Periodic fever, aphthous stomatitis, pharyngitis and adenitis
Encyclopedia
Periodic fever, aphthous stomatitis, pharyngitis and adenitis or periodic fever aphthous pharyngitis and cervical adenopathy (PFAPA) syndrome is a medical condition, typically starting in young children, in which high fever
occurs periodically at intervals of about 3–5 weeks, frequently accompanied by aphthous ulcer
s, pharyngitis
and/or adenitis
. The syndrome was described in 1987 and named two years later.
at intervals of about 3–5 weeks, as well as aphthous ulcer
s, pharyngitis
and/or adenitis
. In between episodes, and even during the episodes, the children appear healthy. At least 6 months of episodes. Recurrent negative throat cultures. Other causes excluded (EBV, CMV, FMF).
s, but it is unknown whether the cause is primarily gene
tic or due to an initial infection
.
The condition appears to be the result of a disturbance of innate immunity. The changes in the immune system are complex and 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 gene
s (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 proinflammatory cytokine
s (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 counterregulatory IL-1 receptor antagonist.
(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 one study, adenotonsillectomy 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.
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
occurs periodically at intervals of about 3–5 weeks, frequently accompanied by aphthous ulcer
Aphthous ulcer
An aphthous ulcer , also known as a canker sore, is a type of mouth ulcer which presents as a painful open sore inside the mouth or upper throat characterized by a break in the mucous membrane. Its cause is unknown, but they are not contagious...
s, pharyngitis
Pharyngitis
Pharyngitis is an inflammation of the throat or pharynx. In most cases it is quite painful, and is the most common cause of a sore throat.Like many types of inflammation, pharyngitis can be acute – characterized by a rapid onset and typically a relatively short course – or chronic....
and/or adenitis
Adenitis
Adenitis is a general term for an inflammation of a gland or lymph node.-Lymph node adenitis:"Lymph adenitis" or "lymph node adenitis" is caused by bacterial infection in lymph nodes. The infected lymph nodes typically become enlarged, warm and tender. A swelling of lymph nodes due to growth of...
. The syndrome was described in 1987 and named two years later.
Signs and symptoms
The key symptoms of PFAPA are those in its name: periodic high feverFever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
at intervals of about 3–5 weeks, as well as aphthous ulcer
Aphthous ulcer
An aphthous ulcer , also known as a canker sore, is a type of mouth ulcer which presents as a painful open sore inside the mouth or upper throat characterized by a break in the mucous membrane. Its cause is unknown, but they are not contagious...
s, pharyngitis
Pharyngitis
Pharyngitis is an inflammation of the throat or pharynx. In most cases it is quite painful, and is the most common cause of a sore throat.Like many types of inflammation, pharyngitis can be acute – characterized by a rapid onset and typically a relatively short course – or chronic....
and/or adenitis
Adenitis
Adenitis is a general term for an inflammation of a gland or lymph node.-Lymph node adenitis:"Lymph adenitis" or "lymph node adenitis" is caused by bacterial infection in lymph nodes. The infected lymph nodes typically become enlarged, warm and tender. A swelling of lymph nodes due to growth of...
. In between episodes, and even during the episodes, the children appear healthy. At least 6 months of episodes. Recurrent negative throat cultures. Other causes excluded (EBV, CMV, FMF).
Cause
PFAPA is frequently discussed together with other periodic fever syndromePeriodic fever syndrome
The periodic fever syndromes are a set of disorders, many of which are genetic disorders in which the mechanisms which initiate and control inflammation are disturbed, leading to uncontrolled inflammation throughout the body...
s, but it is unknown whether the cause is primarily gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
tic or due to an initial infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
.
The condition appears to be the result of a disturbance of innate immunity. The changes in the immune system are complex and 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
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
induced (AIM2, IP-10/CXCL10) genes. T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
associated gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s (CD3
CD3
CD3 or CD-3 may be:* CD3 , an antigen, cluster of differentiation protein , part of the T cell receptor complex on a mature T lymphocyte* Ford CD3 platform* MediaMax CD-3, copy protection scheme* MiniCD, a 3-inch CD...
, CD8B) are down regulated. Flares are accompanied by increased serum levels of activated T lymphocyte chemokines (IP-10/CXCL10, MIG/CXCL9), G-CSF and proinflammatory cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s (interleukin 6, interleukin 18). Flares also manifest with a relative lymphopenia. Activated CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
(+)/CD25
CD25
CD25 is the alpha chain of the IL-2 receptor. It is a type I transmembrane protein present on activated T cells, activated B cells, some thymocytes, myeloid precursors, and oligodendrocytes that associates with CD122 to form a heterodimer that can act as a high-affinity receptor for IL-2.CD25 is...
(+) 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 counterregulatory IL-1 receptor antagonist.
Treatment
A possible treatment for PFAPA is a single dose of prednisonePrednisone
Prednisone is a synthetic corticosteroid drug that is particularly effective as an immunosuppressant drug. It is used to treat certain inflammatory diseases and some types of cancer, but has significant adverse effects...
(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
Colchicine
Colchicine is a medication used for gout. It is a toxic natural product and secondary metabolite, originally extracted from plants of the genus Colchicum...
, which is used in the treatment of FMF. In one study, adenotonsillectomy 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
Interleukin
Interleukins are a group of cytokines that were first seen to be expressed by white blood cells . The term interleukin derives from "as a means of communication", and "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes"...
-1 inhibition appears to be effective in treating this condition.