●When to suspect the diagnosis of ACD – The anemia of chronic disease (ACD) is suspected in a patient with a chronic infectious, inflammatory, or malignant condition who has a mild to moderate normocytic, normochromic hypoproliferative anemia. The presence of laboratory findings consistent with ACD in a patient with no obvious underlying condition should initiate a search for the cause. (See 'Typical presentation' above and 'Suspecting the diagnosis' above.)
●Making the diagnosis of ACD – Appropriate initial studies for patients with suspected ACD include the following (see 'Laboratory findings' above):
•Complete blood count, reticulocyte percentage, white blood cell and platelet counts
•Serum iron studies (ie, serum iron, total iron binding capacity [transferrin], ferritin)
•Serum creatinine and estimated glomerular filtration rate (eGFR)
•Measurement of acute phase reactants (eg, sedimentation rate, C-reactive protein)
ACD is most likely when all of the following are present (see 'Making the diagnosis' above):
•Low serum iron
•Normal to low serum transferrin (total iron binding capacity)
•Normal to increased serum ferritin
•Elevated erythrocyte sedimentation rate and/or C-reactive protein
●Differential diagnosis – Although the differential diagnosis of mild to moderate anemia is wide, the following conditions should be considered (see 'Differential diagnosis' above):
•Hypoproliferative anemias (eg, renal disease, endocrine disorders).
•Iron deficiency anemia (IDA).
•Thalassemia.
•Sideroblastic anemias, including inherited disorders and sideroblastic myelodysplastic syndrome/myeloproliferative syndrome variants. (See "Sideroblastic anemias: Diagnosis and management".)
●Coexisting iron deficiency – Coexisting iron deficiency may be seen in patients with ACD. Its presence is suggested by the finding of low serum ferritin levels, absence of stainable iron on bone marrow aspiration/biopsy, an increased soluble transferrin receptor (sTfR)/ferritin index, and/or a response to administration of oral or intravenous iron. (See 'Concomitant iron deficiency' above.)
●Treatment – Most patients with ACD have mild anemia that produces no symptoms, being compatible with the patient's often limited lifestyle. Accordingly, treatment should be limited to those with symptomatic anemia.
•First-line therapy in ACD is directed at treatment of the underlying cause. (See 'Underlying disorder' above.)
•For most patients with ACD who do not have an underlying malignancy and who have symptomatic anemia and a hemoglobin <10 g/dL, we suggest use of an erythropoiesis-stimulating agent (ESA) at the same time as the underlying cause is being sought and treated (Grade 2C). Observational evidence suggests that response to an ESA is most likely to occur only if the erythropoietin level is less than 500 international units/L. (See 'Erythropoietin' above.)
Use of an ESA for the treatment of anemia in patients with malignancy and for the treatment of anemia in those infected with HIV are discussed separately. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'ESAs: efficacy, side effects, and clinical use' and "Hematologic manifestations of HIV infection: Anemia", section on 'Recombinant human erythropoietin'.)
We prefer the use of EPO over darbepoetin because a short-term response is preferred.
In order to achieve maximal response, supplemental iron should be administered, as needed, to maintain a transferrin saturation of ≥20 percent, and a serum ferritin level of ≥100 ng/mL. Intravenous iron is more effective than oral iron. (See 'Treatment issues' above.)
•Red blood cell transfusion is only warranted when patients with ACD develop symptomatic anemia despite treatment of the underlying cause and administration of an ESA with intravenous iron, or when waiting for such a response is not a viable clinical option. (See 'Transfusion' above.)
•Evidence supporting the decision to treat patients with highly symptomatic anemia and a hemoglobin level between 10 and 12 g/dL is indirect. This decision should be made based on clinical judgment, consideration of the risks and benefits of ESAs and blood transfusions, and patient preference. (See 'Initial approach' above and "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'Summary and recommendations' and "Indications and hemoglobin thresholds for red blood cell transfusion in the adult", section on 'Overview of our approach'.)
Workup for Aplastic vs. ACD
T. Stool workup
Stool tests for bacterial pathogens
Indications — For most patients who do not have severe illness or high-risk comorbidities, it is reasonable to continue expectant management for several days without microbiologic stool testing (either stool cultures or multiplex molecular panel tests). However, we obtain microbiologic stool testing for patients with acute community-acquired diarrhea and the following features (algorithm 1) [7,8,13]:
●Severe illness
•Profuse watery diarrhea with signs of hypovolemia
•Passage of >6 unformed stools per 24 hours
•Severe abdominal pain
•Need for hospitalization
●Other signs or symptoms concerning for inflammatory diarrhea
•Bloody diarrhea
•Passage of many small volume stools containing blood and mucus
•Temperature ≥38.5ºC (101.3ºF)
●High-risk host features
•Age ≥70 years
•Comorbidities, such as cardiac disease, which may be exacerbated by hypovolemia or rapid infusion of fluid
•Immunocompromising condition (including advanced HIV infection)
•Inflammatory bowel disease
•Pregnancy
●Symptoms persisting for more than one week
●Public health concerns (eg, diarrheal illness in food handlers, health care workers, and individuals in day care centers)
The main reason for microbiologic stool testing in patients with acute diarrhea is to identify a potential bacterial pathogen that would inform the potential for complications and treatment decisions. However, most infectious cases of acute diarrhea are self-limited and of viral etiology, and the rate of positive stool cultures in all comers with acute diarrhea is generally low [7,14,15]. Thus, microbiologic stool testing is typically reserved for those patients who are more likely to have a bacterial infection or who would warrant treatment if a bacterial infection were identified, as suggested by the above characteristics.
We typically perform stool cultures for microbiologic stool testing, which can identify the most common bacterial causes of diarrhea. If patients have exposures associated with certain other bacterial pathogens, special culture work-up may be warranted, as below. Many laboratories are adopting multiplex molecular panels to perform microbiologic stool testing. These issues are further discussed below. (See 'Stool culture' below and 'Multipathogen molecular panels' below.)
Routine stool cultures are of little value in patients who develop diarrhea after being hospitalized for 72 hours or more [16]. Testing for C. difficile is much more likely to be helpful [17]. (See "Clostridium difficile infection in adults: Clinical manifestations and diagnosis".)
T. Hyperammonemia
patients assigned to lactulose (30 to 60 mL in two to three divided doses so that patients passed two to three soft stools per day) had significantly fewer episodes of recurrent overt hepatic encephalopathy than patients who received placebo during 14 months of follow-up (20 versus 47 percent) [24].
30-60cc
divided by 2-3times
for 2-3times of BM / day.
T. Hemonc rec
Anemia, acute, worsening
Though she has ongoing anemia with uptrending LDH, she had negative haptoglobin on 8/26 and bilirubins are normal. This is unlikely ongoing hemolysis. She has CKD stage IV and looking back, anemia has been worsening concordant with CKD worsening (not acute exacerbation). At least some component of anemia 2/2 CKD.
- Recommend to repeat reticulocyte with CBC, no objection for repeating hapto and bil, though again hemolysis is less likely at this point
- Recommend to start erythropoietin, either epogen 50-100U/kg/wk 3 times/week or darbepoietin 0.45mcg/kg q 4weeks
Iron Overload (Liver / Spleen)
- Incidental findings on MRCP. Hepatology was consulted, discussed with Radiololgy again and determined this is MILD T1 intensity and less likely to be iron overload.
- No need for further w/u per Hepatology unless other signs to believe iron overload.
Patient discussed with Dr. Barrett
ia: Acute on chronic anemia.
likely 2/2 aplastic? viral vs. drug and/or hemolytic and/or worsening IDA
less likely 2/2 bleeding
- Obtain H&H, CMP, Coag(PT/PTT),
Anemia workup
- Reti-count, LDH, haptoglobin, Iron panel, Vit B12, Folate level, peripheral smear, stool occult
- viral workup: Parvovirus(PCR, Serology), CMV, EBV serology and DNA quantification.
- consider hemonc consult with further workup? including HIV, hepatitis panel, etc.
- Will close monitor any sign of active bleeding, VS, AM labs including CBC.
- Cont. Ferrous sulfate for now.
- Will transfuse 1 unit of pRBC
2. OHT status: 2/2 rCMP.
- Euvolemia.
- No sign of acute changes in condition.
- Basic workup: CBC, CMP, Troponin
- EKG
- Cont. current regimen.
- Cyclosporin 75mg po q12HR.
- Prednisone 10mg po qday
- Will obtain level of cyclosporin Tr. in AM.
T. Aplastic Anemia
DRUG:
Infectious causes, such as hepatitis viruses, Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), parvovirus, and mycobacteria
- hepatitis, EBV, HIV, Parvo, Mycobacteria
(mainly Parvo, EBV)
parvovirus- serology, nuclear test
CMV-
Serologic testing — A thorough serologic analysis of B19-specific antibody status includes testing for both IgM and IgG antibodies recognizing viral capsid antigen(s) (VP1 and/or VP2).
Unlike NAAT, serology testing does not appear to suffer from recognition issues between genotypes 1, 2, and 3 as the level of divergence among the strains at the amino acid level is significantly less than that seen at the nucleotide level.
●IgM antibody assays — Detecting parvovirus B19-specific IgM antibodies to viral capsid antigen(s) is the cornerstone in determining whether immunocompetent individuals are actively infected. Several parvovirus B19-specific IgM enzyme immunoassays (EIAs) are commercially available. However, the performance of these assays can vary considerably both in sensitivity (70 to 100 percent) and specificity (76 to 100 percent) [69-71].
In a study that was designed to compare correlations between parvovirus B19 viral DNA loads and antibody responses to viral antigens VP1 and VP2, the anti-VP2 EIA (Biotrin, Ltd, Dublin, Ireland, recently acquired by Diasorin S.p.A., Saluggia, Italy) demonstrated significantly better sensitivity compared to the anti-VP1 immunofluorescence assay (91 versus 66 percent); both assays had good specificity (94 and 97 percent, respectively) [72].
Parvovirus B19-specific IgM assay performance and thus its accuracy is greatly enhanced when the serologic method includes a step in its protocol to deplete or remove IgG antibodies from the serum sample [71,73]. Because IgG antibodies are present in significantly higher concentrations than IgM antibodies, assays lacking this design are subject to higher rates of false negative results due to antibody competition. The mu capture format helps minimize false negative IgM results resulting in excellent sensitivity and specificity [70,74,75]. The presence of rheumatoid factor, anti-nuclear antibodies, and Epstein-Barr virus IgM in a specimen can generate false positive IgM results.
●IgG antibody assays — Several EIA kits are commercially available for parvovirus B19-specific IgG analysis, many of which have excellent sensitivity and specificity. The different kits vary in their antigen composition: some contain recombinant VP2 alone, while others consist of a combination of VP1 and VP2 antigens. Kits containing conformational B19 antigens have improved performance over kits containing only linear B19 antigens [69].
It is well established that for better accuracy, the parvovirus B19-specific IgG enzyme immunoassay should incorporate a conformational capsid antigen. This is based on the fact that circulating IgG antibodies directed against linear epitopes of the capsid antigens gradually decline postinfection; however, parvovirus B19-specific IgG directed against conformational epitopes of those capsid antigens are maintained long term [69,76].
The choice of antigen(s) is critical when selecting a diagnostic serology assay [77,78]. Commercial companies cannot rely on native virus as a source of antigen for their kits, since parvovirus B19 isn't readily propagated in a tissue culture system. As a result, recombinant viral antigens are used. These antigens have been produced both in a prokaryotic expression vector (E. coli) and a eukaryotic expression system (Baculovirus) [79,80]. The viral antigens produced in the baculovirus system can self-assemble into empty capsids as demonstrated by electron microscopy studies, and as such are more similar to native virions than the linear antigens produced in E. coli.
Nucleic acid detection — Detecting parvovirus B19 DNA using NAAT is now routinely performed in many clinical laboratories and has been shown to be much more sensitive than antigen-based detection systems [81-83].
Appropriate clinical specimens for NAAT analysis include serum, plasma, bone marrow, amniotic fluid, and placental and fetal tissues. To ensure diagnostic testing accuracy, it is critical that the laboratory has adequately assessed the analytical performance characteristics (eg, analytical sensitivity, analytical specificity, reproducibility, and limit of detection) of the parvovirus B19 NAAT prior to its clinical implementation on each sample type that will be analyzed. As with any diagnostic test, NAAT can produce false positive and/or false negative results.
False negative NAAT results can occur in the following situations:
●If the individual's infection is due to the less common genotypes 2 or 3 if the primer and probe sequences used are located in a non-homologous gene set being used targets a divergent region [4,5,84]. Numerous PCR-based primer and probe sets have been described for detecting parvovirus B19-specific DNA target(s). Most of these oligonucleotides were designed to detect genotype 1 DNA, but not genotypes 2 or 3, which can lead to failure in detecting non-genotype 1 erythrovirus infections [4,5,84,85]. The LightCycler-Parvovirus B19 quantitative assay (Roche Diagnostics, Indianapolis, IN) is highly sensitive for genotype 1 but is not suitable for detecting genotypes 2 or 3. RealArt Parvo B19 LC PCR (Qiagen, Hamburg, GmbH) has been reported to detect all three genotypes by some investigators, but not by others [86,87].
●When specimens contain inhibitor(s). This is especially true when using a crude cell lysate rather than purified nucleic acid in the NAAT assay. An internal control should be included in each run when analyzing samples so that significant levels of inhibitors can be detected. This approach allows one to be more confident that the negative result is due to lack of detectable target and not to inhibitors in the specimen.
False positive NAAT results can occur in the following situations:
●In some immunocompromised patients, among whom parvovirus B19-specific DNA has been described to be found circulating for months or even years after the infection. This is especially true when testing bone marrow or synovial fluid [24,45,88]. Thus, detection of parvovirus B19 DNA, especially at very low levels, does not necessarily indicate an acute or recent infection.
●Contamination of either carry-over of genomic DNA during processing of a specimen containing a high viral load, or from high levels of the amplified target generated from a previous run. This is especially true in laboratories using a nested PCR assay for parvovirus B19 DNA amplification and those that do not incorporate pre-amplification contamination control steps. Risk of contamination can be reduced significantly if real-time PCR testing is used. In this approach, amplification and detection are performed in a closed, self-contained vessel that is not opened during the analysis, which eliminates post amplification handling of the amplicons.
Another strength of the real-time PCR assay is its ability to be quantitative. However, at this time it does not appear that determining viral load has a prognostic value outside of the blood banking industry [89]. Several real-time PCR assays have been described for detecting parvovirus B19 DNA. Although none have been cleared by the Food and Drug Administration, some NAAT kits comply with European requirements for health and safety (ie, Roche Molecular Diagnostics, Abbott Molecular, Altona Diagnostics) [90-94]. Several manufacturers now offer analyte specific reagents for detecting parvovirus B19 DNA; some have been designed to detect and differentiate between all three genotypes while others do not [87].
With the introduction of a World Health Organization International Standard for parvovirus B19 DNA (NIBSC 99/800), quantitative PCR assay standardization is possible [95].
A new approach to detecting disseminated viral infections, including parvovirus B19 infection, is PCR/electrospray ionization mass spectrometry (PCR/ESI-MS) [96]. This method combines target specific PCR amplification with mass spectrometry. The limit of detection for B19 using mass spectrometry, which provided sequence-derived base composition analysis, was 1.2 x 103 copies/mL.
Antigen detection — Immunohistochemical (IHC) techniques can be used to detect parvovirus B19 antigens in a variety of tissues, especially fetal and placental tissues [97-99]. There are commercially available sources of monoclonal or polyclonal parvovirus B19 specific antibodies that recognize parvovirus B19 capsid proteins VP1 and VP2. Antibodies recognizing NS1 protein have been reported, but are not yet commercially available. Although IHC techniques allow for direct visualization of virus within a tissue, it suffers from suboptimal sensitivity compared with NAAT and if used alone for diagnosis will miss parvovirus B19-positive cases [100].
Virus isolation — Freshly harvested bone marrow or fetal cord blood, or several continuous cell lines can support low level parvovirus B19 replication in vitro. However, these in vitro systems have not been used for clinical applications [101,102].
#. NEUTROPENIA (drug induced?)
2. Continue immunosuppression:
-Prednisone 5mg daily
-MMF suspended in the setting of leukopenia
-Continue tacrolimus 3mg at 0600 and 4mg at 1800
- Tac level 6.4 today
Continue immunoprophylaxis:
- nystatin resumed in the setting of neutropenia
- Valgan stopped, as course completed
-Continue Bactrim tiw
MEDS- MMF,
Hematologic & oncologic: Leukopenia (23% to 46%), anemia (26% to 43%), leukocytosis (22% to 41%), thrombocytopenia (24% to 38%), hypochromic anemia (25%)
Cont. Tac
?Cyclosporin
Hematologic & oncologic: Leukopenia (<1% to 6%), lymphoma (<1% to 6%), anemia, thrombocytopenia, upper gastrointestinal hemorrhage
T.
OHT anemia workup
- medication: MMF, + ?
- CMV, Parvovirus, Reticount/Iron/VitB12/Folate
- 1pRBC
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