,22,23 highlighting the strong association of this treatment modality with nocardiosis. Acquaintance with the varied clinical presentations of these OIs is crucial, because they may require unique diagnostic tests (eg, selective culture media and prolonged observation for Nocardia colonies) and specific treatments differing from those targeting more common pathogens. Febrile pemphigus patients with no clear infectious foci should be evaluated for OIs, especially CMV and Nocardia. In pemphigus patients with CNS disease, clinicians should assess for Nocardia24 and Listeria,25 which can cause invasive CNS infections, and consider empiric antibiotic coverage against these organisms. With pulmonary infections, bear in mind pathogens such as Nocardia, CMV, and Legionella in addition to the common respiratory pathogens. When treating abscesses and local wounds, think beyond S aureus and include Nocardia in the differential diagnosis. Finally, CMV can involve almost every organ system. CMV disease can present as CMV syndrome (ie, viremia with symptoms including fever and malaise) or tissue-invasive disease (ie, colitis, pneumonitis, and hepatitis),26 as represented in our cohort. Dermatologists should also be aware of the possible involvement of the skin by CMV,27,28 as in patient 11, who presented with fever and refractory ulcers different from his pemphigus lesions (Fig 2), which were found to be a part of his CMV disease. CMV infections developed on lower cumulative CS doses than Nocardia infections. The use of CS-free transplant protocols lowers the incidence of CMV disease, but it remains to be seen if lowering CS doses could offer the same benefit in pemphigus.29,30 Although our study was not designed to assess the utility of prophylactic therapy, we will briefly discuss prophylaxis for OIs. The major prophylactic interventions include antibacterial prophylaxis
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Fig 2. Cutaneous cytomegalovirus infection in a patient with pemphigus (patient 11). Round, punched-out ulcers covered with scale crust on the neck (A) and forearm (B).
against Pneumocystis jirovecii pneumonia (PCP), possibly effective against Listeria and Nocardia, and antiviral prophylaxis. These measures have been shown to be beneficial in immunosuppressed populations, such as HIV-infected patients,5 hematologic cancer patients,31 and solid organ transplant patients.32 Previous studies could not justify PCP prophylaxis in patients treated with CS for immune-mediated dermatologic conditions.33-35 This means that the risk:benefit ratio of this treatment as Listeria and Nocardia prophylaxis needs to be addressed separately. The magnitude of risk reduction by TMP-SMX for these pathogens is unknown. Moreover, there are increasing reports of breakthrough infections by TMP-SMXesusceptible Nocardia isolates, creating doubt about the use of this agent for the prevention of nocardiosis.18 Future prospective studies designed to assess the value of this or other interventions are needed. This is also true for CMV prophylaxis with ganciclovir, which has been proven effective in patient populations with much higher rates of CMV disease, such as bone marrow transplant patients.36 It is noteworthy to mention patient guidance strategies derived from the findings in our study, because they may help limit exposure to potential pathogens. This includes hand washing after food
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preparation and gardening, avoiding crosscontamination by washing all utensils and surfaces, especially after preparation of meat,37 and avoidance of close contact with people who have respiratory illnesses. Dietary advice might include avoidance of raw milk, unpasteurized soft cheeses, delicatessen meats, inadequately heated hot dogs, and smoked seafood, because these items can be highly contaminated with Listeria. These are simple, health-promoting measures that can be advocated by the dermatologist. When interpreting our results, it is important to stress that our study design a priori excluded conditions such as aseptic meningitis and several other pathogens—most notably S aureus. We did not consider S aureus to be an opportunistic pathogen because the immune impairments related to its virulence38—the most important being defects in neutrophils39—are generally not caused by pemphigus treatments. Moreover, the breach of the skin barrier key to S aureus infection is related to underlying pemphigus and not immunosuppresion.39 Nevertheless, S aureus is an important pathogen in pemphigus patients, and has been reported to be causative in a majority of infection-related deaths.40 We used a historical approach to data extraction from written records, limiting data availability regarding risk factors associated with OI development. Nevertheless, the overall study is of a prospective (cohort) nature, enabling the calculation of incidence rates. The number of OIs could have been underestimated because of the potential omission of OIs occurring in institutions outside of our database. Although the observed infections are not endemic to Israel, outcomes may differ in other locations. Additional studies in diverse patient populations could expand on the generalizability of our results. To our knowledge, this is the first study on OIs in a large group of patients with pemphigus, and we found a significant risk of OIs during the first year after pemphigus diagnosis. Although most patients fully recovered, some suffered severe outcomes, including death. The dermatologist is required to be well acquainted with the different OIs to make a timely diagnosis. A high index of suspicion is essential, especially throughout the first year after the initiation of immunosuppressive treatment—and more so in older and possibly diabetic patients. Educating patients on limiting pathogen exposure is recommended. Whether lower immunosuppressant exposure could reduce the occurrence of OIs while maintaining pemphigus control needs to be addressed in future prospective comparative trials, as does the value of prophylactic therapies.
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liver transplantation: a meta-analysis and meta-regression of outcomes. Transpl Int 2009;22:892-905. Yahav D, Gafter-Gvili A, Muchtar E, Skalsky K, Kariv G, Yeshurun M, et al. Antiviral prophylaxis in haematological patients: systematic review and meta-analysis. Eur J Cancer 2009;45:3131-48. Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Danziger-Isakov L, et al. Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation 2013;96:333-60. Green H, Paul M, Vidal L, Leibovici L. Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients. Cochrane Database Syst Rev 2007;3: CD005590. Lehman JS, Kalaaji AN. Role of primary prophylaxis for pneumocystis pneumonia in patients treated with systemic corticosteroids or other immunosuppressive agents for immune-mediated dermatologic conditions. J Am Acad Dermatol 2010;63:815-23. Li F, Jin H-Z, Su F, Jia L, Sun Q-N. Pneumocystis pneumonia in patients with immunobullous dermatoses. Int J Dermatol 2011;50:1144-9. Meyers JD, Reed EC, Shepp DH, Thornquist M, Dandliker PS, Vicary CA, et al. Acyclovir for prevention of cytomegalovirus infection and disease after allogeneic marrow transplantation. N Engl J Med 1988;318:70-5. Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med 2007;357:2601-14. Miller LS, Cho JS. Immunity against Staphylococcus aureus cutaneous infections. Nat Rev Immunol 2011;11:505-18. Lowy FD. Staphylococcus aureus infections. N Engl J Med 1998; 339:520-32. Ahmed AR, Moy R. Death in pemphigus. J Am Acad Dermatol 1982;7:221-8.
ARTICLE
Opportunistic infections in patients with pemphigus Yael A. Leshem, MD,a Michael Gdalevich, MD, MPH,b,c Michael Ziv, MD,d Michael David, MD,e,f Emmilia Hodak, MD,e,f and Daniel Mimouni, MDe,f Portland, Oregon; and Beer Sheva, Afula, Petach Tikva, and Tel Aviv, Israel Background: Opportunistic infections (OIs) can be defined as infections in immunosuppressed patients that are more frequent or severe because of immunosuppression. The literature on OIs in pemphigus is sparse. Objective: We assessed the incidence, risk factors, and characteristics of OIs in patients with pemphigus. Methods: This was a historical prospective study following a cohort of 172 patients with newly diagnosed pemphigus for the development of OIs. Results: Fourteen patients developed OIs at a mean of 4 months from the time of diagnosis while taking a mean dose of 0.8 mg/kg/day of prednisone, 5 in conjunction with azathioprine. The risk of developing an OI in the first year after the diagnosis of pemphigus was 9.3%, subsequently dropping to 0. Advanced age and possibly diabetes were found to be risk factors for OI development. Infectious agents included Nocardia, cytomegalovirus, Legionella, and Listeria. Two patients died within 2 months of OI diagnosis, and 2 more had neurologic impairment. Limitations: Limitations include the extraction of historical data and the cohort originating from a single geographic region. Conclusion: OIs present in a significant number of patients with pemphigus during the first year after the diagnosis of pemphigus, with potential deleterious effects. Older and possibly diabetic patients are at increased risk. Physician vigilance and patient education on limiting pathogen exposure is recommended. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2014.03.020.) Key words: corticosteroids; cytomegalovirus; legionella; listeria; nocardia; opportunistic infection; pemphigus.
P
emphigus is a group of organ-specific autoimmune mucocutaneous disorders characterized by intraepithelial blisters and erosions of the skin and mucous membranes.1 The mainstay of treatment for pemphigus is systemic corticosteroids (CS) and other immunosuppressive medications administered for prolonged periods of time, which predispose patients to infections. In a large cohort of 1209 patients with pemphigus, infections were the most common complication, observed in 19% of patients—half of which
From the Department of Dermatology,a Oregon Health and Science University, Portland; Faculty of Health Sciences,b Ben-Gurion University of the Negev, and the South District Health Office,c Ministry of Health, Beer Sheva; Department of Dermatology,d Ha’emek Medical Center, Afula; Department of Dermatology,e Beilinson Hospital, Petach Tikva; and the Sackler Faculty of Medicine,f Tel Aviv University, Tel Aviv. Funding sources: None. Conflicts of interest: None declared.
Abbreviations used: CS: OI: TMP-SMX: PCP:
corticosteroids opportunistic infection trimethoprim-sulfamethoxazole Pneumocystis jirovecii pneumonia
were skin infections.2 Another series of 155 pemphigus patients found an even higher infection rate (60%).3 The most common infections in this series were oral candidiasis, skin infections Accepted for publication March 16, 2014. Reprint requests: Yael A. Leshem, MD, Department of Dermatology, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR 97239. E-mail: [email protected]. Published online May 6, 2014. 0190-9622/$36.00 Ó 2014 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2014.03.020
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(primarily Staphylococcus aureus), and herpes The beginning of 2003 was selected as the starting simplex infections, comprising about 75% of all point for the study because the hospital’s database infectious episodes. Moreover, infections are a leadwas fully computerized in mid-2002. Third, the ing cause of mortality in pemphigus patients and computerized and hardcopy files of the cohort popwere responsible for 18% of deaths in a cohort of 835 ulation were reviewed from the date of pemphigus patients—second only to malignancies as the cause diagnosis onwards for noncutaneous OIs. of mortality in this patient population.4 Verification of the offending organism was mandaOne unique type of infectory for a diagnosis of OI. For tions in immunosuppressed additional substantiation, the CAPSULE SUMMARY patients are opportunistic Beilinson Hospital Inpatient infections (OIs), which can computer system (Ofek) was Little is known about opportunistic be defined as infections that queried for International infections (OIs) in patients with are more frequent or more Classification of Diseases, pemphigus. severe because of immuno9th revision diagnoses of We found a significant risk for OIs in the suppression.5 Different OIs pemphigus crossed with first year after pemphigus diagnosis, develop in different types the following: Listeria, increasing with advancing age and of immunosuppression. For Salmonella, Nocardia, Mycopossibly diabetes. example, Candida and bacteria, Legionella, BartoAspergillus infections are nella, cytomegalovirus Educating patients on limiting pathogen the most frequent invasive (CMV), herpes simplex exposures and acquaintance with the mycoses in patients with virus, varicella zoster virus, presentation of OIs is recommended. neutropenia.6 The OIs that Candida, cryptococcosis can be expected in and pneumocystis. These pemphigus patients are those related to impaired pathogens were selected because they are the cell-mediated immunity, which is suggested to be the OIs associated with states of impaired cellprimary immunosuppressive effect of pemphigus mediated immunity.14,15 Finally, all patient files 7 treatments. were assessed for sex, age at pemphigus diagThe current literature on OIs in pemphigus— nosis, pemphigus treatments, diabetes mellitus, excluding cutaneous infections, such as oral and prophylactic OI treatment. The course and candidiasis—consists of case reports.8-13 Although characteristics of OI cases were also extracted. OIs are seemingly rare in pemphigus patients when deducing from the dearth of literature, a constructed Statistical analysis study on this topic has not been performed. Baseline characteristics were summarized using We aimed to assess the incidence and descriptive statistics and compared using the t or characteristics of severe (noncutaneous) OIs in a ManneWhitney tests for numerical observations, the cohort of patients with pemphigus. Fisher exact test for comparison of proportions, and logistic regression for multivariable analysis. All analyses were performed with WinPepi METHODS software (version 11.39; available for download at Study design http://www.brixtonhealth.com/pepi4windows.html). This was a historical prospective study conducted P \ .05 was considered statistically significant. in the Autoimmune Bullous Disease Clinic of the Department of Dermatology in Beilinson Hospital, Rabin Medical Center, Petach Tikva, Israel. The study RESULTS cohort was established using the following protocol: The cohort included 172 patients with pemphigus first, the hospital outpatient clinic’s computerized diagnosed beginning on January 1, 2003 and database was queried for the names of all patients followed-up within the designated 10-year period who attended the Autoimmune Bullous Disease (Fig 1). The mean follow-up time of the cohort was Clinic between January 1, 2003 and December 31, 3.5 6 2.7 years. Within this group, 14 patients 2012. Second, patient files were reviewed, and only developed OIs, and all of these patients required those with a clinical, histologic, and immunofluoreshospitalization. Two patients who developed aseptic cence diagnosis of pemphigus (variants vulgaris, meningitis were excluded from the OI group foliaceus, erythematosus, or vegetans) were because an offending organism was not isolated. extracted. Patients diagnosed before January 1, OIs developed exclusively during the first year 2003 or those lacking a documented date of after pemphigus diagnosis, at an average interval of pemphigus diagnosis were excluded from the study. 4 6 3.2 months (range, 2 weeks to 11 months) from d
d
d
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Fig 1. Pemphigus patient cohort assembly.
Table I. Pemphigus cohort patient characteristics stratified by opportunistic infection development Cohort characteristics
M:F (ratio) Age at diagnosis, y 6 SD (range) Diabetes mellitus Treatment, n (%) Prednisone Azathioprine Mycophenolate mofetil Rituximab Methotrexate Intravenous immunoglobulin Dapsone Cyclophosphamide
OIs (n = 14)
No OIs (n = 158)
P value
6:8 (1:1.3) 66 6 16 (35-94) 8 (57%) pretreatment, 1; posttreatment, 7*
67:91 (1:1.4) 54 6 16 (21-94) 42 (27%) pretreatment, 20; posttreatment, 22
NS .011 .028y
14 (100) 6 (43) 0 0 0 0 0 0
157 70 22 20 8 8 3 2
(99) (44) (14) (13) (5) (5) (2) (1)
NS NS NS NS NS NS NS NS
F, Female; M, male; NS, not significant; OI, opportunistic infection. *Diabetes that developed after pemphigus treatment but before the OI. y Comparison between the presence or absence of diabetes.
diagnosis. The incidence of OIs in that first year was 8.1%, subsequently dropping to 0. This risk could be an underestimation, because 23 of the patients who did not develop an OI had \1 year of follow-up, and
may have developed an OI later. Of these patients, 9 were diagnosed during the last year of data collection (2012) and therefore could not be followed-up for a full year, and 14 were lost to
Patient no. Sex
Previous comorbidities
Age at Past onset, y treatment(s)
Pemphigus treatment complications
1
F HTN, HLD, atrial fibrillation, and fatty liver
61
CS
2
M NAD
35
CS and AZA
3
F DM type 2, HLD, €gren Sjo syndrome, and OP M NAD
60
CS
42
CS
Myopathy
4
OIs
DM, myopathy, Nocardia, and depression disseminated brain, meninges, and pulmonary Nocardia, DM, OP, acne, disseminated recurrent pulmonary and staphylococcal abscesses, HTN, hematogenous glaucoma, and Kaposi sarcoma Myopathy Nocardia, pulmonary
Cumulative Treatment onset to OI, Treatment at time prednisone Disease status dose at OIy* during OI months of OI per dayy
3
11
Prednisone 50 mg (0.7 mg/kg)
9310 mg
No lesions
19,000 mg No lesions Prednisone 40 mg (0.7 mg/kg); AZA 200 mg
Treatment for OI and outcome
Meropenem plus amikacin; mild neurologic impairment and partial rehabilitation TMP-SMX plus imipenem; full recovery
4
Prednisone 50 mg (1 mg/kg)
8200 mg
Minimal activity
TMP-SMX; full recovery
Nocardia, pulmonary
3
8970 mg
Active oral lesions
TMP-SMX; full recovery
Nocardia, shin abscess after spontaneous shin muscle rupture Nocardia, shin abscess at site of mild skin trauma
5
Prednisone 110 mg (1 mg/kg) Prednisone 50 mg (0.8 mg/kg)
8460 mg
No lesions
Debridement, TMP-SMX plus amikacin and ceftriaxone; full recovery
F Alopecia areata and hypothyroidism
66
CS
DM and OP
6
M HTN, glaucoma, BPH, and skin SCC
78
CS
NAD
7
F HTN, HLD, IHD, and PVD
74
CS and AZA
DM
Systemic CMVz
1
8
M NAD
67
CS
DM and myopathy
CMV, pulmonaryz
3
9
F Hypothyroidism
61
CS and AZA
DM
CMV, hepaticz
3
11
Prednisone 10 mg (0.1 mg/kg)
11,260 mg Minimally active disease
2850 mg Prednisone 85 mg (1.5 mg/kg); AZA 150 mg 5060 mg Prednisone 60 mg (0.75 mg/kg) CS 65 mg/d 5370 mg (1 mg/kg)
Minimal activity
TMP-SMX; recurrent Nocardia osteomyelitis after 1 y resolved with surgical drainage and TMP-SMX; full recovery Ganciclovir; death 2 months after OI of unknown causes
No lesions
Ganciclovir; complete recovery
No lesions
Ganciclovir; complete recovery
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Table II. Pemphigus patients with opportunistic infections: Characteristics and course
M Glaucoma and Alzheimer disease
94
CS and AZA
None
CMV, pulmonaryz
4
Prednisone 60 mg; AZA 50 mg
11
M S/P malignant thymoma, myasthenia gravis, bone Paget disease, and HTN F Alzheimer disease, HTN, CHF, PEG, and Parkinson disease F HLD and psoriasis
70
CS and AZA
DM
CMV,z skin and pulmonary
2
5100 mg Prednisone 45 mg (0.6 mg/kg); AZA 100 mg
Moderate activity
86
CS
NA
Legionella, pulmonary
3
Prednisone 25 mg
NA
72
CS and AZA
NAD
Legionella, pulmonary
1
57
CS
OP
Listeria meningoencephalitis
2
4960 mg Prednisone 95 mg (1.6 mg/kg); AZA 100 mg Prednisone 4375 mg 75 mg (1.2 mg/kg)
12
13
14
F HLD, fatty liver, and s/p thyroiditis
6260 mg
NA
No lesions
Ganciclovir; OI outcome unknown, death 4 years after OI of unknown causes Ganciclovir with recovery’ 9 months later, recurrent CMV pneumonitis and death because of respiratory failure Levofloxacin; full recovery, but death 6 months later because of urinary sepsis
Active disease
Levofloxacin; full recovery
Minimal activity
TMP-SMX plus meropenem; mild left-side hemiparesis
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AZA, Azathioprine; BPH, benign prostate hypertrophy; CHF, congestive heart failure; CMV, cytomegalovirus; CS, systemic corticosteroids; DM, diabetes mellitus; F, female; HLD, hyperlipidemia; HTN, hypertension; IHD, ischemic heart disease; M, male; MI, myocardial infarction; NA, not available; NAD, no appreciable disease; OP, osteoporosis; PEG, percutaneous endoscopic gastrostomy; PV, pemphigus vulgaris; PVD, peripheral vascular disease; SCC, squamous cell carcinoma; S/P, status post; TMP-SMX, trimethoprim-sulfamethoxazole. *Cumulative doses in milligrams. y Prednisone or prednisone equivalents per day. Numbers in parentheses indicate the corticosteroid treatment per day (mg/kg/day). z The diagnosis of CMV disease required compatible clinical findings and the detection of CMV using a validated method in the appropriate clinical specimen. In our institution, these include the shell vial (rapid culture) technique, CMV pp65 antigenemia, and polymerase chain reaction studies. Because pre-CMV serology was not available, differentiation of primary infections from virus reactivation could not be accomplished.
Leshem et al 5
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follow-up in \1 year for unknown reasons. To address the loss to follow-up during the first year of the study, we calculated the OI incidence during that period using the person-time incidence approach; the number of incident cases was divided by the observed person-years (summation of the months under follow-up per patient within the first year, translated into years). Using this approach, the OI incidence rate in the first year after pemphigus diagnosis was 9.3 OIs per 100 patients. Patient characteristics stratified by OI development are shown in Table I. Only 1 patient in the cohort was treated prophylactically with trimethoprim-sulfamethoxazole (TMP-SMX) because of triple immunosuppression (ie, CS, azathioprine, and rituximab), and he did not develop an OI during the follow-up period. In a univariable analysis, age at diagnosis and presence of diabetes were found to be significantly associated with OI development, while sex and treatment regimens were not. The associations between diabetes and age at diagnosis with OIs were reevaluated with a multivariable model, because the possibility of confounding arose because of the association of age and diabetes. Using a logistic approach, adjusted for the influence of diabetes, the association between age at diagnosis and OI remained significant and substantial, showing an additional 4% estimate of risk difference for each year of age (odds ratio [OR], 1.042; 95% confidence interval [CI], 1.002-1.084). The adjusted association between diabetes and OI, even though it presented a strong risk estimate (OR, 2.89), was of borderline significance (P = .068 [95% CI, 0.92-9.04]). Elaboration on the OI cases is presented in Table II. All patients were diagnosed with pemphigus vulgaris except for patient 6, who was diagnosed with pemphigus foliaceus. All patients were undergoing systemic CS therapy during OI development. The mean prednisone (or equivalent) daily dosage was 59 6 27 mg or 0.8 6 0.4 mg/kg (for 2 patients without a recorded weight, 70 kg was substituted). The mean cumulative prednisone dose was 7629 6 4170 mg. Five patients received concomitant azathioprine (1 more received azathioprine previously, but it was discontinued before OI development). No patients were neutropenic at the time of OI development. HIV status was checked in patients 1, 2, 4, 5, 11, 13, and 14, and was negative in all of these cases. Ten patients had minimal to no pemphigus activity during the OI, implying that disease severity is not related to this complication. Four patients suffered severe adverse outcomes. Two patients with CMV disease died; 1 during a
relapse of CMV pneumonitis (patient 11) and another of unknown causes 2 months after hospitalization for CMV (patient 7). The 2 patients who had central nervous system (CNS) involvement (patient 1, with Nocardia; patient 14, with Listeria) remained with neurologic impairment. The cumulative prednisone dose was significantly higher in patients who developed a Nocardia compared to a CMV infection (median 9140 mg vs 5100 mg, accordingly; P \ .01). There were no significant differences in age, CS dose, or the presence of diabetes mellitus at the time of OI among the different OIs.
DISCUSSION Patients with pemphigus are expected to be at risk for developing OIs because of their immunosuppressive treatments. However, only few such cases have been reported to date,8-13 limiting our understanding of this serious complication. This contrasts with other fields of medicine that deal with immunosuppressed patients, such as transplant medicine, oncology, and HIV medicine, which offer abundant knowledge on OIs. Some concluded that because of the paucity of reports, OIs are very rare in pemphigus patients,9 but our findings argue differently. In our cohort of 172 patients with pemphigus followed-up for a mean of 3.5 years, 14 patients developed OIs, all during the first year after diagnosis. The risk of developing an OI in that first year was 9.3%, while no risk was shown later. Some OIs led to devastating outcomes. One patient died an OI-related death, another died in temporal proximity to the OI, and 2 patients remained with permanent neurologic and functional impairment. It is important to recognize these unusual infections, because dermatologists are often the primary physicians attending to these patients because of their chronic skin disease and complex immunosuppressive therapy. Our study highlights a few important findings that were not discussed previously in the literature. The patients in our cohort developed OIs at a mean of 4 months from the initiation of pemphigus treatment while taking a mean prednisone dose of 0.8 mg/kg/ day. Therefore, OIs did not develop while patients were taking maximum daily CS doses (1-2 mg/kg at treatment initiation16), but rather on lower daily doses yet after several months of cumulative CS exposure. Of note, adjuvant azathioprine in standard daily doses was administered to 5 of the patients when they developed an OI. The patients who developed OIs were significantly older than patients who did not (mean age, 66 vs 54 years). In a univariable analysis,
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diabetes mellitus was also significantly associated with OIs, but this association became less significant when adjusting for age (P = .068). However, this attenuated result could be attributed to the paucity of diabetes cases in the study and does not necessarily reflect the lack of impact of diabetes on the development of OIs. The opportunistic pathogens observed in our study include, in decreasing frequency, Nocardia, CMV, Legionella, and Listeria, which are known to cause OIs17-21 in patients with impaired cell-mediated immunity.14,15 Of interest is the unexpectedly high incidence of Nocardia cases, comparable to reported frequencies of nocardiosis in solid organ transplant patients.18 Several studies reported high-dose chronic CS treatment to be the major risk factor for nocardiosis,22,23 highlighting the strong association of this treatment modality with nocardiosis. Acquaintance with the varied clinical presentations of these OIs is crucial, because they may require unique diagnostic tests (eg, selective culture media and prolonged observation for Nocardia colonies) and specific treatments differing from those targeting more common pathogens. Febrile pemphigus patients with no clear infectious foci should be evaluated for OIs, especially CMV and Nocardia. In pemphigus patients with CNS disease, clinicians should assess for Nocardia24 and Listeria,25 which can cause invasive CNS infections, and consider empiric antibiotic coverage against these organisms. With pulmonary infections, bear in mind pathogens such as Nocardia, CMV, and Legionella in addition to the common respiratory pathogens. When treating abscesses and local wounds, think beyond S aureus and include Nocardia in the differential diagnosis. Finally, CMV can involve almost every organ system. CMV disease can present as CMV syndrome (ie, viremia with symptoms including fever and malaise) or tissue-invasive disease (ie, colitis, pneumonitis, and hepatitis),26 as represented in our cohort. Dermatologists should also be aware of the possible involvement of the skin by CMV,27,28 as in patient 11, who presented with fever and refractory ulcers different from his pemphigus lesions (Fig 2), which were found to be a part of his CMV disease. CMV infections developed on lower cumulative CS doses than Nocardia infections. The use of CS-free transplant protocols lowers the incidence of CMV disease, but it remains to be seen if lowering CS doses could offer the same benefit in pemphigus.29,30 Although our study was not designed to assess the utility of prophylactic therapy, we will briefly discuss prophylaxis for OIs. The major prophylactic interventions include antibacterial prophylaxis
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Fig 2. Cutaneous cytomegalovirus infection in a patient with pemphigus (patient 11). Round, punched-out ulcers covered with scale crust on the neck (A) and forearm (B).
against Pneumocystis jirovecii pneumonia (PCP), possibly effective against Listeria and Nocardia, and antiviral prophylaxis. These measures have been shown to be beneficial in immunosuppressed populations, such as HIV-infected patients,5 hematologic cancer patients,31 and solid organ transplant patients.32 Previous studies could not justify PCP prophylaxis in patients treated with CS for immune-mediated dermatologic conditions.33-35 This means that the risk:benefit ratio of this treatment as Listeria and Nocardia prophylaxis needs to be addressed separately. The magnitude of risk reduction by TMP-SMX for these pathogens is unknown. Moreover, there are increasing reports of breakthrough infections by TMP-SMXesusceptible Nocardia isolates, creating doubt about the use of this agent for the prevention of nocardiosis.18 Future prospective studies designed to assess the value of this or other interventions are needed. This is also true for CMV prophylaxis with ganciclovir, which has been proven effective in patient populations with much higher rates of CMV disease, such as bone marrow transplant patients.36 It is noteworthy to mention patient guidance strategies derived from the findings in our study, because they may help limit exposure to potential pathogens. This includes hand washing after food
8 Leshem et al
preparation and gardening, avoiding crosscontamination by washing all utensils and surfaces, especially after preparation of meat,37 and avoidance of close contact with people who have respiratory illnesses. Dietary advice might include avoidance of raw milk, unpasteurized soft cheeses, delicatessen meats, inadequately heated hot dogs, and smoked seafood, because these items can be highly contaminated with Listeria. These are simple, health-promoting measures that can be advocated by the dermatologist. When interpreting our results, it is important to stress that our study design a priori excluded conditions such as aseptic meningitis and several other pathogens—most notably S aureus. We did not consider S aureus to be an opportunistic pathogen because the immune impairments related to its virulence38—the most important being defects in neutrophils39—are generally not caused by pemphigus treatments. Moreover, the breach of the skin barrier key to S aureus infection is related to underlying pemphigus and not immunosuppresion.39 Nevertheless, S aureus is an important pathogen in pemphigus patients, and has been reported to be causative in a majority of infection-related deaths.40 We used a historical approach to data extraction from written records, limiting data availability regarding risk factors associated with OI development. Nevertheless, the overall study is of a prospective (cohort) nature, enabling the calculation of incidence rates. The number of OIs could have been underestimated because of the potential omission of OIs occurring in institutions outside of our database. Although the observed infections are not endemic to Israel, outcomes may differ in other locations. Additional studies in diverse patient populations could expand on the generalizability of our results. To our knowledge, this is the first study on OIs in a large group of patients with pemphigus, and we found a significant risk of OIs during the first year after pemphigus diagnosis. Although most patients fully recovered, some suffered severe outcomes, including death. The dermatologist is required to be well acquainted with the different OIs to make a timely diagnosis. A high index of suspicion is essential, especially throughout the first year after the initiation of immunosuppressive treatment—and more so in older and possibly diabetic patients. Educating patients on limiting pathogen exposure is recommended. Whether lower immunosuppressant exposure could reduce the occurrence of OIs while maintaining pemphigus control needs to be addressed in future prospective comparative trials, as does the value of prophylactic therapies.
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