DOI: https://doi.org/10.21203/rs.2.9517/v1
Nocardiosis is an either acute purulent or chronic granulomatous disease caused by the infection of nocardia bacteria, which is a gram-positive branching rod-shaped aerobic bacterium from the genus Actinomyces[1, 2]. Nocardia is an opportunistic pathogen with a relatively low incidence, and it's usually infectious in the immunocompromised patients, such as autoimmune disease or receiving immunosuppressive treatments. They can cause local or disseminated nocardiosis in humans. With the immunosuppressive agents becoming more and more popular, the incidence of nocardiosis is increasing as well[3-5]. Patients with myasthenia gravis (MG) are commonly treated with immunosuppressive agents for a long time and have the potential risk of nocardia infection.
Nocardiosis is a life-threatening infectious disease, especially when the patients can't be treated appropriately in the early stage of the disease. However, the heterogeneous clinical presentations and laboratory test limitations make the diagnosis of nocardiosis very difficult. Therefore, it is important for physicians to diagnose the disease and treat the patients in time. Here, we present a case of disseminated nocardiosis in MG patient with multiple systems involved, based on which we also made a literature review.
A 66-year-old Chinese man presented with fever, cough, dyspnea and lumbodynia after falling from an exercise equipment on July 6, 2015. He had a medical history of blood hypertension and diabetes mellitus. He was diagnosed as generalized MG and received glucocorticoids therapy since November, 2014. The maximum dose of methylprednisolone was 56mg per day, which had been tapered to 20mg per day when he came to the emergency. In addition, he also took 100mg azathioprine daily for MG therapy.
Physical examination disclosed that the patient had a temperature of 38 centigrade degrees. Other vital signs waved in normal range. There were multiple rales in the bilateral lungs on auscultation. Multiple, irregular, and tender masses were found on patient’s chest, back, neck, and right limbs. These masses were high temperature and red color. There was an infectious ulcer mass on the right lower limb. Except for the weakness of the right lower limb (5-/5), there were no other abnormal findings on neurological examination.
Routine laboratory investigations, including blood routine tests,hepatic and renal functions,electrolyte and coagulation function, were in normal range. C reactive protein (CRP) was 37mg/L (normal range <5mg/L). Tuberculosis infection T lymphocytes and Anti-tuberculosis antibody were not positive. Antibodies of Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), Human Immunodeficiency Virus (HIV) and syphilis were negative.
The lumbar spine X-ray scan showed there were compressive fractures in L1 and L2 vertebral body. Neck Computed Tomography (CT) scan found a mass on the left, and the diagnosis of swollen lymph node, abscess or tumor was considered (Figure1A). Chest CT scan revealed multiple nodular and patchy shadows in bilateral lungs, and pleural effusion as well as pericardial effusion (Figure1B-C). Abdomen CT scan found gallstone and a small cyst on right renal.
The patient was diagnosed as pneumonia and received moxifloxacin treatment. The patient’s body temperature gradually returned to the normal range, and cough as well as dyspnea also relieved after treatment. However, he had fever with chill, heavy dyspnea, headache, and pain on right leg after 20 days of treatment. He also felt great pain in the left eye, and the vision became blurred and rapidly aggravated to blindness. For the differential diagnoses, both brain CT scan and Magnetic Resonance imaging(MRI) were performed. In the end, the CT scan showed multiple low-intensity lesions in different brain areas, and MRI revealed marked multiple abnormalities in bilateral cerebrum and cerebellum with low signal intensity on T1-weighted images as well as high signal intensity on T2-weighted images. After administration of gadolinium contrast material, these lesions demonstrated ring-enhanced (Figure2A-D). Accordingly, diagnoses of abscess or multiple brain metastases were considered. Importantly, MRI of orbit showed abnormal enhanced lesion behind left eyeball and retinal detachment (Figure3A-C). In order to identify the characteristics of these lesions, we performed the percutaneous drainage from the mass on the left neck guided by ultrasound. Nocardia bacteria was found from the culture of puncture fluid, and so the diagnosis of disseminated nocardiosis was confirmed.
After the diagnosis of nocardiosis, the patient was treated with trimethoprim-sulfamethoxazole (TMP-SMX) tablets (TMP0.08g+SMX0.4g/per tablet), 2 pills every 8 hours. In the meantime, imipenem/meropenem/ceftriaxone and sporanox were also given for the bacteria and fungus infection. 2 weeks later, the patient was found leukocytopenia, and then received bone marrow puncture examination. The result indicated a suspected diagnosis of Myelodysplastic syndrome (MDS). The therapy of TMP-SMX tablets was adjusted to1 pills every 12 hours plus etimicin sulfate injection. Meanwhile, the therapy of azathioprine was replaced with berbamine in order to treat leukocytopenia. 3 weeks later, the patient had TMP-SMX tablets alone, 1 pills every 12 hours. After the treatment, except for the left eye blindness, all the symptoms, including fever, dyspnea, headache, pain in the leg and left eye, were remitted gradually. In addition, one month of TMP-SMX treatment also reduced pleural effusion and bilateral lung lesions from repeat chest CT results (Figure 1D). One and half months of TMP-SMX treatment, multiple brain lesions became smaller or even disappeared from repeat brain MRI (Figure2 E-H). Following the in-hospital treatment, the patient was continuously out-hospital treatment with TMP-SMX tablets, 1 pill every 12 hours for one and a half years. The blood cells were monitored every two weeks. Six months after discharge, the subcutaneous masses disappeared, and the repeat brain MRI showed that the encephalic lesions disappeared as well. To that end, the dose of methylprednisolone was taped slowly till stopped because of the improvement of his myasthenia gravis, and there were no recurrent syndromes at 2 years’ follow-up.
Disseminated nocardiosis is defined as two or more noncontiguous sites of involvement, including pulmonary focus or not. The infection in our patient involved multiple systemic organs and nocardia bacteria was found by the culture of puncture fluid, based on which the diagnosis of disseminated nocardiosis was established. After receiving combination antibiotic treatment, the patient almost completely recovered from the disease.
The clinical manifestations of nocardia infections are very heterogeneous and nonspecific. Lung, brain and skin are the most common affected sites[6]. Lung is the primary site for nocardia infection in more than 70% patients. Brain infection is found in approximately 20% cases. The infection also involved skin, muscle, heart, and kidney. Our patient had the lesions in these common sites, including lung, brain, and skin. Furthermore, ocular tissue of our patient was also involved, which finally induced retinal detachment. To our best knowledge, this is the first case report of disseminated nocardiosis with ocular lesion in MG patients.
Ocular tissue is an unusual site for disseminated nocardiosis, and the ocular infection generally is diagnosed as local nocardiosis, presented with keratitis or endophthalmitis from ocular trauma or surgery [7]. Occasionally, the ocular infection might also be caused by hematogenous dissemination via the choroidal circulation [8]. The ocular nocardia infection in our patient may be caused by the hematogenous spread because the patient didn’t have eye trauma or surgery history, or had any abnormal signs on his eyeball. The prognosis of ocular nocardiosis is generally poor. Blindness was a common consequence, and ophthalmectomy was given in about 30% of patients. For these reasons, regular ophthalmologic screening should be performed in patients with suspected disseminated nocardiosis [8, 9]. In our patient, the ocular lesion located behind left eyeball which finally led to retinal detachment. After given suitable treatment, the ocular lesion completely vanished, but the vision was not restored.
Due to the paucity of trials, there are no formal guidelines to direct drug choice and treatment duration for nocardiosis. Most clinicians would agree that CNS nocardiosis warrants a long course of treatment, and 12 months is commonly recommended [10]. Empirical treatment of disseminated nocardiosis is usually with three antibiotics, including imipenem or ceftriaxone, TMP-SMX, and amikacin. TMP-SMX is thought as the cornerstone of treatment for nocardia infections, and it is also the drug of choice for cerebral nocardiosis due to its good penetration in the CNS. Other drugs, including meropenem, cefotaxime, minocycline, moxifloxacin, levofloxacin, linezolid, tigecycline, and amoxicillinclavulanicacid, are also used for the treatment [11]. Patients with nocardiosis often have underlying autoimmune disease or with immunosuppressive treatment. Therefore, the combination antibiotics is recommended in the beginning, and single drug can be maintained after the clinical symptoms are relieved [11]. Before the definitive diagnosis, our patient was treated empirically with moxifloxacin and imipenem, which were also suitable for treatment of nocardiosis. But the patient’s body temperature decreased temporarily, and exacerbated again some days later. It indicated that these drugs were not sufficient for the illness in our patient. After definitive diagnosis with nocardiosis, the patient received TMP-SMX in combination with ceftriaxone and etimicin therapy in short time, and then switched to TMP-SMX alone for one and half years.
Because of the nonspecific manifestations of nocardiosis, most patients with nocardia infection are not diagnosed in early stage of the disease, and it normally took from 42 days to 12 months for clear diagnosis after the appearance of symptoms [12, 13], which caused a lot of both physical and emotional burden to these patients. The prognosis of nocardiosis is depend on the location and severity of infection as well as the overall condition of the patients. The curable rate of pulmonary nocardiosis was about 90% with in time treatment, while the one-year mortality rate of patients with CNS involvement is high. The mortality in patients with solid organ transplantation from nocardiosis was 10-fold higher than those without [11, 14].
In general, Nocardia bacteria is opportunistic bacteria and mainly infects immunocompromised patients. Even though MG is an autoimmune disease with often immunosuppressive treatments, the nocardia infection was rarely observed in these patients. We then performed the literature review by searching the MEDLINE database using the key words “nocardia,” “nocardiosis, “and “myasthenia gravis.” To date, only 7 case reports of MG patients with nocardiosis from our literature study[15-20]. To further understand the disease process, we summarized the clinical characters of these patients which were listed in table 1. Interestingly, only one female was found, and the rest were male with median age at 59 years old. Among these MG patients, 3 patients also had thymoma, 1 patient had tuberculosis in the young period and 1 patient had Good’s syndrome. All the patients had been treated with glucocorticoids and other different immunosuppressant, such as tacrolimus and cyclosporine. 3 patients received thymectomy. Similar to these patients in the literatures, the patient in our report was a 66-years old man, and he was given glucocorticoid and azathioprine therapy for 8 months before he had nocardia infection. From the literatures and our case, the following factors maybe the preconditions for nocardia infections in MG patients. The primary factor was the usage of immunomodulator and/or immunosuppressive agents, which were consistent with the previous numerous literatures[11, 14]. The second factor was the age. These MG patients were all middle aged and even older people. According to the epidemiologic studies the peak age of MG patients was either 20-30 years or 50-60 years old. Given our finding that MG patients with nocardia infection was 49-79 years old, which was close to MG patients with age at 50-60 years old, and so the older patients with MG might be more susceptible to narcodosis. The last factor maybe the gender, which is based on that 6 out of 7 MG patients with nocardia infection was male. In sum, the old male MG patients with immunomodulator and/or immunosuppressive agents might be the susceptible population for nocardia infection.
Nocardiosis is a life-threatening infectious disease, diagnosis in early stage and appropriate antibiotic therapy is crucial for prognosis. Ocular involvement is rare in disseminated nocardiosis, patients who are suspected having disseminated nocardiosis should receive ophthalmologic screening. Neurological physicians should be aware of the nocardia infection in MG patients.
MG:Myasthenia gravis CRP:C reactive protein HBV:Hepatitis B Virus HCV:Hepatitis C Virus HIV:Human Immunodeficiency Virus CT:Computed Tomography MRI:Magnetic Resonance imaging TMP-SMX:trimethoprim-sulfamethoxazole MDS:Myelodysplastic syndrome CNS:Central nervous system
Ethics approval and consent to participate
The institutional review board of Beijing Friendship Hospital approved this case report. Written informed consent was obtained from the patient for the publication of the present case report.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and material
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Competing interests
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding
This work was supported by Research Foundation of Beijing Friendship Hospital, Capital Medical University (No. yyqdkt2018-30).
Authors' contributions
SHW: patient examination, medical data collection, and article preparation; BJ and YL: patient examination and medical data collection; YCS and ZSL: medical data analysis, article preparation, and correction and translation; YBZ: medical and scientific consultation, and article preparation.
Acknowledgements
We thank Prof. Henry Kaminski (The George Washington University) for his valuable suggestions on the writing of the paper.
Table 1 Clinical characteristics of MG patients with disseminated nocardiosis.
Case |
Age /sex |
Y |
Symptoms |
Underlying disease |
Immune suppression |
Operation |
Sites of disease |
Treatments |
Outcome |
1 |
59/male |
Kim 2002 |
skin lesions; fever; cough |
MG; thymoma |
prednisolone |
thymectomy |
skin; lung |
sulfamethoxazole-trimethoprim |
resolution |
2 |
49/male |
El-Herte 2012 |
fever, chills, chest pain, weight loss |
MG; thymoma |
prednisone |
thymectomy |
lung;brain;heart |
Imipenem;amikacin; trimethoprim; sulfamethoxazole |
resolution |
3 |
59/female |
Tanioka 2012 |
malaise; cough |
MG |
Prednisolone;tacrolimus;Cyclosporine |
na |
lung; kidney; brain |
imipenem-cilastatin;trimethoprim;sulphamethoxazole;minocycline;meropenem;amikacin;linezolid |
resolution |
4 |
79/male |
Patel 2013 |
left leg pain, cough |
MG |
prednisone |
na |
Leg; lung |
moxifloxacin |
na |
5 |
77/male |
Garcia 2015 |
night sweats, cough |
MG;TB |
Prednisone; plasmapheresis |
thymectomy |
lung;brain |
trimethoprim;sulfamethoxazole; meropenem;linezolid |
resolution |
6 |
79/male |
Veerappan 2015 |
leg abscesses |
MG |
steroid |
na |
lung; muscle |
Vancomycin;piperacillin-tazobactam;ampicillin; ceftriaxone; doxycycline;moxifloxacin;linezolid |
resolution |
7 |
52/male |
Wargo 2015 |
cough, dyspnea, weight loss, subcutaneous nodules, fatigue |
MG;thymoma;Good’s syndrome |
Prednisone;chemotherapy;radiation |
na |
Lung,skin;brain |
Meropenem;trimethoprim/Sulfamethoxazole;imipenem;Linezolid |
resolution |
8 |
66/male |
Wang 2017 |
fever; dyspnea; headache; pain on left eye and right leg; skin ulcer; blindness; muscle strength decreased; |
MG |
Methylprednisolone; azathioprine |
na |
lung;brain;skin; ocular |
TMP-SMX; etimicin sulfate ; moxifloxacin; ceftriaxone;imipenem; meropenem |
resolution |