Throughout history treatment relied primarily on β-lactam antibiotics. In the 1960s nearly all strains of "S. pneumoniae" were susceptible to penicillin, but more recently there has been an increasing prevalence of penicillin resistance especially in areas of high antibiotic use. A varying proportion of strains may also be resistant to cephalosporins, macrolides (such as erythromycin), tetracycline, clindamycin and the quinolones. Penicillin-resistant strains are more likely to be resistant to other antibiotics. Most isolates remain susceptible to vancomycin, though its use in a β-lactam-susceptible isolate is less desirable because of tissue distribution of the drug and concerns of development of vancomycin resistance. More advanced beta-lactam antibiotics (cephalosporins) are commonly used in combination with other drugs to treat meningitis and community-acquired pneumonia. In adults recently developed fluoroquinolones such as levofloxacin and moxifloxacin are often used to provide empiric coverage for patients with pneumonia, but in parts of the world where these drugs are used to treat tuberculosis resistance has been described.

Susceptibility testing should be routine with empiric antibiotic treatment guided by resistance patterns in the community in which the organism was acquired. There is currently debate as to how relevant the results of susceptibility testing are to clinical outcome. There is slight clinical evidence that penicillins may act synergistically with macrolides to improve outcomes.

Fulminant infection from meningococci bacteria in the bloodstream is a medical emergency and requires emergent treatment with adequate antibiotics. Benzylpenicillin was once the drug of choice with chloramphenicol as a good alternative in allergic patients. Ceftriaxone is an antibiotic commonly employed today. Hydrocortisone can sometimes reverse the adrenal insufficiency. Plastic surgery and tissue grafting are sometimes needed to treat tissue necrosis resulting from the infection.

Because of the increased risk of infection, physicians administer oral antibiotics as a prophylaxis after a surgical splenectomy (or starting at birth, for congenital asplenia or functional asplenia).

Those with asplenia are also cautioned to start a full-dose course of antibiotics at the first onset of an upper or lower respiratory tract infection (for example, sore throat or cough), or at the onset of any fever.

An overwhelming post-splenectomy infection (OPSI) or Overwhelming post-splenectomy sepsis (OPSS) is a rare but rapidly fatal infection occurring in individuals following removal of the spleen. The infections are typically characterized by either meningitis or sepsis, and are caused by encapsulated organisms including "Streptococcus pneumoniae".

The risk of OPSI is 0.23–0.42 percent per year, with a lifetime risk of 5 percent. Most infections occur in the first few years following splenectomy, but the risk of OPSI is lifelong. OPSI is almost always fatal without treatment, and modern treatment has decreased the mortality to approximately 40–70 percent. Individuals with OPSI are most commonly treated with antibiotics and supportive care. Measures to prevent OPSI include vaccination and prophylactic antibiotics.

The suppression of CD4 T cells by HIV (or by immunosuppressive drugs) causes a decrease in the body's normal response to certain infections. Not only does this make it more difficult to fight the infection, it may mean that a level of infection that would normally produce symptoms is instead undetected (subclinical infection). If the CD4 count rapidly increases (due to effective treatment of HIV, or removal of other causes of immunosuppression), a sudden increase in the inflammatory response produces nonspecific symptoms such as fever, and in some cases a worsening of damage to the infected tissue.

There are two common IRIS scenarios. The first is the “unmasking” of an opportunistic infection. The second is the “paradoxical” symptomatic relapse of a prior infection despite microbiologic treatment success. Often in paradoxical IRIS, microbiologic cultures are sterile. In either scenario, there is hypothesized reconstitution of antigen-specific T cell-mediated immunity with activation of the immune system following HIV therapy against persisting antigen, whether present as intact organisms, dead organisms, or debris.

Though these symptoms can be dangerous, they also indicate that the body may now have a better chance to defeat the infection. The best treatment for this condition is unknown. In paradoxical IRIS reactions, the events will usually spontaneously get better with time without any additional therapy. In unmasking IRIS, the most common treatment is to administer antibiotic or antiviral drugs against the infectious organism. In some severe cases, anti-inflammatory medications, such as corticosteroids are needed to suppress inflammation until the infection has been eliminated.

Infections most commonly associated with IRIS include "Mycobacterium tuberculosis" and cryptococcal meningitis. Persons living with AIDS are more at risk for IRIS if they are starting for the first time, or if they have recently been treated for an opportunistic infection (OI). It is generally advised that when patients have low initial CD4 T cell count and opportunistic infection at the time of their HIV diagnosis, they receive treatment to control the opportunistic infections before HAART is initiated approximately two weeks later. This is true for most OIs, except for OIs involving the central nervous system.

It is suggested that splenectomized persons receive the following vaccinations, and ideally prior to planned splenectomy surgery:

- Pneumococcal polysaccharide vaccine (not before 2 years of age). Children may first need one or more boosters of pneumococcal conjugate vaccine if they did not complete the full childhood series.

- Haemophilus influenzae type b vaccine, especially if not received in childhood. For adults who have not been previously vaccinated, two doses given two months apart was advised in the new 2006 UK vaccination guidelines (in the UK may be given as a combined Hib/MenC vaccine).

- Meningococcal conjugate vaccine, especially if not received in adolescence. Previously vaccinated adults require a single booster and non-immunised adults advised, in UK since 2006, to have two doses given two months apart. Children too young for the conjugate vaccine should receive meningococcal polysaccharide vaccine in the interim.

- Influenza vaccine, every winter, to help prevent getting secondary bacterial infection.

The spleen contains many macrophages (part of the reticuloendothelial system), which are immune cells that phagocytose (eat) and destroy bacteria. In particular, these macrophages are activated when bacteria are bound by IgG antibodies (IgG1 or IgG3) or the complement component C3b. These types of antibodies and complement are immune substances called opsonizers, molecules that bind to the surface of bacteria to facilitate phagocytosis.

When the spleen is no longer present (asplenia), IgG and C3b are still bound to bacteria, but they cannot be removed from the blood circulation due to the loss of the splenic macrophages. Hence the bacteria are free to cause infection.

Patients without spleens often need immunizations against pathogens that normally require opsonization and phagocytosis by macrophages in the spleen. These include common human pathogens with bacterial capsules ("Streptococcus pneumoniae, Salmonella typhi, Neisseria meningitidis, E. coli, Hemophilus influenzae, Streptococcus agalactiae, Klebsiella pneumoniae"). Capsules made of polysaccharides (sugars) permit bacteria to evade phagocytosis by macrophages alone, since only proteins are directly recognized by macrophages in phagocytosis. So humoral immunity in forms of IgG and complement proteins is the human immune system's response against bacterial capsules.

Treatment is directed at the prevention of haemorrhagic shock. Standard dose prednisolone does not increase the platelet count. High-dose methylprednisolone therapy in children with Onyalai has been shown to improve platelet count and reduce the requirement for transfusions. Vincristine sulphate may be of benefit to some patients. Splenectomy is indicated in patients with severe uncontrollable haemorrhage. High-dose intravenous gammaglobulin may help in increasing the platelet count and cessation of haemorrhage.

Splenectomy is usually ineffective for the treatment of cold agglutinin disease, because the liver is the predominant site of sequestration. However, if the patient has splenomegaly, then the disease may respond to splenectomy. More importantly, a lymphoma localized to the spleen may only be found after splenectomy.

Discontinuation of heparin is critical in a case of heparin-induced thrombocytopenia (HIT). Beyond that, however, clinicians generally treat to avoid a thrombosis, often by starting patients directly on warfarin. For this reason, patients are usually treated with a direct thrombin inhibitor, such as lepirudin or argatroban, which are approved by the FDA for this use. Other blood thinners sometimes used in this setting that are not FDA-approved for treatment of HIT include bivalirudin and fondaparinux. Platelet transfusions are not routinely used to treat HIT because thrombosis, not bleeding, is the primary problem.

A single case report suggested that oral dapsone may be useful for prevention. However, the efficacy of oral dapsone as prevention has not been demonstrated very clearly until now.

Corticosteroids and immunoglobulins are two commonly used treatments for warm antibody AIHA. Initial medical treatment consists of prednisone. If ineffective, splenectomy should be considered.

If refractory to both these therapies, other options include rituximab, danazol, cyclosphosphamide, azathioprine, or ciclosporin.

High-dose intravenous immune globulin may be effective in controlling hemolysis, but the benefit is short lived (1–4 weeks), and the therapy is very expensive.

Patients with cold agglutinin disease should include good sources of folic acid, such as fresh fruits and vegetables, in their diet. Activities for these individuals should be less strenuous than those for healthy people, particularly for patients with anemia. Jogging in the cold could be very hazardous because of the added windchill factor.

Due to the high mortality of untreated TTP, a presumptive diagnosis of TTP is made even when only microangiopathic hemolytic anemia and thrombocytopenia are seen, and therapy is started. Transfusion is contraindicated in thrombotic TTP, as it fuels the coagulopathy. Since the early 1990s, plasmapheresis has become the treatment of choice for TTP. This is an exchange transfusion involving removal of the patient's blood plasma through apheresis and replacement with donor plasma (fresh frozen plasma or cryosupernatant); the procedure must be repeated daily to eliminate the inhibitor and abate the symptoms. If apheresis is not available, fresh frozen plasma can be infused, but the volume that can be given safely is limited due to the danger of fluid overload. Plasma infusion alone is not as beneficial as plasma exchange. Corticosteroids (prednisone or prednisolone) are usually given. Rituximab, a monoclonal antibody aimed at the CD20 molecule on B lymphocytes, may be used on diagnosis; this is thought to kill the B cells and thereby reduce the production of the inhibitor. A stronger recommendation for rituximab exists where TTP does not respond to corticosteroids and plasmapheresis.

Caplacizumab is an alternative option in treating TTP as it has been shown that it induces a faster disease resolution compared with those patient who were on placebo. However, the use of caplacizumab was associated with increase bleeding tendencies in the studied subjects.

Most patients with refractory or relapsing TTP receive additional immunosuppressive therapy, e.g. vincristine, cyclophosphamide, splenectomy or a combination of the above.

Children with Upshaw-Schülman syndrome receive prophylactic plasma every two to three weeks; this maintains adequate levels of functioning ADAMTS13. Some tolerate longer intervals between plasma infusions. Additional plasma infusions may necessary for triggering events, such as surgery; alternatively, the platelet count may be monitored closely around these events with plasma being administered if the count drops.

Measurements of blood levels of lactate dehydrogenase, platelets, and schistocytes are used to monitor disease progression or remission. ADAMTS13 activity and inhibitor levels may be measured during follow-up, but in those without symptoms the use of rituximab is not recommended.

Bats recovering from white-nose syndrome (WNS) may be the first natural occurrence of IRIS, in a report released by the USGS. WNS is typified by a cutaneous infection of the fungus "Pseudogymnoascus destructans" during hibernation, when the immune system is naturally suppressed to conserve energy through the winter. This study suggests that bats undergoing an intense inflammation at the site of infection after a return to euthermia is a form of IRIS.

If the splenomegaly underlies hypersplenism, a splenectomy is indicated and will correct the hypersplenism. However, the underlying cause of the hypersplenism will most likely remain; consequently, a thorough diagnostic workup is still indicated, as, leukemia, lymphoma and other serious disorders can cause hypersplenism and splenomegaly. After splenectomy, however, patients have an increased risk for infectious diseases.

Patients undergoing splenectomy should be vaccinated against "Haemophilus influenzae", "Streptococcus pneumoniae", and "Meningococcus". They should also receive annual influenza vaccinations. Long-term prophylactic antibiotics may be given in certain cases.

In cases of infectious mononucleosis splenomegaly is a common symptom and health care providers may consider using abdominal ultrasonography to get insight into a person's condition. However, because spleen size varies greatly, ultrasonography is not a valid technique for assessing spleen enlargement and should not be used in typical circumstances or to make routine decisions about fitness for playing sports.

There is no real treatment for Felty's syndrome, rather the best method in management of the disease is to control the underlying rheumatoid arthritis. Immunosuppressive therapy for RA often improves granulocytopenia and splenomegaly; this finding reflects the fact that Felty's syndrome is an immune-mediated disease. A major challenge in treating FS is recurring infection caused by neutropenia. Therefore, in order to decide upon and begin treatment, the cause and relationship of neutropenia with the overall condition must be well understood. Most of the traditional medications used to treat RA have been used in the treatment of Felty's syndrome. No well-conducted, randomized, controlled trials support the use of any single agent. Most reports on treatment regimens involve small numbers of patients.

Splenectomy may improve neutropenia in severe disease.

Use of rituximab and leflunomide have been proposed.

Use of gold therapy has also been described.

Prognosis is dependent on the severity of symptoms and the patient's overall health.

Treatment primarily consists of reducing eosinophil levels and preventing further damage to organs. Corticosteroids, such as Prednisone, are good for reducing eosinophil levels and antineoplastics are useful for slowing eosinophil production. Surgical therapy is rarely utilised, however splenectomy can reduce the pain due to spleen enlargement. If damage to the heart (in particular the valves), then prosthetic valves can replace the current organic ones. Follow-up care is vital for the survival of the patient, as such the patient should be checked for any signs of deterioration regularly. After promising results in drug trials (95% efficiency in reducing blood eosinophil count to acceptable levels) it is hoped that in the future hypereosinophilic syndrome, and diseases related to eosinophils such as asthma and eosinophilic granulomatosis with polyangiitis, may be treated with the monoclonal antibody Mepolizumab currently being developed to treat the disease. If this becomes successful, it may be possible for corticosteroids to be eradicated and thus reduce the amount of side effects encountered.

NEH is self-limited and usually resolves without treatment. In the overwhelming majority of the cases, spontaneous resolution occurs within 1–2 weeks.

However, if the patient developed NEH after chemotherapy, the offending cytotoxic drug has to be discontinued, and the patient must avoid this particular cytotoxic drug in the future, because NEH usually re occurs upon re exposure to the same cytotoxic drug.

Despite the fact that NEH is self limited and usually resolves without treatment, some researchers use treatment, mainly systemic corticosteroids, although the efficacy of such a therapy has not been demonstrated in a large randomised controlled clinical trial until now.

Doxycycline and minocycline are the medications of choice. For people allergic to antibiotics of the tetracycline class, rifampin is an alternative. Early clinical experience suggested that chloramphenicol may also be effective, however, in vitro susceptibility testing revealed resistance.

Thrombopoietin receptor agonists are pharmaceutical agents that stimulate platelet production in the bone marrow. In this, they differ from the previously discussed agents that act by attempting to curtail platelet destruction. Two such products are currently available:

- Romiplostim (trade name Nplate) is a thrombopoiesis stimulating Fc-peptide fusion protein (peptibody) that is administered by subcutaneous injection. Designated an orphan drug in 2003 under United States law, clinical trials demonstrated romiplostim to be effective in treating chronic ITP, especially in relapsed post-splenectomy patients. Romiplostim was approved by the United States Food and Drug Administration (FDA) for long-term treatment of adult chronic ITP on August 22, 2008.

- Eltrombopag (trade name Promacta in the USA, Revolade in the EU) is an orally-administered agent with an effect similar to that of romiplostim. It too has been demonstrated to increase platelet counts and decrease bleeding in a dose-dependent manner. Developed by GlaxoSmithKline and also designated an orphan drug by the FDA, Promacta was approved by the FDA on November 20, 2008.

Side effects of thrombopoietin receptor agonists include headache, joint or muscle pain, dizziness, nausea or vomiting, and an increased risk of blood clots.

Bone marrow/stem cell transplants are the only known cures for this genetic disease. Frequent platelet transfusions are required to keep the patient from bleeding to death before the transplant can be performed, although this is not always the case.

There is increasing use of immunosuppressants such as mycophenolate mofetil and azathioprine because of their effectiveness. In chronic refractory cases, where immune pathogenesis has been confirmed, the off-label use of the "vinca" alkaloid and chemotherapy agent vincristine may be attempted. However, vincristine has significant side effects and its use in treating ITP must be approached with caution, especially in children.

Routine vaccination against meningococcus is recommended by the Centers for Disease Control and Prevention for all 11- to 18-year-olds and people who have poor splenic function (who, for example, have had their spleen removed or who have sickle-cell disease which damages the spleen), or who have certain immune disorders, such as a complement deficiency.

Antibiotic ointment is typically applied to the newborn's eyes within 1 hour of birth as prevention against gonococcal ophthalmia. This maybe erythromycin, tetracycline, or silver nitrate.