Absolutely! A significant number of patients with B-12 deficiency are neither anemic nor have macrocytosis but may still have related neurological symptoms.
A large study involving a nationally representative sample of older U.S. adults (aged >50 y) sponsored by the CDC reported a prevalence of B-12 deficiency without anemia or without macrocytosis of about 4% each . 1 Interestingly, in this study, there was no evidence that mandatory folic acid fortification of certain foods was associated with lower prevalence of B-12 deficiency without anemia or macrocytosis.
In another study, the proportion of subjects with low serum B-12 but without macrocytosis was 70% or higher, irrespective of pre- or post-fortification period.2 Interestingly, in the age group <65 y, the post-fortification was associated with significantly higher proportion of patients without macrocytosis (85% vs. 45% in the prefortification period) in this study.
Younger age groups seem to also be overrepresented among patients with B-12 deficiency but no anemia, with a prevalence of 50% in <60 y age group with B-12 deficiency compared to 38% and 31% among older age groups (60-74 y and >74 y, respectively).3
So, keep B-12 deficiency in mind in the presence of compatible neurological symptoms even in the absence anemia or macrocytosis!
- Qi YP, Do AN, Hamner HC, et al. The prevalence of low serum vitamin B-12 status in the absence of anemia or macrocytosis did not increase among older U.S. adults after mandatory folic acid fortification. J Nutr 2014;144:170-76. http://jn.nutrition.org/content/144/2/170.abstract
- Wyckoff KF, Ganji V. Proportion of individuals with low serum vitamin B-12 concentrations without macrocytosis is higher in the post-folic acid fortification period than in the pre-folic acid fortification period. Am J Clin Nutr 2007;86:1187-92. https://www.ncbi.nlm.nih.gov/pubmed/17921401
- Mills JL, Von Kohorn I, Conley MR, et al. Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain. Am J Clin Nutr 2003;77:1474-7. http://ajcn.nutrition.org/content/77/6/1474.full.pdf+html
More often than you might think! The relationship between pneumonia and heart failure (HF) appears bidirectional with pneumonia precipitating heart failure (HF) and HF predisposing to it.
Although It’s often quoted that acute respiratory tract infection accounts for 3-16% of patients hospitalized with decompensated heart failure (HF) (based primarily on small observational studies),1 a 2016 large prospective study involving nearly 100,000 HF admission from 305 US hospitals has reported “pneumonia/respiratory process” as the most common precipitating clinical factor, present in 28.2% of cases (arrhythmia and medication noncompliance came in as 2nd and 3rd).2
Interestingly, the same study reported that pneumonia/respiratory process was most prevalent among patients with preserved (≥50%) ejection fraction (EF) compared to those with borderline ( 40%-49%) or reduced (<40%) EF (33% vs 30% vs 24%, respectively). 2
Pulmonary edema may in turn predispose to bacterial pneumonia through adverse effects of edema fluid on lung bacterial defense mechanisms and establishment of a culture medium for bacterial growth by the presence of fluid in the alveolar space.3
So don’t be surprised if you have to treat for both!
- Thomsen RW, Kasatpibal N, Riis A, et al. The impact of pre-existing heart failure on pneumonia prognosis: Population-based cohort study. J Gen Intern Med 2008;23:1407-13. https://www.ncbi.nlm.nih.gov/pubmed/18574639
- Kapoor JR, Kapoor R, Ju C, et al. Precipitating clinical factors, heart failure characterization, and outcomes in patients hospitalized with heart failure with reduced, borderline, and preserved ejection fraction. JACC 2016;4:464-72. https://www.scholars.northwestern.edu/en/publications/precipitating-clinical-factors-heart-failure-characterization-and
- Harris GD, Woods DE, Fine R, et al. The effect of intraalveolar fluid on lung bacterial clearance. Lung 1980; 158;91-100 Harris GD, Woods DE, Fine R, et al. The effect of intraalveolar fluid on lung bacterial clearance. Lung 1980; 158;91-100. https://link.springer.com/article/10.1007/BF02713708
An “indeterminate” QuantiFeron Gold in-Tube (QFT-IT) simply means the result can’t be interpreted. It does NOT mean “intermediate” or “borderline positive”!
Although there are several reasons for an indeterminate QFT-IT, a common explanation is an immunocompromised state involving inadequate T-cell response (eg, corticosteroids, HIV, cancer). Improper storage of tubes and specimen handling, baseline elevated interferon (IFN)-ɣ due to heterophile antibodies, recovery phase of an infection or vaccination may also be associated with indeterminate QFT-IT results. 1,2 For these reasons, the test should be repeated for confirmation.
It all makes more sense if we understand the basis for the test. QFT-IT involves blood obtained in 3 separate test tubes:
- Tube 1: Contains only the patient’s blood with nothing added (NIL) (“Negative control”)
- Tube 2: Contains non-specific mitogens that stimulate patient’s T-cells (“Positive control”)
- Tube 3: Contains specific TB antigens
Since QFT-IT is an IFN- ɣ release assay, IFN- ɣ is measured in each tube after 16-24 h incubation. A negative QFT-IT is when there is not much difference between IFN- ɣ levels in negative control and TB tubes (“TB-[minus]NIL”) AND the positive control works (“MITOGEN-[minus]NIL” is elevated).
You can now see why a negative result in the TB tube doesn’t mean much (ie, the result is “indeterminate”) when the T-cells don’t respond to non-specific antigens. This situation is analogous to calling a PPD “negative” when a patient is anergic!
- Herrera V, Yeh E, Murphy K, et al. Immediate incubation reduces indeterminate results for QuantiFERON-TB Gold in-Tube assay. J Clin Microbiol 2010;48:2672-2676. http://jcm.asm.org/content/48/8/2672.full
- Bui DHP, Cruz AT, Graviss EA. Indeterminate QuantiFERON-TB Gold in-Tube assay results in children. Ped Infect Dis J 2014; 33: 220-22. https://www.ncbi.nlm.nih.gov/pubmed/24413410
Methemoglobinemia coupled with hemolytic anemia (HA) has been reported under different clinical scenarios and may have therapeutic implications for treatment of methemoglobinemia in the setting of G6PD deficiency.
Increased methemoglobin levels have been observed during the hemolytic crisis of patients with favism due to G6PD deficiency. This finding has been attributed to excessive oxidative stress generated by divicine, an oxidizing constituent of fava beans, and the inability to reduce its stress because of an insufficient G6PD-dependent hexose monophosphate shunt. 1Hemolytic anemia may also follow drug-induced methemoglobinemia, especially with exposure to dapsone, sulfasalazine, or phenacetin, and may be a feature of hemoglobin MSaskatoon and MHyde Park , abnormal hemoglobin variants associated with genetic methemoglobinemia. 2The concurrence of hemolysis due to G6PD deficiency and methemoglobinemia is not just an academic curiosity and may in fact pose a therapeutic quandary. This is because methylene blue, the treatment of choice for methemoglobinemia, is also an oxidant and works only after it is reduced to leukomethylene blue by (you guessed it!) nicotinamide adenine nucleotide phosphate (NADPH), a G6PD-dependent process. 2,3 With plenty of methylene blue on hand and little leukomethylene around in G6PD-deficiency, treatment may be ineffective or even cause worsening of methemoglobinemia. It’s never simple!
Final fun fact: Did you know that methylene blue is the first synthetic drug (>100 years ago) and has been used in the prevention of UTIs in the elderly, and treatment of pediatric malaria and Alzheimer’s disease? 4References
- Schuurman M, van Waardenburg D, Da Costa J, et al. Severe hemolysis and methemoglobinemia following fava beans ingestion in glucose-6-phosphate dehydrogenase: Case report and literature review. Eur J Ped 2009;168:779-782. https://link.springer.com/article/10.1007/s00431-009-0952-x
- Rehman HU. Methemoglobinemia. West J Med 2001;175:193-96. https://www.researchgate.net/publication/11817876_Methemoglobinemia
- Hassan KS, Al-Riyami AZ, Al-Huneini M, et al. Methemoglobinemia in an elderly patient with glucose-6-phosphate dehydrogenase deficiency: A case report. Oman Med J 2014;29:135-37. https://squ.pure.elsevier.com/en/publications/methemoglobinemia-in-an-elderly-patient-with-glucose-6-phosphate-
- Schirmer RH, Adler H, Pickhardt M, et al. “Lest we forget you—Methylene blue…” Neurobiology of Aging 2011; 32:2325. https://www.ncbi.nlm.nih.gov/pubmed/21316815
Suprapubic tenderness, costovertebral angle tenderness (CVAT) and fever seem to be more helpful in ruling in than ruling out infection. And, before you hang your hat on the available data, remember that most of the studies involve women with uncomplicated UTI in primary care or emergency department settings, not our older hospitalized patients at risk of complicated infections. With these caveats in mind….
Suprapubic tenderness has been reported in only about 15-20% of women with acute cystitis. 1
CVAT has been associated with symptomatic UTI but with only a weakly positive LR (1.7, 1.1-2.5), and an insignificant negative LR. 2 In a single center study involving hospitalized patients (mean age 53 y), CVAT was either absent or “obscure” in about 10% of patients with acute pyelonephritis on CT.3
Fever was associated with a positive likelihood ratio (1.6, 1.0-2.6) by 1 systematic study 2 but not another, 4 with insignificant negative LR in both. Fever was also absent in about 10% of hospitalized patients with pyelonephritis in the single center study above.3
So, when evaluating a patient with possible symptomatic UTI (particularly cystitis), the presence of physical exam findings may be more helpful than their absence.
- Kurowski K. The woman with dysuria. Am Fam Physician 1998, 57:2155-2164. https://www.aafp.org/afp/1998/0501/p2155.html
- Bent S, Nallamothu BK, Simel DL, et al. Does this woman have an acute uncomplicated urinary tract infection? JAMA 2002;287:2701-2710. https://www.ncbi.nlm.nih.gov/pubmed/12020306
- Lee Y-J, Cho S, Kim SR. Unilateral and bilateral acute pyelonephritis: differences in clinical presentation, progress and outcome. Postgrad Med 2014;90:80-85. https://www.ncbi.nlm.nih.gov/pubmed/24255118
- Median-Bombardo D, Jover-Palmer A. Does clinical examination aid in the diagnosis of urinary tract infections in women? A systematic review and meta-analysis. BMC Family Practice 2011;12:111. https://bmcfampract.biomedcentral.com/articles/10.1186/1471-2296-12-111