The prognosis is guarded with an overall mortality of 50%. Poor prognostic factors included HLH associated with malignancy, with half the patients dying by 1.4 months compared to 22.8 months for non-tumour associated HLH patients.

Secondary HLH in some individuals may be self-limited because patients are able to fully recover after having received only supportive medical treatment (i.e., IV immunoglobulin only). However, long-term remission without the use of cytotoxic and immune-suppressive therapies is unlikely in the majority of adults with HLH and in those with involvement of the central nervous system (brain and/or spinal cord).

Five genetic subtypes (FHL1, FHL2, FHL3, FHL4, and FHL5) are described, with an estimated prevalence of one in 50,000 and equal gender distribution. Molecular genetic testing for four of the causative genes, PRF1 (FHL2), UNC13D (FHL3), STX11 (FHL4), and STXBP2 (FHL5), is available on a clinical basis. Symptoms of FHL are usually evident within the first few months of life and may even develop "in utero". However, symptomatic presentation throughout childhood and even into young adulthood has been observed in some cases.

The five subtypes of FHL are each associated with a specific gene:

- FHL1: "HPLH1"

- FHL2: "PRF1" (Perforin)

- FHL3: "UNC13D" (Munc13-4)

- FHL4: "STX11" (Syntaxin 11)

- FHL5: "STXBP2" (Syntaxin binding protein 2)/UNC18-2

Nearly half of the cases of type 2 familial hemophagocytic lymphohistiocytosis are due to bi-allelic PRF1 mutations.

Iatrogenic causes of pancytopenia include chemotherapy for malignancies if the drug or drugs used cause bone marrow suppression. Rarely, drugs (antibiotics, blood pressure medication, heart medication) can cause pancytopenia.

The antibiotics Linezolid and Chloramphenicol can cause pancytopenia in some individuals.

Rarely, pancytopenia may have other causes, such as mononucleosis, or other viral diseases. Increasingly, HIV is itself a cause for pancytopenia.

- Familial hemophagocytic syndrome

- Aplastic anemia

- Gaucher's disease

- metastatic carcinoma of bone

- Multiple Myeloma

- overwhelming infections

- Lymphoma

- myelofibrosis

- Dyskeratosis congenita

- Myelodysplastic syndrome

- Leukemia

- Leishmaniasis

- Severe Folate or vitamin B12 deficiency

- Systemic lupus erythematosus

- Paroxysmal nocturnal hemoglobinuria (blood test)

- Viral infections (such as HIV, EBV--undetermined virus is most common).

- Alimentary toxic aleukia

- Copper deficiency

- Pernicious anemia

- Medication

- Hypersplenism

- Osteopetrosis

- Organic acidurias (Propionic Acidemia, Methylmalonic Aciduria, Isovaleric Aciduria)

- Low dose arsenic poisoning

- Sako disease (Myelodysplastic-cytosis)

- Chronic radiation sickness

- LIG4 syndrome

The disease is marked by an inappropriate and ineffective T cell activation that leads to an increased hemophagocytic activity. The T cell activated macrophages engulf erythrocytes, leukocytes, platelets, as well as their progenitor cells. Such finding is common in the syndrome, which is also referred to as hemophagocytic lymphohistiocytosis (HLH). Along with pancytopenia, HLH is characterized by fever, splenomegaly, and hemophagocytosis in bone marrow, liver, or lymph nodes.

This rare form of leukemia is more common among Asians in comparison to other ethnic groups. It is typically diagnosed in adolescents and young adults, with a slight predominance in males.

Secondary immunodeficiencies, also known as acquired immunodeficiencies, can result from various immunosuppressive agents, for example, malnutrition, aging, particular medications (e.g., chemotherapy, disease-modifying antirheumatic drugs, immunosuppressive drugs after organ transplants, glucocorticoids) and environmental toxins like mercury and other heavy metals, pesticides and petrochemicals like styrene, dichlorobenzene, xylene, and ethylphenol. For medications, the term "immunosuppression" generally refers to both beneficial and potential adverse effects of decreasing the function of the immune system, while the term "immunodeficiency" generally refers solely to the adverse effect of increased risk for infection.

Many specific diseases directly or indirectly cause immunosuppression. This includes many types of cancer, particularly those of the bone marrow and blood cells (leukemia, lymphoma, multiple myeloma), and certain chronic infections. Immunodeficiency is also the hallmark of acquired immunodeficiency syndrome (AIDS), caused by the human immunodeficiency virus (HIV). HIV directly infects a small number of T helper cells, and also impairs other immune system responses indirectly.

Various hormonal and metabolic disorders can also result in immune deficiency including anemia, hypothyroidism, diabetes and hypoglycemia.

Smoking, alcoholism and drug abuse also depress immune response.

By definition, primary immune deficiencies are due to genetic causes. They may result from a single genetic defect, but most are multifactorial. They may be caused by recessive or dominant inheritance. Some are latent, and require a certain environmental trigger to become manifest, like the presence in the environment of a reactive allergen. Other problems become apparent due to aging of bodily and cellular maintenance processes.

The cause of immunodeficiency varies depending on the nature of the disorder. The cause can be either genetic or acquired by malnutrition and poor sanitary conditions. Only for some genetic causes, the exact genes are known. Although there is no true discrimination to who this disease affects, the genes are passed from mother to child, and on occasion from father to child. Women tend not to show symptoms due to their second X chromosome not having the mutation while man are symptomatic, due to having one X chromosome.

Platelet storage pool deficiency is a type of coagulopathy characterized by defects in the granules in platelets, particularly a lack of granular non-metabolic ADP. Individuals with ADP deficient "storage pool disease" present a prolonged bleeding time due to impaired aggregation response to fibrillar collagen.

The "presentation" (signs/symptoms) of an individual with platelet storage pool deficiency is as follows:

A survey of 10,000 American households revealed that the prevalence of diagnosed primary immunodeficiency approaches 1 in 1200. This figure does not take into account people with mild immune system defects who have not received a formal diagnosis.

Milder forms of primary immunodeficiency, such as selective immunoglobulin A deficiency, are fairly common, with random groups of people (such as otherwise healthy blood donors) having a rate of 1:600. Other disorders are distinctly more uncommon, with incidences between 1:100,000 and 1:2,000,000 being reported.

A similar disease is diffuse histiocytic sarcoma, a term used to designate a localized histiocytic sarcoma that has spread throughout the body.

Another disease of histiocytic origin that affects Bernese Mountain Dogs is systemic histiocytosis. This condition generally begins as lesions on the eyelids, nasal mucosa, and skin, especially the scrotum. It progresses to a more generalized disease affecting the lymph nodes, bone marrow and spleen. Other signs and symptoms include weight loss and loss of appetite. It also has a very poor prognosis.

Pralatrexate is one compound currently under investigations for the treatment of PTCL.

Treatment with chemotherapy has been used with some success, particularly using lomustine, prednisone, doxorubicin, and cyclophosphamide. Because of the rapid progression of this aggressive disease, the prognosis is very poor.

In many cases a trigger is identified, often a viral infection, or a medication. There is uncontrolled activation and proliferation of macrophages, and T lymphocytes, with a marked increase in circulating cytokines, such as IFN-gamma, and GM-CSF. The underlying causative event is unclear, and is the subject of ongoing research. In many cases of MAS, a decreased natural killer cell (NK-cell) function is found.

Strangely, in boys with X-linked lymphoproliferative disorder, there is an inability to mount an immune response to the Epstein-Barr virus (EBV), which often leads to death from bone marrow failure, irreversible hepatitis, and malignant lymphoma. However, the connection between EBV and X-linked lymphoproliferative disorder is yet to be determined.

Patients produce insufficient numbers of CD27 memory B cells.

A second form is associated with "XIAP".

Some sources recommend classifying this condition as "X-linked familial hemophagocytic lymphohistiocytosis" instead of X-linked lymphoproliferative disease.

Primary immune deficiency diseases are those caused by inherited genetic mutations. Secondary or acquired immune deficiencies are caused by something outside the body such as a virus or immune suppressing drugs.

Primary immune diseases are at risk to an increased susceptibility to, and often recurrent ear infections, pneumonia, bronchitis, sinusitis or skin infections. Immunodeficient patients may less frequently develop abscesses of their internal organs, autoimmune or rheumatologic and gastrointestinal problems.

- Primary immune deficiencies

- Severe combined immunodeficiency (SCID)

- DiGeorge syndrome

- Hyperimmunoglobulin E syndrome (also known as Job’s Syndrome)

- Common variable immunodeficiency (CVID): B-cell levels are normal in circulation but with decreased production of IgG throughout the years, so it is the only primary immune disorder that presents onset in the late teens years.

- Chronic granulomatous disease (CGD): a deficiency in NADPH oxidase enzyme, which causes failure to generate oxygen radicals. Classical recurrent infection from catalase positive bacteria and fungi.

- Wiskott-Aldrich syndrome (WAS)

- Autoimmune lymphoproliferative syndrome (ALPS)

- Hyper IgM syndrome: X-linked disorder that causes a deficiency in the production of CD40 ligand on activated T-cells. This increases the production and release of IgM into circulation. The B-cell and T-cell numbers are within normal limits. Increased susceptibility to extracellular bacteria and opportunistic infections.

- Leukocyte adhesion deficiency (LAD)

- NF-κB Essential Modifier (NEMO) Mutations

- Selective immunoglobulin A deficiency: the most common defect of the humoral immunity, characterized by a deficiency of IgA. Produces repeating sino-pulmonary and gastrointestinal infections.

- X-linked agammaglobulinemia (XLA; also known as Bruton type agammaglobulinemia): characterized by a deficiency in tyrosine kinase enzyme that blocks B-cell maturation in the bone marrow. No B-cells are produced to circulation and thus, there are no immunoglobulin classes, although there tends to be a normal cell-mediated immunity.

- X-linked lymphoproliferative disease (XLP)

- Ataxia-telangiectasia

- Secondary immune deficiencies

- AIDS

Certain mutations in the fibrinogen Aα-chain gene cause a form of familial renal amyloidosis termed hereditary fibrinogen Aα-Chain amyloidosis. The disorder is due to autosomal dominant inheritance of Aα chain mutations the most common of which is hemoglobin Indianopolis, a heterzyogus missense (c.1718G>T: Arg554Leu) mutation. Other missense mutations causing this disorder are unnamed; they include 1634A>T: Glu526Val; c.1670C>A: Thr538lys; c.1676A.T:Glu540Val; and c1712C>A:Pro552Hi. A deletion mutation causing a frameshift viz., c.1622delT: Thr525Leufs, is also a cause of the disorder. The fibrinogen bearing these mutant Aα-chains is secreted into the circulation and gradually accumulates in, and causes significant injury to, the kidney. The mutant fibrinogen does not appear to accumulate in, or injure, extra-renal tissues.

Individuals experiencing episodic bleeding as a result of congenital dysfibrinogenemia should be treated at a center specialized in treating hemophilia. They should avoid all medications that interfere with normal platelet function. During bleeding episodes, treatment with fibrinogen concentrates or in emergencies or when these concentrates are unavailable, infusions of fresh frozen plasma and/or cryoprecipitate (a fibrinogen-rich plasma fraction) to maintain fibrinogen activity levels >1 gram/liter. Tranexamic acid or fibrinogen concentrates are recommended for prophylactic treatment prior to minor surgery while fibrinogen concentrates are recommended prior to major surgery with fibrinogen concentrates usage seeking to maintain fibrinogen activity levels at >1 gram/liter. Women undergoing vaginal or Cesarean child birth should be treated at a hemophilia center with fibrinogen concentrates to maintain fibrinogen activity levels at 1.5 gram/liter. The latter individuals require careful observation for bleeding during their post-partum periods.

Individuals experiencing episodic thrombosis as a result of congenital dysfibrinogenemia should also be treated at a center specialized in treating hemophilia using antithrombotic agents. They should be instructed on antithrombotic behavioral methods fur use in high risk situations such as long car rides and air flights. Venous thrombosis should be treated with low molecular weight heparin for a period that depends on personal and family history of thrombosis events. Prophylactic treatment prior to minor surgery should avoid fibrinogen supplementation and use prophylactic anticoagulation measures; prior to major surgery, fibrinogen supplementation should be used only if serious bleeding occurs; otherwise, prophylactic anticoagulation measures are recommended.

Macrophage-activation syndrome (MAS) is a severe, potentially life-threatening, complication of several chronic rheumatic diseases of childhood. It occurs most commonly with systemic-onset juvenile idiopathic arthritis (SoJIA). In addition, MAS has been described in association with systemic lupus erythematosus (SLE), Kawasaki disease, and adult-onset Still's disease. It is thought to be closely related and pathophysiologically very similar to reactive (secondary) hemophagocytic lymphohistiocytosis (HLH). The incidence of MAS is unknown as there is a wide spectrum of clinical manifestations, and episodes may remain unrecognized.

An allergy is an abnormal immune reaction to a harmless antigen.

- Seasonal allergy

- Mastocytosis

- Perennial allergy

- Anaphylaxis

- Food allergy

- Allergic rhinitis

- Atopic dermatitis

Griscelli syndrome type 2 (also known as "partial albinism with immunodeficiency") is a rare autosomal recessive syndrome characterized by variable pigmentary dilution, hair with silvery metallic sheen, frequent pyogenic infections, neutropenia, and thrombocytopenia.

Sideroblastic anemias are often described as responsive or non-responsive in terms of increased hemoglobin levels to pharmacological doses of vitamin B.

1- Congenital: 80% are responsive, though the anemia does not completely resolve.

2- Acquired clonal: 40% are responsive, but the response may be minimal.

3- Acquired reversible: 60% are responsive, but course depends on treatment of the underlying cause.

Severe refractory sideroblastic anemias requiring regular transfusions and/or that undergo leukemic transformation (5-10%) significantly reduce life expectancy.

Causes of sideroblastic anemia can be categorized into three groups: congenital sideroblastic anemia, acquired clonal sideroblastic anemia, and acquired reversible sideroblastic anemia. All cases involve dysfunctional heme synthesis or processing. This leads to granular deposition of iron in the mitochondria that form a ring around the nucleus of the developing red blood cell. Congenital forms often present with normocytic or microcytic anemia while acquired forms of sideroblastic anemia are often normocytic or macrocytic.

- Congenital sideroblastic anemia

- X-linked sideroblastic anemia: This is the most common congenital cause of sideroblastic anemia and involves a defect in ALAS2, which is involved in the first step of heme synthesis. Although X-linked, approximately one third of patients are women due to skewed X-inactivation (lyonizations).

- Autosomal recessive sideroblastic anemia involves mutations in the SLC25A38 gene. The function of this protein is not fully understood, but it is involved in mitochondrial transport of glycine. Glycine is a substrate for ALAS2 and necessary for heme synthesis. The autosomal recessive form is typically severe in presentation.

- Genetic syndromes: Rarely, sideroblastic anemia may be part of a congenital syndrome and present with associated findings, such as ataxia, myopathy, and pancreatic insufficiency.

- Acquired clonal sideroblastic anemia

- Clonal sideroblastic anemias fall under the broader category of myelodysplastic syndromes (MDS). Three forms exist and include refractory anemia with ringed sideroblasts (RARS), refractory anemia with ringed sideroblasts and thrombocytosis (RARS-T), and refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS). These anemias are associated with increased risk for leukemic evolution.

- Acquired reversible sideroblastic anemia

- Causes include excessive alcohol use (the most common cause of sideroblastic anemia), pyridoxine deficiency, lead poisoning, and copper deficiency. Excess zinc can indirectly cause sideroblastic anemia by decreasing absorption and increasing excretion of copper. Antimicrobials that may lead to sideroblastic anemia include isoniazid, chloramphenicol, cycloserine, and linezolid.