4 pathogenic bacterial co-infections! Patients with nephrotic syndrome are complicated by severe pneumonia

preface

Severe pneumonia is caused by different etiologies and different pathogens caused by inflammation of lung tissue (bronchiolar alveolar stroma) to a certain stage of disease, worsening and aggravating the formation, causing severe ventilation and ventilation dysfunction of the lungs, as well as systemic organ dysfunction and even life-threatening [1].

In this case, the patient was complicated by severe pneumonia after more than 2 months of oral administration of glucocorticoids due to nephrotic syndrome, and mixed infection with Nocardia, Aspergillus spp.

Case passed

The patient, Chen Mou, male, 71 years old, 2022-02-28 to 2022-03-05 was hospitalized in a local hospital for "sudden edema of both lower extremities for 2 days", diagnosed with nephrotic syndrome, and continued to "prednisone acetate tablets 55mg po qd" for two months
after being discharged from the hospital.

2022-5-13 Due to "dry mouth and drink for half a month, mouth corner ulcer for 1 week, cough and sputum cough for more than 1 month" to our hospital emergency department
.

Figure 1 2022-05-13 CT chest

Admission symptoms see: mental tiredness, dry mouth and drinking, blurred vision, lack of strength and shortness, cough and cough of yellow phlegm, ulceration of the right corner of the mouth, redness and swelling, exudate, numbness of both upper limbs, no fever and chills
.

Previous: hypertension, nephrotic syndrome, denial of diabetes mellitus
.

Initial treatment options: intravenous insulin control of blood glucose, moxifloxacin sodium chloride injection anti-infective
.

Complete the relevant examination after admission (2022-5-14): blood gas analysis: blood pH: 7.

2022-5-14In the morning, the endocrinology department sent the morning sputum specimen of the patient to the microbial room for bacterial culture and smear to check the bacteria for two examinations, the smear Gram stain can see more gram-positive mycelia filamentosis, weak acid-resistant staining is positive (Figure 2), the laboratory telephone contact clinical, smear preliminary consideration of Nocardia infection, specific identification results and other follow-up culture
.

Image

Fig.

2022-05-15In the morning, the patient's shortness of breath was significantly worse
than before.

Fig.

2022-05-16 Microbial chamber report results: Nocardia was identified as African/Nocardia neonocardia by Merrier VITEKMS mass spectrometer (Figure 4); Aspergillus is Aspergillus fumigatus and Aspergillus flavus (Figures 3d, e); Alveolar lavage fluid hexaamine silver staining to find pneumocystis cysts (Figures 3g, h); serum (1,3)-β-D dextran (G test) 199.

Fig.

2022-05-17Review blood routine: leukocytes: 18.

Figure 5 2022-05-17 Chest CT

2022-5-20 Results of multiple combination tests (tNGS) of respiratory pathogens sent to a third-party testing center on May 18 (Figure 6): Pneumocystis jirba (sequence number 49315), Haemophilus influenzae influenzae (sequence number 19), Mycobacterium tuberculosis complex (sequence number 3), herpes virus in person (sequence number 1893).

Figure 6 tNGS result return

2022-5-21The patient is critically ill, with unstable vital signs and poor prognosis
.
Family members of the patient abandon active treatment
.

Case studies

Clinical case studies

The patient is an older male with a history of nephrotic syndrome and a history
of heavy hormone use.
Due to pneumonia and steroidal diabetes, the onset of the disease was slow, and the disease progressed rapidly after admission, and sputum specimen smears and cultures detected Nocardia, Aspergillus spp.
, Pneumocystis jirba and Mycobacterium
.
The cases of simultaneous co-infection of 4 rare bacteria and their rarity also reflect the serious damage to the patient's immune system, which greatly increases the difficulty of treatment, and requires a combination of multiple antibacterial drugs for treatment, and the treatment time is long and the cost is high
.
Early diagnosis and early treatment are of decisive significance for the prognosis
of the patient.
After the patient was admitted to the hospital with the assistance of the microbiology laboratory, the pathogenic bacteria were quickly clarified, we used the drug in time, the patient's basic condition was poor, despite the active treatment, the pneumonia continued to progress, the condition was critical, and the patient's condition improved not significantly under the support treatment of anti-infection, respiration, circulation, blood filtration, etc.
, and finally the family gave up active treatment
.

Inspection case studies

After receiving the patient's specimen, the microbiology room carefully reads the film, analyzes layer by layer, looks for clues, actively communicates with the clinic, puts forward relevant examination suggestions to the clinic, actively cooperates clinically, and clarifies the co-infection of 4 pathogenic bacteria in a relatively short period of time through the simplest morphological method, which is basically consistent with the molecular detection results of the follow-up third-party for testing, providing a very timely and effective pathogenic basis
for the clinical diagnosis and treatment of patients 。 Among them, tNGS did not detect Nocardia and Aspergillus nocardia, and the analysis found that the bacteria library of the test item did not contain African/neonocardia; The absence of Aspergillus may be due to too few sequences or due to the difficulty of extracting the fungal wall
.

Combined with the clinician's analysis of the patient's situation: the patient has a high-risk host factor for fungal infection, multiple nodules and mass shadows can be seen on chest CT, and the original sputum direct smear can find Aspergillus hyphae, alveolar lavage fluid GM test > 5.
0, and it is considered that the possibility of coexisting Aspergillus infection is very large
.
For patients with nephrotic syndrome, autoimmune diseases and other patients who need to take glucocorticoids for a long time, there are different degrees of immune damage, it is easy to become infected, lung infection is the most common, clinically such patients should be vigilant against the possibility
of infection of opportunistic pathogenic bacteria such as Nocardia, Aspergillus and Pneumocystis jirba and so on.
Sometimes the simplest and most economical morphological approach can be used to give the greatest help
to the clinic and the patient.

Knowledge development

1.
Nephrotic syndrome

Nephrotic syndrome is a group of clinical syndromes characterized by massive proteinuria (≥ 3.
5 g/d) and hypoalbumin (≤30 g/d) and is usually accompanied by edema, dyslipidemia, coagulation/fibrinolytic system abnormalities, decreased renal function, and immune disturbances
.
The disease may be seen in primary or secondary glomerular lesions
.
Because of its powerful anti-inflammatory, immunosuppressive, anti-allergic and anti-shock effects, glucocorticoids are widely used in clinical practice and are also the drugs
of choice for the treatment of nephrotic syndrome.
Corticosteroids play a major role in the treatment of systemic diseases, but long-term use of large amounts of hormones can also bring many side effects to the body, such as Corshing syndrome, severe infections, osteoporosis, peptic ulcers, and steroidal diabetes [2].

The main mechanism is to inhibit the phagocytic function of neutrophils and monocytes/macrophages, interfere with their killing of bacteria and fungi, create conditions for some conditionally pathogenic bacteria, and invade the body with severe infection[3].

In this case, the patient has no previous history of diabetes, and the infection is further aggravated by steroidal diabetes mellitus secondary to the use of glucocorticoids, because the phagocytic function of neutrophils is inhibited in the hyperglycemic state and the body's resistance is reduced; At the same time, a high-sugar environment can promote the growth and reproduction of pathogenic bacteria[4].

Insulin is the drug of choice for the treatment of steroidal diabetes, and the difference with type 2 diabetes is that it is rarely complicated by ketoacidosis, and the high-sugar state can mostly improve
rapidly with the reduction of hormones.
Therefore, for patients who need to take glucocorticoids for a long time, follow-up monitoring of blood glucose and prevention of infection
must be closely strengthened.

2.
Nocardia pneumonia

Nocardia is gram-positive filamentous or beaded mycobacteria, negative for acid staining, weak acid staining (decolorant is 1% aqueous sulfuric acid solution), relatively slow growth, generally takes 2 to 7 days, widely present in soil, decaying plants, dust and water
.
Mainly caused by skin contact or respiratory inhalation, the most common involvement is the lungs, and the susceptible population is those with cellular immunodeficiency or impairment, and glucocorticoids have been found to be most closely related to the occurrence of nocardiosis [5-7].

The clinical symptoms and imaging manifestations of Nocardia pneumoniae are not specific, and are common symptoms of respiratory infections such as fever, cough, and cough of yellow purulent sputum; CT may manifest as bronchiectasis, ground glass shadows, patches or lung consolidation of the lungs, single or multiple nodules, and cavitation formation
.
The treatment of Nocardia is mostly advocated in combination, and the preferred combination of sulfamethoxazole and imipramine is recommended according to fever, and the alternative is imipenem plus amikacin
.

The Nocardia bacteria isolated in this case were identified by mass spectrometry as Nocardia Africana/nova
.
Both are closely related to Nocardia africana and Nocardianova, both of which belong to the Nocardianova Complex, which is classified as a protostar Nocardia III type, including Nocardiaveterana and unnamed species
.
The VITEKMS mass spectrometry identification system version 3.
0 used in our laboratory cannot distinguish them and requires further 16SrRNA sequencing
.
We compared to CLSIM24 standard for its susceptibility test, 8 drugs except ciprofloxacin (MIC>=4) and gentamicin (MIC=16) resistance to the rest are sensitive, sensitive drugs MIC values are as follows: compound sulfameoxazole < = 0.
5/9.
5, ceftriaxone 8, cefpyrime 8, imipramine< = 1, amikacin < = 4, linezolid 2
.
From the results of in vitro drug susceptibility, the combination of compound sulfamethoxazole and imipernem selected in clinical experience is an effective solution
for the treatment of Nocardia.

3.
Invasive pulmonary aspergillosis

Aspergillus is one of the most widely distributed fungi in nature, its spore size is 2 ~ 5 μm, easy to suspend in the air and spread with the air flow, after entering the human respiratory tract can temporarily adhere and resident, if the inhalation amount is large or human immune function damage, can grow in the lungs and cause disease
.
The most common cause of pulmonary aspergillosis is Aspergillus fumiganus, followed by Aspergillus flavus, Aspergillus niger, and Aspergillus terrevisiae
.
There are three main categories of pulmonary aspergillosis: invasivepulmonary aspergillosis IPA, chronicpulmonary Aspergillosis CPA, and allergic bronchopulmonary aspergillosis ABPA
.

CPA refers to chronic pulmonary Aspergillus infection, the course of the disease is more than 3 months, often occurs in patients with pre-existing lung disease or mild immunosuppression; In this case, pneumonia has a short onset of disease, and Aspergillus infection belongs to IPA, and if IPA does not respond well to treatment, it can progress to fatal pneumonia, which is the main cause of death [9
].
Aspergillus is a conditioned pathogen that can easily cause opportunistic infections in immunocompromised hosts
.
Risk factors are high risk factors (> 65 years), COPD, diabetes, long-term use of broad-spectrum antibiotics, and high levels of glucocorticoids
.
The history of extensive use of hormones and the hyperglycemic status of this patient provided favorable conditions
for the invasive infection of Aspergillus.

4.
Tuberculosis

Tuberculosis is a chronic infectious disease caused by tuberculosis infection, widely popular around the world, is a public health and social concern worldwide, of which pulmonarytuberculosis is the most important type of
tuberculosis.
The pathogens of tuberculosis are a complex of tuberculosis bacteria, including Mycobacterium tuberculosis, Mycobacterium bovis , Mycobacterium africanus, and Mycobacterium vole vole, and 90% of the pathogens of human tuberculosis are Mycobacterium tuberculosis [11
].

People susceptible to tuberculosis include infants and young children with imperfect cellular immune systems, the elderly, people living with HIV, glucocorticoids and immunosuppressant users, and patients with chronic diseases such as diabetes and pneumoconiosis [11].

Clinical symptoms are fever (mostly afternoon hot flashes), fatigue, night sweats, weight loss, cough, sputum production, may be accompanied by hemoptysis, dyspnea, etc
.
Chest x-ray is the conventional preferred method for diagnosing tuberculosis, and the lesions are polymorphic and can be co-existing with infiltrates, proliferation, cheese, and fibrocalciferous lesions, which are prone to cavitation and transmission foci
.
Direct smear to find acid-fast bacilli is simple, rapid, and easy, but the sensitivity is low, and a positive only indicates the presence of acid-fast bacteria in sputum and cannot distinguish between tuberculous and non-tuberculous diseases
.
TB culture is often used as the "gold standard" for TB diagnosis, but the culture cycle is long
.
Molecular biology diagnostic methods detect the nucleic acids of tuberculosis bacteria in specimens, with good sensitivity and specificity, and are safe and reliable [12].

5.
Pneumocystis jirba pneumonia

Pneumocystis is an opportunistic pathogenic fungus that primarily causes pneumocystis pneumonia
.
Pneumocystis parasitizes in the lungs of almost all mammals and is parasitized in humans called Pneumocystisjiroveci (PJ
).
Pneumocystis can parasitize in immunocompetent people without clinical symptoms, while in immunocompromised or immunocompromised people, such as HIV infection, tumor chemotherapy, organ transplantation, long-term use of glucocorticoids or immunosuppressants, once infected with Pneumocystis bacteria, it will multiply and cause pneumonia and even death [13].

Three forms of Pneumocystis have been found to develop: trophozoans, cysts, and spores-containing cysts (or endosomes
).

Pneumocystis has not been able to be cultured in vitro to date
.
Because the cyst wall is rich in 1,3-β-dextran, which can be stained by high-iodic acid-schiff and silver, the trophosome does not contain this component, so the hexaamine silver staining can only see the cyst form and not the trophozoic form
.
Most of the clinical symptoms of Pneumocystis pneumonia are a triad of fever, cough, and dyspnea after activity, elevated lactate dehydrogenase (LDH), 1,3-β-dextran (G test) levels, and decreased arterial oxygen partial pressure (PaO2), usually less than 75 mmHg, which continues to decrease as the disease progresses; Imaging is bilateral hilaria-centered ground glass transformation
.
In this case, the patient due to long-term large doses of glucocorticoids complicated by pneumonia, belongs to the high-risk population of pneumocystis infection, and the blood LDH is elevated, the arterial partial pressure of oxygen is progressively reduced, and the laboratory highly suspects that the patient may be infected with Pneumocystis jirophyllaris, so it is necessary to contact the clinical improvement of the alveolar lavage fluid hexaamine silver staining for testing, and finally confirmed that the prejudgment is correct
.
The progression of pneumocystis pneumonia in HIV-infected patients is relatively slow, and the disease progression in non-HIV patients is rapid and dangerous [14
].

The pathogenic mechanism of Pneumocystis is mainly the attachment of the organism to the type I alveolar epithelium, causing the host's own inflammatory response, resulting in severe diffuse pulmonary damage and obstruction of gas exchange, further leading to hypoxia and respiratory failure [15].

The cell wall of Pneumocystis is rich in cholesterol, unlike other fungi that contain ergosterol, so it is not sensitive to azole and polyene antifungals with ergosterol as the binding site, but echinococin with β-1,3-dextran as the binding site can be used as therapeutic agents [16].

。 Recommend co-trimoxazole (TMP-SMX) as the drug of choice for the treatment of pneumocystis pneumonia according to fever treatment guidelines; The secondary drugs are clindamycin, primaquine, pentamidine and the like; If the patient shows no signs of improvement after 4 to 8 hours of treatment, treatment is considered to have failed and clindamycin and primaquine or pentamidine can be switched to, or capofenazine can be added as a salvage option
.

Case summary

The patient in this case was hospitalized
for steroidal diabetes mellitus and pneumonia after long-term oral administration of large amounts of glucocorticoids for the treatment of nephrotic syndrome.
After the microbiology laboratory found clinically rare pathogenic bacteria in the process of testing the patient's specimens, it took the initiative to communicate with the clinic, understand the patient's condition, carefully analyze, and put forward suggestions for supplementing and improving the relevant test items to the clinic, and actively cooperated with the clinical examination, assisting the clinic to clarify in a short period of time that the patient's pneumonia was jointly caused by
four pathogenic bacteria, Nocardia, Aspergillus, Mycobacterium tuberculosis and Pneumocystis jer.
It provides a very timely and powerful pathogenic basis for the timely diagnosis and treatment of patients and rational adjustment of drug use in
the clinic.
The patient's sputum culture and alveolar lavage fluid after admission to the hospital were detected with short detection time and high efficiency, which played a decisive role
in the choice of antibiotics in patients with severe clinical infections.
Rapid and accurate pathogenic diagnosis is crucial to the patient's prognosis, and the patient's access to targeted treatment of the pathogen can accelerate the patient's recovery, save medical costs for the patient, and save medical resources
for the society.

Through this case, we deeply understand that the clinical department and the laboratory department are complementary, and the two sides should establish a good communication and collaboration mechanism in order to better improve the detection rate and detection efficiency
of pathogenic bacteria in patients with infectious diseases.
The detection of pathogenic bacteria is inseparable from the full assistance of colleagues in the microbiology department of the laboratory department, and clinicians need to take the initiative to communicate with the laboratory staff when encountering special cases, inform patients of basic diseases and therapeutic drugs, and prompt pathogenic bacteria that need to be paid attention to, so that laboratory work can be targeted
.
Laboratory personnel should continue to strengthen the study of professional knowledge and pay attention to the cultivation of clinical thinking, take the initiative to go out of the laboratory, to the clinical promotion of laboratory projects and new technologies, to understand the needs of clinicians and nurses, to participate in clinical consultations and difficult case discussions, to learn from each other, in order to make progress together, in order to better serve patients
.

Expert reviews

This patient with nephrotic syndrome was admitted to the hospital
due to long-term heavy use of hormones complicated by steroidal diabetes mellitus and pneumonia.
With the full collaboration and joint efforts of clinical and microbiology laboratories, the mixed infection
of four atypical pathogens, namely Nocardia, Aspergillus spp.
, Mycobacterium and Pneumocystis jiris was quickly identified by morphological methods.
The diagnostic efficiency is high and accurate, providing a very timely and critical pathogenic basis
for clinical diagnosis and treatment of patients and adjustment of medication.
It also reflects that close and good communication between clinical and laboratory has played a very important role
in the diagnosis and treatment of patients' diseases.

In recent years, the development of molecular diagnostic technology is very fast, especially the metagenome second-generation sequencing technology sensitivity and specificity are high, can detect many special pathogens that cannot be detected by conventional testing and culture methods at the same time, which provides a very great help for the definite diagnosis of difficult infection cases, and is highly recognized and respected by the clinic, but the current second-generation sequencing still has shortcomings such as unstandardized and expensive and also limits its wide promotion
in the clinic 。 Morphological testing technology as the most traditional microbial testing technology, can play a role in rapid diagnosis, we make good use of new technology at the same time, do not ignore the basic morphological technology, such as this case, simple and economical morphological technology can also play a great role, some advantages are molecular diagnostic technology can not be compared
.
Therefore, the relationship between new technology and traditional technology is not replaced, but a complementary and hand-in-hand relationship
.
(Wu Weiqiang, Chief Technician, Department of Clinical Laboratory, Zhongshan Hospital of Traditional Chinese Medicine)

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