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Unravelling the rare case of Kikuchi Fujimoto disease
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Unravelling the rare case of Kikuchi Fujimoto disease

DNA tales January 12, 2022January 12, 2022

– Urvi Agrawal

The rarity of some diseases often leads to people confusing its signs and symptoms with those of other abnormalities. Sometimes, this can delay their diagnosis and the initiation of treatment. One such rare disease is the Kikuchi-Fujimoto disease. This disease is often confused with lymphoma or Systemic Lupus Erythematosus (SLE). To attain a deeper understanding of this disease, let us read some cases :

# CASE STUDY

Arjun is a 30-year-old man who returned to the UK after his trip to Delhi. Upon his return, he developed fever, mild breathlessness, night sweats, and knee ache. These symptoms lasted for over two weeks. His temperature was 38.2°C. His heartbeats were faster than usual. He also had a blood pressure of 142/84 mmHg, with 98% oxygen saturation. His pharynx, cardiovascular, abdominal, and respiratory examinations came to be normal. He also had a normal white blood cell count. But, showed elevated inflammatory markers. Interestingly, the physicians observed lymphadenopathy or swelling of lymph nodes in his cervical region. These lymph nodes were rubbery and hard. The doctors thought that this may be a case of mumps or a travel-associated disease. They started him on broad-spectrum antibiotics and continued their investigation.

Since he had visited a tropical country, doctors tested him for malaria and dengue. But both tests were negative. Serological tests for other viruses such as HIV, CMV, hepatitis A, B, and C gave negative results as well. At the same time, his fever did not subside and continued to persist for two more weeks (a total of 4 weeks now). Also, his cervical lymphadenopathy continued. The doctors kept their investigation on. They decided to stop his antibiotics as those were not helping improve his situation. Upon conducting ultrasounds, it was revealed that he had many hypoechoic or solid lymph nodes. These were localized in his groin and neck areas. Then seeing that he also had high levels of serum lactate dehydrogenase, they concluded his case to be that of lymphoma. After concluding, they performed a biopsy of the cervical lymph node to confirm their investigation. But they were yet again puzzled as the surgical procedure revealed areas of necrosis. Also, lymphoid cells showed proliferation and enlargement.

Finally, they were able to realise that this pathology was indicative of Kikuchi Fujimoto disease. After 4-5 weeks from the onset of symptoms, the swollen lymph nodes gradually reduced in size. But this could only occur because of supportive treatment, and not because of the initial treatment with antibiotics.

What do we know about this rare and complex disease?

Kikuchi Fujimoto is categorized as an extremely rare disease as there are very few records of it in the medical literature. As we understand from the given case study, it was not the first disease that doctor could hypothesize during initial diagnosis. Its diagnosis requires careful and prolonged investigation, with the gradual elimination of other possible diseases along the way. Even though the disease has not been widely reported, it is known to be more common in Asians, especially the Japanese. It is not well known in the western parts of the world. Doctors M. Kikuchi and Y. Fujimoto independently first described the condition in 1972 in Japan. It typically affects young people with a mean age of 21 years. Cases of the disease have not been found in children. Earlier reports have suggested a higher chance of occurrence of the disease in women (male to female ratio 1:4). But recent reports have updated this by stating that the actual male to female ratio is about 1:1.

The condition is also known as histiocytic necrotizing lymphadenitis. The disease is self-limiting, meaning it resolves without any treatment as such. Just like Arjun, we can see the patients of this condition suffer from major symptoms like fever (30-50%) and cervical lymphadenopathy (70-80%). Other less common symptoms are rash, weight loss, fatigue, and arthralgia. The swollen lymph nodes are solid, painless, and mobile. They are present in regions like cervical areas, groin, and axilla (armpit or underarm).

The underlying causes of the disease

Perhaps the most interesting aspect of this condition is the mystery around its pathogenesis. The exact cause of the disease remains unknown. But there have been many speculations in terms of what the most-likely causative factors of the disease are. Experts suggest that certain infections or an autoimmune disorder can lead to the onset of this condition.

The clinical features of KFD are often similar to those of viral infections. The histopathological features of the disease such as the predominance of T cells, necrosis, the proliferation of immunoblasts are also seen in viral diseases. Also, the disease does not respond to antibiotic treatments.

Various organisms such as the human immunodeficiency virus (HIV), Epstein-Barr virus, human herpes virus-6, cytomegalovirus, Toxoplasma gondii (causes toxoplasmosis), and Yersinia enterocolitica (causes yersiniosis) have been implicated as the potential causative agents for the disease. But their role remains a subject of controversy. 

In a study, researchers used in situ hybridization and detected EBV in the tissue samples from 10 KFD patients. However, immunochemistry techniques could only detect EBV-related proteins in only one patient. Hence, it has been difficult for researchers to collect evidence to claim the direct or indirect contribution of the virus in the manifestation of KFD. 

The claim for the autoimmune basis of the disease was obtained from electron microscopic studies. These have revealed the presence of reticular structures in the cytoplasm of lymphocytes of KFD patients. These structures are also present in patients with systemic lupus erythematosus and other such autoimmune disorders. Thus, scientists proposed that KFD is an autoimmune condition that occurs because of virus-infected transformed lymphocytes. Some overlap has been observed between SLE and KFD. But, unlike SLE, patients of KFD test negative for antinuclear or anti-dsDNA antibodies. Still, the overlap between the two requires some investigation. 

Diagnosis Methods:

There are no specific laboratory tests for the diagnosis of KFD. The disease is detected based on the biopsy of the characteristic enlarged or swollen lymph nodes. Most tests in this condition give normal results, as we saw in Arjun’s case. Even if laboratory tests are conducted, the varying results of multiple tests can confuse and not point towards a single direction. For example, Arjun had elevated levels of (lactate dehydrogenase) LDH and other inflammatory markers. These results are not specific to KFD. They can be observed for many malignant and infectious diseases as well.

Another diagnosis option is through imaging techniques such as magnetic resonance imaging (MRI) or computed tomography (CT) scanning. But these are not confirmatory, as they are unable to distinguish between the swollen lymph nodes of KFD from those of other conditions such as certain cancers. Instead, the help from these scanning techniques is in their ability to identify the exact site, from where a further biopsy of the lymph node can be conducted to arrive at a conclusive inference.

Even though KFD is uncommon, we must include it in the differential diagnosis of enlarged lymph nodes. This is necessary because its treatment and progression are different from lymphoma or SLE. It can be difficult at times to differentiate between SLE and KFD. This is because of similarities in their histological and clinical features. The misdiagnosis of KFD may occur if the early lesions lack necrosis. It is important to recognize KFD so that one can prevent the wastage of time and energy in investigating lymphoproliferative and infectious diseases, as we saw in Arjun’s case.

Here are some images taken from a case report where a group of doctors diagnosed an individual to be suffering from KFD. (Wilson et al. 2014):

CT scan revealing multiple bilateral enlarged cervical lymph nodes. (Wilson et al. 2014)
Paracortical necrosis seen after Hematoxylin and Eosin staining. (Wilson et al. 2014)
Zoomed in (x400) depicting individual cell death and nuclear debris (karyorrhexis) (Hematoxylin and Eosin stain). (Wilson et al. 2014)

Treatment options

Although there are no cures, treatment has depicted a substantial contribution to the recovery of KFD patients. KFD treatments are largely focused on relieving the symptoms of the condition. These include the use of non-steroidal anti-inflammatory drugs for high fevers, tender lymph nodes, flu, etc. The good thing is that the symptoms tend to subside on their own in about 6 months from the onset of the condition.

Future Prospects:

Answers to many of the questions regarding how well we understand the disease are necessary as much remain unknown. This is important so that we can improve the diagnosis and treatment measures. One of the important aspects that future studies need to focus on is in correlating clinical features of the disease with its outcomes. Research on backtracing or evaluating the different body responses of the patients towards the existing treatments might provide valuable insight in getting towards how and why particular treatments can treat the condition. This might lead to the identification of certain proteins or pathways that are involved in KFD. This can further help to design treatments to manage the rare complications of the condition.

Also read: Universal influenza vaccine under development

Sources:

  1. Bosch, X., & Guilabert, A. (2006). Kikuchi-Fujimoto disease. Orphanet Journal of Rare Diseases, 1(1), 18. https://doi.org/10.1186/1750-1172-1-18
  2. Perry, A. M., & Choi, S. M. (2018). Kikuchi-fujimoto disease: A review. Archives of Pathology & Laboratory Medicine, 142(11), 1341–1346. https://doi.org/10.5858/arpa.2018-0219-RA
  3. Wilson, M. R., Milne, G., & Vryonis, E. (2014). Kikuchi-fujimoto disease: A rare cause of fever in the returning traveller. Case Reports in Medicine, 2014, 1–4. https://doi.org/10.1155/2014/868190
  4. Fisher, A., Kalra, S., Tucci, V., & Bezek, S. (2014). State of the globe: Time to revisit kikuchi Fujimoto disease. Journal of Global Infectious Diseases, 6(4), 139. https://doi.org/10.4103/0974-777X.145228
  5. Hudnall, S. D. (2000). Kikuchi-fujimoto disease. American Journal of Clinical Pathology, 113(6), 761–764. https://doi.org/10.1309/N4E2-78V9-QTFH-X4FF
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