Repeated fever and swollen lymph nodes, what kind of strange disease did she get?

*For reference only for medical professionals, a young woman has repeated fever and her white blood cell level is like a roller coaster ride.
What's wrong? At the 3rd Peking University Rheumatology Hot Forum held recently, Zhao Juan, deputy chief physician of the Department of Rheumatology and Immunology, Peking University First Hospital, shared an interesting case.

What about lymphatic enlargement and jaundice in young women? The 24-year-old female patient complained of "Lymph node enlargement for 1 month, fever for 2 weeks, and yellowish skin for 2 days.
"
 When the patient found swollen lymph nodes a month ago, he did not pay much attention to it, and only took cefixime and metronidazole for treatment.

After 2 weeks, he did not get better.
The lymph nodes were enlarged and increased, and the fever was 38~39℃ intermittently, accompanied by rash, sore throat and cough, similar to upper respiratory tract infection.

The patient went to the hospital for laboratory examination and found that white blood cells, hemoglobin, platelets, erythrocyte sedimentation rate and C-reactive protein (CRP) were not high.

Taking Chinese patent medicines and antipyretics, the effect is not good.

 After another week, the patient continued to have a fever and his body temperature reached 39.
5°C with intermittent rash.

At this time, white blood cells are slightly elevated, and hemoglobin and platelets are normal.

The patient continued to use traditional Chinese medicine and antipyretic drugs.

Until 2 days ago, the patient had yellowish skin and pain in his hands, wrists and knees.

 A comprehensive examination revealed that the patient’s white blood cells and CRP had increased significantly, and procalcitonin (PCT) was 1.
46, suggesting infection.

It is worth noting that severe liver damage has occurred-alanine aminotransferase (ALT) is as high as 2203U/L, aspartate aminotransferase (AST) is also 1532U/L, and total bilirubin is 96.
7μmol/L, which means severe jaundice.

The patient was hospitalized for treatment.

It turns out that she has this disease! Reviewing the patient’s medical history, two key words can be extracted, namely, lymphadenopathy and fever.

Liver damage is also a prominent manifestation, but whether it is caused by the condition itself or caused by a large number of medications is still unknown.

 How did the patient's infection come about? Possible causes are viruses, bacteria, tuberculosis and special pathogens.

In terms of autoimmune diseases, systemic lupus erythematosus, vasculitis, dermatomyositis, etc.
may need to be considered.

In terms of tumors, lymphoma, Castleman disease, etc.
need to be considered.

 In terms of infection, no positive findings were found in multiple pathogenic screening.

Lung CT, echocardiography, abdominal ultrasound and other examinations also showed no positive results.

The two experimental treatments of cefixime + metronidazole and vancomycin + imipenem were ineffective.

 In terms of tumors, B-ultrasound and biopsy of the lymph nodes showed no abnormalities, which can rule out lymphoma and Castleman's disease.

A variety of imaging examinations and tumor marker detection also ruled out solid tumors.

 Then what needs to be considered is autoimmune disease.

We can divide autoimmune diseases into two categories, namely those with autoantibodies (systemic lupus erythematosus, vasculitis, etc.
) or without autoantibodies, such as arteritis.

Several diseases with autoantibodies can be ruled out based on the results of antibody examinations.

In the end, if the result is excluded, the patient is likely to be suffering from Adult Still's Disease (AOSD).

 AOSD has 4 main criteria: body temperature>39℃, arthralgia or arthritis; rheumatoid factor (RF)<1:80; antinuclear antibody (ANA)<1:100; another 4 minor criteria: white blood cell> 15x109/L, skin rash, pleurisy or pericarditis.

To meet the diagnosis of AOSD disease, two of the four main criteria and four minor criteria must be met.

The patient happened to meet the definition of AOSD, and therefore received a preliminary diagnosis.

After two days of hormonal therapy and plasma exchange in the hospital, the patient's fever was significantly reduced and the first battle was won! However, only 3 days later, the enemy counterattacked: the patient had a sudden high fever (near 40°C), rash, congestion, itching, and doubled white blood cells.

 What needs to be done at this time is to "truce" and clearly discuss the reasons for the fever again.

There are two possibilities, one is that the original disease has not been controlled, and the other is that a new one has occurred.

If it is the former, it is necessary to increase the amount of hormones and introduce biological agents; if it is co-infected, it needs to be screened again for the pathogen.

In other aspects, it is necessary to rule out complicated tumors or hematopoietic syndrome (HPS).

The cause of repeated fever has finally been found! At this point in the analysis, there was a sudden turn of events, and there was a glimmer of light.

At this time, the patient's previous test-soluble CD25 and NK cell activity also yielded results, confirming the diagnosis of HPS.

Some readers may be wondering, how do you think of this disease? Dr.
Zhao Juan explained that this was because the patient was admitted to the infectious disease department before, and the infectious doctor was very vigilant about the disease, and was the first to think of this examination; plus the patient’s abdominal ultrasound showed enlarged spleen and super high ferritin.
, Gu Chuan also saw hematopoietic cells, which contributed to the diagnosis of HPS.

 At this time, it can be basically judged that this patient has macrophage activation syndrome (HPS with rheumatism is usually called macrophage activation syndrome, MAS).

After confirming the diagnosis, the first question that needs to be clarified is when did the patient become bloodthirsty, when he had a fever again, or earlier? Figure 1 The patient's body temperature curve.
As can be seen from Figure 1, the patient did not have too many abnormalities in the blood system at the beginning of the illness.
The blood cells, hemoglobin and platelets (collectively referred to as the three lines) are all normal.
Department is still normal.

In traditional perception, HPS will be considered only if at least two of the three lines have declined, which is clearly inconsistent with this patient's situation.

 In fact, in the mechanism of HPS, the initial cause may be infection or drug factors, which induce the decline of NK cell activity and can no longer phagocytize activated macrophages, and the function of cytotoxic T cells may also be defective.

Therefore, the T cells and macrophages in the body will be activated wildly, releasing a large number of inflammatory factors (ie, cytokine storm), causing tissue damage and the appearance of hematopoietic cells.

In this process, it is not necessary to have the participation of hematopoietic cells or the three-line/two-line decline.

 Therefore, it is inferred that once the NK cell or macrophage function defect occurs, hematophagy may have occurred.

It can be seen that bloodthirsty may occur in the early stage of the disease.

 AOSD combined with MAS is not uncommon in clinical practice, about 12%~15%.

MAS can occur at any stage of AOSD, including onset, relapse, or treatment.

The current mechanism is unclear, and infections and drugs are possible triggers.

 The next question is, is this patient's MAS primary or secondary? You might say that she had AOSD first and then MAS, which of course was a secondary issue! In fact, this is not necessarily true, because some patients may have certain genetic defects to cause disease.

Especially this patient developed MAS at the early stage of onset, which is more suspicious.

However, the genetic test results are indeed negative, no clear pathogenic variants have been detected, and primary MAS can be ruled out.

 The third doubt is, why is the patient's three lines not low? A more reasonable explanation is that the patient's white blood cells are not always low, but go up and down like a roller coaster.

 Looking back at the patient’s course of disease, in fact, the onset of her MAS has long been clues: low erythrocyte sedimentation rate, intermittent decrease in white blood cells, decrease in reticulocytes, decrease in plasma fibrinogen (Fib), extremely high ferritin, severe liver damage.
.
.
these All clues.

 After increasing the hormone from 40mg to 80mg, using gamma globulin and plasma exchange treatment, the patient's condition was temporarily stable, and he stopped all the drugs on his own and felt good, but after more than a year, "the smoke came back.
"
The patient developed pain in the right hip and found bilateral femoral head necrosis during the reexamination.
She also developed a rash on the trunk of the extremities and pain in the joints of both wrists and hands.

Laboratory tests found that some indicators of inflammation were elevated.

 The patient was not treated and underwent femoral head replacement surgery after one month of observation.

Intraoperative injection of a compound betamethasone, the rash and joint pain all improved.

After another period of time, history seemed to repeat itself: the patient had a fever again, the highest body temperature was 40°C, and all rashes, arthralgias and sore throat appeared.

 Figure 2 The course of the patient's disease After examination, it was found that the patient's AOSD recurred, but hematophilia did not occur.

The treatment of patients includes tocilizumab 640mg bid, prednisolone 30mg qd and so on.

After treatment, the body temperature was normal, and the blood picture was basically normal except for slightly higher white blood cells; liver function and blood coagulation function were normal.

 Summarizing the patient’s medical history with a picture is as follows: Figure 3 Summary of the patient’s repeated fever.
It is painful and painful.
Dr.
Zhao Juan summarized this case as follows: AOSD combined with MAS often has atypical clinical manifestations; possible blood picture Not low, Fib decreased, triglycerides increased, and splenomegaly was not obvious; hormone curative effect was not good / white blood cell unstable / severe liver damage / severely increased ferritin; beware of recurrence.