PFAPA syndrome and its related diseases

PFAPA syndrome and its related diseases

Prof Ariyanto Harsono MD PhD SpA(K)

Prof Ariyanto Harsono MD PhD SpA(K) 2

Introduction

The recently described PFAPA (Periodic Fever, Aphthous stomatitis, Pharyngitis and Adenitis) syndrome is characterised by periodic fever, aphthous stomatitis, pharyngitis and adenitis . However, there are currently relatively few data on the natural history of this syndrome.

Keywords: PFAPA, reccurent episodic fever, IL1, Hyper IgD syndrome, periodic fever syndrome, auto inflammatory syndrome


EtiologyPFAPA is frequently discussed together with other

periodic fever syndromes, but it is unknown whether the cause is primarily genetic or due to an initial infection.

According to recent information that has been gathered, there has been some genetic links that are possible.

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The condition is a disturbance of innate immunity. The changes in the immune system include increased expression of complement related genes (C1QB, C2, SERPING1), interleulkin-1-related genes (interleukin-1B, interleukin 1 RN, CASP1, interleukin 18 RAP) and interferon induced (AIM2, IP-10/CXCL10) genes. T cell associated genes (CD3, CD8B) are down regulated. Flares are accompanied by increased serum levels of activated T lymphocyte chemokines (IP-10/CXCL10, MIG/CXCL9), G-CSF and pro-inflammatory cytokines (interleukin 6, interleukin 18). Flares also manifest with a relative lymphopenia. Activated CD4(+)/CD25(+) T-lymphocyte counts correlated negatively with serum concentrations of IP-10/CXCL10, whereas CD4(+)/HLA-DR(+) T lymphocyte counts correlated positively with serum concentrations of the counter-regulatory IL-1 receptor antagonist. Fever is considered related to inflammatory effect of IL1

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SymptomsThis syndrome includes: recurrent episodes of fever with aphthous stomatitis (mouth sores) and pharyngitis (sore throat

with redness) (Figure 1a). Occasionally, there also may be exudate white patches on the

tonsils (Figure 1b) usually the lymph nodes in the neck are enlarged (adenitis)

(Figure 1c). Some children have other symptoms like joint pain, abdominal

pain, rash (Figure 1d), headache, vomiting or diarrhea. Children are completely well between episodes.

Episodes of fever start suddenly and last for 3-7 days. Fevers occur routinely every few weeks; often, families know the exact day when an episode will start.Prof Ariyanto Harsono MD PhD SpA(K)


The disease may last for several years but usually will resolve by itself in the second decade of life. However, in nearly 15 percent of patients episodes (although less frequent) may continue to occur during adulthood. Over time, the time between the episodes will increase. Children with PFAPA continue to grow and develop normally.

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Figure 1a. This syndrome includes recurrent episodes of fever with aphthous stomatitis (mouth sores) and pharyngitis (sore

throat with redness)


Figure 1b. there also may be exudate (white patches on the tonsils)


Figure 1c. Cervical adenitis


Figure 1d. Rash


The key symptoms of PFAPA are those in its name: periodic high fever at intervals of about 3–5 weeks, as well as aphthous ulcers, pharyngitis and/or adenitis. In between episodes, and even during the episodes, the children appear healthy. At least 6 months of episodes.


Diagnosis

There are no laboratory tests specific for diagnosing PFAPA. The disease is diagnosed based on symptoms and physical examination. White blood cell counts, sedimentation rate and the C-reactive protein, all of which can be measured with a blood test, increase during attacks. It is important to exclude all other diseases that may present with similar symptoms (especially a Streptococcus infection) before confirming the diagnosis. The dramatic response to treatment also helps diagnose PFAPA. In cases without a classic presentation it may be necessary to exclude other causes of recurrent fever (see other patient sheets on this topic).


Raised IgD levels may represent a non-specific epiphenomenon, which frequently accompanies PFAPA syndrome as well as MKD. Because of the overlapping clinical and laboratory features, genetic testing of the MVK gene is indicated to differentiate these two conditions, if clinical criteria for both are fulfilled. Diagnosis requires recurrent negative throat cultures and that other causes (such as EBV, CMV, FMF) be excluded


The PFAPA syndrome may resemble other periodic fevers, suchas familial Mediterranean fever, hyper IgD syndrome, and the autosomal dominant familial fevers. Because PFAPAsyndrome is a diagnosis of exclusion, cardinal signs and symptomsmust be carefully observed for a differential diagnosis, such as: onset in early childhood, before the age of 5 years (male predominance has been described); periodic abrupt onset of febrile episodes that last 4–5 days and

occur every 4–6 weeks on average; episodes that are often accompanied by intra-oral ulcers,

pharyngitis, and cervical lymph node enlargement.


TreatmentThe aim of the treatment will be:

to control symptoms during the episodes of fever, to shorten the duration of the episodes, to prevent next episodes from occurring.

The fever usually does not respond well to acetaminophen or nonsteroidal anti-inflammatory drugs like ibuprofen. A single dose of steroids (usually prednisone), given when the symptoms first start, has been shown to shorten—and often even end—the episode. However, the time between episodes also may be shortened with this treatment, and the next episode may occur earlier than expected.


Medications like cimetidine and colchicine, when used regularly, may prevent future episodes in about a third of the children. Several studies have found that a tonsillectomy (removing the tonsils by surgery) cures PFAPA in the majority of patients (more than 80%) but the role and timing of surgery in treating PFAPA has still not been fully clarified.


A possible treatment for PFAPA is a single dose of prednisone(1–2 mg per kg body mass) at the beginning of each fever episode. A single dose usually terminates the fever within several hours. However, in some children, prednisone causes the fever episodes to occur more frequently (and more regularly). Parents might then want to consider colchicine, which is used in the treatment of FMF. In several studies, adeno tonsilectomy was found to completely resolve symptoms. Yet other studies had differing results, most being positive. Parents of children with PFAPA regularly report improvements after the children have had surgical treatment. Some children stop having episodes, others have a break in the cycle for a few months and then it comes back but the episodes are less intense. Interleukin-1 inhibition appears to be effective in treating this condition.

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Figure 2. Meta analysis of Medical therapies


The use of antibiotics in PFAPA syndrome is ineffective (P < 0.00001; OR, 0.01; 95% CI, 0.00–0.01). The use of cimetidine [4,14,16,17,19,22] is also ineffective (P = 0.02; OR, 0.15; 95% CI, 0.03–0.75). There is evidence that the use of steroids is effective in the resolution of symptoms (P < 0.00001; OR, 43.82; 95% CI, 10.68–179.69).


Figure 3.Meta-analysis of surgical therapy for the resolution of PFAPA

syndrome (


Tonsillectomy (+/ adenoidectomy) as a treatment of PFAPA was reported in fourteen studies. It was found to be an effective intervention for resolution of symptoms. (P < 0.00001; OR, 27.26; 95% CI, 6.70–110.91).

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Figure 4. Meta-analysis of surgical (tonsillectomy, +/ adenoidectomy)

versus medical therapies


Meta-analysis of surgery versus cimetidine, and surgery versus antibiotics, demonstrated that surgery is a significantly more effective treatment for PFAPA syndrome (P = 0.0003; OR, 11.89; 95% CI, 2.36–60.02) and (P < 0.00001; OR, 106.49; 95% CI, 30.28–374.44), respectively. A comparison of treatment with steroids or surgery did not show any statistically significant difference, confirming the effectiveness of both therapies for the resolution of PFAPA syndrome (P = 0.83;OR, 0.90; 95% CI, 0.36–2.26).


The most effective non-surgical therapy is corticosteroids. However, they do not preventfuture fever cycles. The results of this meta-analysis showed that tonsillectomy (+/ adenoidectomy) is the most effective intervention for long-term resolution of PFAPA syndrome symptoms.


During PFAPA flare-ups, the researchers detected decreased numbers of activated T cells, white blood cells that play a role in the cell's innate immune response. They suspect that these activated T cells migrated to the lymph nodes in the neck, where they accumulate. They also detected over-expression of genes activated in innate immune responses, including interleukin-1, a molecule that is important in triggering fever and inflammation.It is hypothesized that anakinra, a drug that prevents interleukin-1 from binding to its receptor, could be therapeutic. They administered anakinra by injection to five children on the second day of their PFAPA fevers and all showed a reduction in fever and inflammatory symptoms within hours.


Prognosis

According to present research, PFAPA does not lead to other diseases and spontaneously resolves as the child gets older, with no long term physical effects. However, PFAPA has been found in adults and may not spontaneously resolve.

Hyper IgD Syndrome



Introduction

PFAPA Syndrome is to be related with Hyperimmunoglobulinaemia D because the similarity of periodic fever, is more commonly known as hyper-IgD syndrome or HIDS. It is a rare inherited auto inflammatory syndrome that presents with recurrent episodes of fever, skin rash, abdominal pain, headaches and enlarged lymph glands that begin in infancy.

Mevalonic aciduria is a severe variant of HIDS.


Keywords: higds, mevalonate kinase, IL1, inborn error of metebolism, recurrent fever

Hyper-IgD syndrome is a rare autosomal recessive disorder in which recurring attacks of chills and fever begin during the first year of life. Episodes usually last 4 to 6 days and may be triggered by physiologic stress, such as vaccination or minor trauma.

Hyper-IgD syndrome clusters in children of Dutch, French, and other Northern European ancestry and is caused by mutations in the gene coding mevalonate kinase, an enzyme important for cholesterol synthesis. Reduction in the synthesis of anti-inflammatory isoprenylated proteins may account for the clinical syndrome.


Etiology

Virtually all patients with the syndrome have mutations in the gene for mevalonate kinase, which is part of the HMG-CoA reductase pathway, an important cellular metabolic pathway. Indeed, similar fever attacks (but normal IgD) have been described in patients with mevalonic aciduria - an inborn error of metabolism now seen as a severe form of HIDS.

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PathophisiologyThe hyper-IgD syndrome is caused by mutations in

the gene encoding mevalonate kinase (MVK) In addition to HMG-CoA reductase, mevalonate

kinase is involved in the biosynthesis of cholesterol and isoprenoids, and catalyses the conversion of mevalonate to 5-phospho mevalonic acid in the mevalonate metabolism. The enzyme mevalonate kinase is involved in the isoprenoid pathway of cholesterol biosynthesis. The enzyme deficiency results accumulation of mevalonic acid and increased interleukin 1. The mechanism of mevalonate kinase deficiency to cause hyper IgD is not kown.


It is not known how mevalonate kinase mutations cause the febrile episodes, although it is presumed that other products of the cholesterol biosynthesis pathyway, the prenylation chains (geranylgeraniol and farnesol) might play a role.


Immunoglobulins are proteins produced by certain white blood cells. There are five classes of immunoglobulins known as IgA, IgD, IgE, IgG, and IgM. Immunoglobulins play a role in defending the body against foreign substances or microorganisms by destroying them or coating them so they are more easily destroyed by white blood cells. While the specific function of other immunoglobulins is well-known, the specific function of IgD within the immune system is unknown.


Clinical SymptomsIn addition to chills and fever, patients may have: abdominal pain, vomiting or diarrhea, headache, and arthralgias. Signs include cervical lymphadenopathy,

splenomegaly, arthritis, skin lesions (maculopapular rash, petechiae, or purpura), and orogenital aphthous ulcers


Cutaneous signs of HIDSo Skin rash affects up to 80% of patients. A number of skin eruptions or rashes have

been described in this syndrome, and these resolve slowly after the febrile episode settles.

The rashes seen in HIDS are most commonly described as follows: small flat spots (macules) raised bumps (small papules or larger nodules) measles-like rash (morbilliform) hive-like rash (urticarial). Less common or rare skin presentations include: Henoch-Schönlein purpura erythema elevatum diutinum petechiae (tiny bleeding spots or purpura) erythema nodosum.

o Oral and/or vaginal aphthous ulcers affect 50% of patients.

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Symptom Features

Fever over 40C

preceding chills and malaise

Skin rash affects up to 80%

various presentations (see below)

Headache nonspecific

Enlarged lymph nodes in neck characteristic

bilateral

painful

Abdominal pain severe

diarrhoea and vomiting

peritonitis

Joint pain arthralgia (pain) or arthritis (swelling)

most common in young patients

affects large joints

symmetrical, polyarticular, non-destructive

symptoms occur with abdominal pain and settle slowly

Enlarged liver and spleen (hepatosplenomegaly) affects 50% of children

Tendonitis


Trigger

Acute episodes may be triggered by:o Vaccinations – more than 50% report at least

one episode in childhood following an immunisation

o Infectiono Physical and emotional stresso Trauma, including surgery


Diagnosis

The characteristic recurrent acute febrile attacks without a clear infectious or autoimmune cause, suggest the need for investigation.

Clinical criteriaIn addition to the the of febrile attacks outlined above,

clinical diagnostic criteria should include:o Onset before the age of 5 yearso Episodes last less than 14 dayso MVK gene mutations are unlikely if these features are not

present.


IgD levelsRaised levels of IgD can be found in many but not all patients, especially in children under 3 years of age. Levels are raised not only during an attack but between attacks. Elevations of IgD levels can occur in other periodic fever syndromes such as familial Mediterranean fever and TRAPS, and other chronic inflammatory conditions, so it should be interpreted with caution.


Other useful testso Urine organic acids measured during an acute attack usually

show raised levels of mevalonic acid.o During an attack: leukocytosis, Increase erythrocyte sedimentation rate (ESR), increaseC-reactive protein (CRP) and serum amyloid A (SAA). Serum IgA levels may also be increased.o Radiometric assay testing can demonstrate reduced

mevalonate kinase activity in white blood cells or cultured fibroblasts.

o Skin biopsy may show a mild vasculitis which may extend deeply. Changes may resemble Sweet disease or cellulitis.


DNA analysisDNA analysis showing two disease-linked mutations in the MVK gene is used to confirm the diagnosis of HIDS. In most cases the patient has two different mutations, called compound heterozygosity.


Treatment of HIDS

Many treatments have been tried in HIDS, none with uniform success: Colchicine – is generally unhelpful although there are

case reports of its successful use Non-steroidal anti-inflammatory drugs (NSAID) Statins – such as simvastatin, inhibit HMGCoA-reductase

resulting in reduced production of mevalonic acid Systemic corticosteroids – a single dose at the start of an

attack may reduce the severity and duration (1mg/kg)


DapsoneCiclosporinThalidomideIntravenous immunoglobulin (IVIG)Biologic agents– including anakinra (interleukin-1

receptor antagonist) and etanercept (tumour necrosis factor alfa inhibitor) have been reported to reduce the frequency and/or severity of attacks in 80%. However there have also been cases where these agents have increased the frequency and/or prolonged attacks.


Prognosis

There is a tendency to improve with age, with less frequent and less severe attacks by adulthood. Between episodes, health is normal.

A small subgroup of affected patients develop neurologic abnormalities in adulthood, similar to mevalonic aciduria.

Unlike familial Mediterranean fever, amyloidosis is rarely seen in HIDS, affecting less than 3%.

Life expectancy is usually normal, however this can be affected by renal failure due to amyloidosis or severe infections.


Mevalonic aciduriaMevalonic aciduria involves the same gene and enzyme as HIDS, however the resulting enzyme deficiency is virtually complete. The condition is also called mevalonate kinase deficiency. The gene mutations so far identified have been localised to one end of the enzyme. Mevalonic aciduria results in neurological effects that mainly arise because of inadequate cholesterol, which is required for brain and nerve development.


Patients with mevalonic aciduria suffer the same febrile episodes as in HIDS, but in addition develop profound developmental delay, retinal dystrophy (visual defects) and cataracts, mild facial deformities, and liver/spleen enlargement. Those less severely affected have mental retardation, failure to thrive, progressive cerebellar ataxia (unsteadiness) and anaemia. In childhood and adolescence, eye problems develop, including cataracts and uveitis. Myopathy (muscle weakness) can occur. In those severely affected, mevalonic aciduria is commonly fatal in infancy/childhood.


High levels of mevalonic acid are detected in the urine at all times.

Genetic counselling should be performed for families with an affected child and prenatal testing should be considered.

Periodic fever syndromes



PFAPA Syndrome and Periodic fever syndromes are conditions in which the patient experiences recurrent episodes of fever with associated inflammatory symptoms, in the absence of infection, allergy, malignancy, immunodeficiency or autoimmune conditions. They are one category of autoinflammatory syndromes.Familial Mediterranean fever (FMF) is the most common and best known of the hereditary periodic fever syndromes. Inherited (genetic) forms of periodic fever syndromes are also known as hereditary recurrent fever syndromes.


Periodic fever syndromes can be genetic conditions. Therefore some periodic fever syndromes are seen predominantly in specific racial groups. Familial Mediterranean fever, for example, affects races originating from around the eastern Mediterranean area.The hereditary periodic fever syndromes can be classified by the type of inheritance: Autosomal recessiveAutosomal dominant


Autosomal recessive periodic fever syndromesGenetic conditions with this type of inheritance require two copies of the abnormal gene; one copy inherited from each parent. Although the defective gene is usually the same in each parent, the actual mutation may be different, i.e., heterogeneous homozygotes or compound heterozygotes. The parents are asymptomatic carriers of the defect.Autosomal recessive periodic fever syndromes with skin involvement include: Familial Mediterranean fever (FMF) Hyperimmunoglobulinaemia D syndrome (hyperIgD syndrome,

HIDS)


Autosomal dominant periodic fever syndromesOnly a single copy of the defective gene is required to develop symptoms and signs of an autosomal dominant periodic fever syndrome. Therefore the condition is usually inherited from an affected parent or, less commonly, is due to a spontaneous mutation in the affected child.Autosomal dominant periodic fever syndromes with skin involvement include: Tumour necrosis factor receptor-associated periodic fever (TRAPS) Cryopyrin-associated periodic syndromes (CAPS) Familial cold autoinflammatory syndrome (FCAS) Muckle-Wells syndrome (MWS)


Molecular biology of periodic fever syndromesThe defective gene has been identified for these hereditary periodic fever syndromes. The defective gene is different for each of the syndromes with the exception being the three clinically distinct syndromes that are now clustered as the cryopyrin-associated periodic syndromes (CAPS).All periodic fever syndromes result in overstimulation of the innate immune system, usually due to over-activity of interleukin 1.


Nonhereditary periodic fever syndromes with skin involvement include:PFAPA syndromeSchnitzler syndromeThe cause of these syndromes is not yet known.


Symptoms

The one clinical feature in common between all the periodic fever syndromes is the recurrent episodes of fever in the absence of infection, autoimmune disease or malignancy.The frequency of febrile attacks can vary between individuals and syndromes from daily to once every ten years. The duration of the fever during an attak may be hours or be virtually continuous, but is usually typical for a particular syndrome. The height of the fever may range from a slight elevation of temperature to over 40 degrees Celsius.


The age at which the febrile attacks begin is also highly variable between the different syndromes with some beginning at or shortly after birth but others being delayed even as late as middle age.In some periodic fever syndromes there are well-recognised triggers for a febrile attack, such as generalised exposure to cold triggering a fever in familial cold autoinflammatory syndrome (FCAS) But in others no trigger is identified.


Most periodic fever syndromes have associated symptoms and signs of inflammation at the same time as the fever. Commonly these affect the serosal surfaces, joints, eyes and skin. In some forms the predominant associated symptom is severe abdominal pain often leading to unnecessary exploratory surgery. In others, joint or neurological involvement can result in major disability.


Quality of life can be severely impacted, particularly if febrile attacks are frequent or in those forms of periodic fever syndrome that develop joint or neurological complications.Secondary systemic amyloidosis develops in some periodic fever syndromes and this can result in life-threatening complications.


Diagnosis

Periodic fever syndromes should be suspected clinically when the patient presents with recurrent episodes of fever associated with other inflammatory symptoms. However this can be difficult if the attacks are very infrequent, such once every few years, or continuous. A family history of such episodes is not always present, but is helpful if known.


Periodic fever syndromes can only be considered after infections, allergies, malignancy, immunodeficiencies and autoimmune diseases are excluded.In children, it can be difficult to distinguish hereditary periodic fevers from the much commoner PFAPA syndrome as there are overlapping clinical features. The Gaslini score may help identify those most likely to benefit from genetic testing, and then to determine the order in which genes should be sequenced.


Some specific periodic fever syndromes can be diagnosed on biochemical testing or challenge with the known trigger. An example of the former is HIDS, which typically is associated with a very high level of IgD in the blood. Triggering of an attack within hours of generalised exposure to cold in FCAS is an example of the latter category.


Genetic testing is often definitive if positive, but not all mutations are known or easily tested for. A negative test does not exclude the diagnosis. In these cases, the diagnosis must be reached on clinical criteria. Genetic testing of the MEFV, TNFRSF1A and MVK genes detects a mutation in 20% of patients with clinical symptoms suggestive of a periodic fever syndrome.


A rapid and complete response to a trial of therapy may support the clinical diagnosis. Familial Mediterranean fever (FMF) responds to colchicine in over 90% of cases. Interleukin-1 blockade with biologic agents results in dramatic resolution of symptoms within hours of the first injection in some specific syndromes.


TreatmentAcute attacks of hereditary periodic fever syndromes are usually treated with bed rest, anti-inflammatory agents, analgesics and sometimes systemic corticosteroids. The fever does not respond to aspirin or paracetamol.Avoidance of triggers, where known, can reduce the frequency of attacks. Sufferers of familial cold-associated syndrome (FCAS) often move to temperate climates to avoid cold winters and hot summers, for example.


To prevent febrile episodes, improve quality of life and minimise longterm complications, continuous treatment may be required for some forms. Apart from colchicine for familial Mediterranean fever, treatment of the hereditary periodic fever syndromes is with biologic agents such as anakinra, given by subcutaneous injection. Treatment should be started as early as possible to prevent the development of life-threatening complications in such periodic fever syndromes.

Autoinflammatory syndromes



PFAPA is to be related with Auto inflammatory syndromes because the similarity of periodic fever, are defined as conditions caused by an exaggerated innate immune system response resulting in episodes of spontaneous inflammation affecting multiple organs. An auto inflammatory syndrome can only be diagnosed when infective conditions, malignancy, allergic and immunodeficiency conditions have been excluded. Compared to classical autoimmune diseases, auto inflammatory syndromes lack pathogenic autoantibodies and antigen-specific T cells.


Classification of autoinflammatory syndromes

Autoinflammatory syndromes may be inherited through mutations to a single gene (monogenic autoinflammatory syndromes), or, more commonly, are polygenic immune conditions that resemble autoimmune collagen disorders. The number of conditions included is increasing as molecular and genetic studies reveal disease mechanisms.A classification system, with examples of syndromes with dermatologic manifestations, follows.


Hereditary fever syndromesFamilial Mediterranean fever (FMF)Tumour necrosis factor receptor-associated

periodic fever syndrome (TRAPS)Hyper-IgD syndrome (HIDS)


Other monogenic autoinflammatory syndromes Cryopyrin-associated periodic syndromes (CAPS)

o Familial cold autoinflammatory syndrome ( FCAS)o Muckle-Wells syndrome (MWS)o Neonatal onset multisystem inflammatory disease/chronic Infantile

neurologic cutaneous arthropathy syndrome (NOMID/CINCA) Syndrome of pyogenic arthritis, pyoderma gangrenosum and

acne (PAPA syndrome, PAPAS, PAPGA syndrome) Juvenile systemic granulomatosis (Blau syndrome, early onset

sarcoidosis) Deficiency of interleukin-1 receptor antagonist (DIRA) Mevalonic aciduria Majeed syndrome


Nonhereditary or polygenic disordersSchnitzler syndromeCrohn diseaseBehcet diseasePsoriatic arthritisSyndrome of periodic fever, aphthous stomatitis,

pharyngitis and adenitis (PAPAS, PFAPA syndrome)Systemic-onset juvenile idiopathic arthritisAdult-onset Still disease


Treatment

Treatment varies with the actual syndrome. In many forms, systemic corticosteroids have only a modest effect. Biologic agents such as anakinra (which targets IL-1) result in a dramatic and consistent improvement in those syndromes where a clear link to IL-1 has been shown. There is less consistent benefit in other conditions where a direct link with IL-1 has not been found.


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PFAPA syndrome and its related diseases

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